This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics
Vikram K Mahajan
Vikram K Mahajan, Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda 176001, Himachal Pradesh, India
ORCID number: $[AuthorORCIDs]
Author contributions: Mahajan VK contributed to concept, literature review and analysis, drafting and critical revision, editing and final approval.
Conflict-of-interest statement: No potential conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Vikram K Mahajan, MBBS, MD, Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda 176001, Himachal Pradesh, India. firstname.lastname@example.org
Telephone: +91-1892-287161 Fax: +91-1892-267115
Received: August 17, 2015 Peer-review started: August 19, 2015 First decision: October 13, 2015 Revised: October 25, 2015 Accepted: December 17, 2015 Article in press: December 18, 2015 Published online: February 2, 2016
Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient’s quality of life. Management of triggers for flare-ups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted (e.g., Alefacept, Efalizumab) or cytokine modulating (e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic (methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical (tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities (hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.
Core tip: The clinicians must be aware of all available antipsoriasis therapies in view of variable therapeutic outcome(s) that may test one’s ingenuity in managing some “difficult to treat” psoriasis patients. The nonstandard and off-label therapies will remain an important alternative to more widely used measures in rotational/intermittent treatment(s) or until a therapy that is affordable, safe, effective, and more importantly, remittiv becomes available.
Citation: Mahajan VK. Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics. World J Dermatol 2016; 5(1): 17-51
Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide and with an estimated prevalence of 2.2% to 2.63% in the United States with approximately 150000 newly diagnosed cases per year. All its clinical forms may eventually evolve into chronic plaque psoriasis characterized clinically by well demarcated, erythematous, scaly plaques. Guttate psoriasis is often self limiting, lasting for 12 to 16 wk, without treatment. However, 1/3rd-2/3rd of these patients may later develop chronic plaque psoriasis. Spontaneous remissions in chronic plaque psoriasis, lasting for variable periods of 1 year to several decades, may occur in up to 50% patients. Erythrodermic and generalized pustular psoriasis tend to be severe and persistent. There is no evidence that the disease is anyway different in either gender. There is no known prevention for psoriasis and in most cases, it remains a life long disease manifesting at unpredictable intervals with weekly, monthly or occasional recurrences. Although not life threatening, psoriasis can significantly impair quality of life with as many as 79% of patients with severe disease reporting a negative impact on their lives, and nearly 5% of them had contemplated suicide in a survey by National Psoriasis Foundation.
A plethora of anti-psoriatic treatments, both topical and systemic, is available for the management of psoriasis (Table 1). During the past four decades or so systemic methotrexate has been used effectively to treat all forms of psoriasis, including erythrodermic pustular and chronic plaque psoriasis. Despite a major concern for hepatotoxicity associated with its long-term use, it is even indicated for long-term management of severe forms of psoriasis. Currently, several biological agents are being used or evaluated for treating severe psoriasis. The Food and Drug Administration (FDA) approved ones are broadly categorized as either T-cell targeted (e.g., Alefacept, Efalizumab) or cytokine modulating (e.g., Adalimumab, Infliximab, Etanercept). Except for being prohibitory expensive, these apparently have an advantage over current systemic therapies, as systemic adverse effects do not mar their efficacy.
The voluminous literature on treatment of psoriasis is itself indicative of limitations of any therapy. It is often confusing while selecting a treatment regimen as most treatment schedules are aimed to decrease disease severity and extent that it no longer interferes with occupation, personal or psychosocial well-being of the patient. However, the patient’s own assessment for their current therapy may remain unsatisfactory. For instance, in two separate surveys 40%-42% of patients felt frustrated with the ineffectiveness of their treatments while 32% reported that treatment was not aggressive enough[2,3]. As psoriasis is a chronic life long disease, safety of a treatment during long-term use too is of major concern. To date there is no absolutely safe, simple and inexpensive treatment for psoriasis and the selection of various strategies has to be individualized. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient’s quality of life. Although reduction of psoriasis area severity index (PASI) score to 50% is currently considered adequate, there is no clear association among illness impact, subjective well-being, and the disease severity. The patients may also assess their psoriasis as more severe than physicians do necessitating the need for more patient centric therapies. Intermittent or rotational therapy with frequent alterations in treatment options is employed to reduce toxicity of anti-psoriatic drugs while search for safer alternatives continues. This paper focuses and reviews the less used and unconventional treatment modalities which can be useful alternatives to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved their recommended cumulative dose, where comorbidities pose unusual challenges, or may be as intermittent, rotational or combination treatment alternatives. As management of triggers for flare-ups, lifestyle modifications, and dietary supplements are recommended frequently, it will be prudent to briefly review them alongwith few first line therapies.
Despite the knowledge accumulated during past few decades that psoriasis is an immune mediated, regeneration-like reaction of the skin in genetically predisposed individuals wherein various cells including keratinocytes, antigen presenting cells, and T-cells play a dominant role at different stages, the exogenous factors which trigger psoriasis or induce flare-ups are poorly understood. A variety of environmental factors such as physical trauma (scratching, insect bites, surgery, sunburn) causing damage to keratinocytes (Koebner’s phenomenon), drugs (antimalarial, clopidogrel, beta blockers, angiotensin-converting enzyme inhibitors, lithium, gemfibrozyl, imiquimod, interferon (IFN)-α, IFN-γ, withdrawal of corticosteroids or cyclosporin), infections (bacterial, viral, and yeast), or metabolic disorders such as hypocalcemia (primary or secondary) are implicated triggers for exacerbations. Exacerbation and persistence of psoriasis has been attributed to increased hyper-reactivity to superantigens that are usually viral or bacterial proteins. Bacterial (Staphylococcus aureus, Streptococcus sp.) endotoxins act as superantigens and activate T-cells, macrophages, Langerhans cells and keratinocyte. Superantigens bind to class II major histocompatibility complex (MHC) molecules and Vβ segments of the T cell receptor resulting in its activation and cytokine release. Balci et al found a high prevalence of colonization of skin lesions and nares of psoriasis patients by toxigenic strains of Staphylococcus aureus as compared to healthy controls. They also observed a significant relationship between PASI scores and toxin production and suggested association between psoriasis and non-classical superantigens such as mecA, etb and see. Although they did not elucidate on therapeutic implications of their findings, antimicrobial therapy may have some role in psoriasis treatment. Other suggested association between Candida albicans, Borrelia burgdorferi, and Pityrosporum ovale remains unsubstantiated[9-11]. HIV-associated psoriasis usually develop in non-terminal stages of AIDS that is frequently severe, recalcitrant to therapy and has associated arthritis six times more often. Although zidovudine has not been found effective for psoriasis in HIV-negative patients, it reportedly improves HIV-associated psoriasis[13,14]. However, exacerbations in HIV-associated psoriasis were treated more effectively with triple antiretroviral therapy (stavudine 30 mg, lamivudine 150 mg, nevirapine 200 mg; all twice daily). The role of human papillomavirus type 5, demonstrated in scrapping of lesional skin in nearly 90% of a large series of psoriasis patients, in the etiology of the disease remains to be determined.
The association of psoriasis, pustular psoriasis in particular, with hypocalcemia, mostly from hypoparathyroidism (both idiopathic and familial), that resolved after treatment with calcium has been described by several workers[17-20]. Similarly, experimental and clinical demonstration of association between vitamin D deficiency and psoriasis has been further supported by the effectiveness of vitamin D analog (calcitriol) in the treatment of psoriasis.
Factors such as obesity, smoking and alcohol consumption, diet, and stressful life events have been suggested to affect the course of psoriasis. Although their exact role in the etiology of psoriasis remains unclear, being modifiable they may be important adjunct to the therapeutic management of psoriasis. Psoriasis patients have been observed to present more frequently with obesity than the general population and severe psoriasis, i.e., PASI > 10 and > 20% body surface area involvement[21-23]. Duarte et al considered obesity a risk factor for severe psoriasis by observing a strong correlation between PASI > 10 and all obesity parameters; waist circumference, waist hip ratio, and body mass index (BMI). Setty et al examined data linking weight gain and incident psoriasis in 78626 women and observed that the relative risk of psoriasis increased with the rise in BMI during the study period of 14 years. The authors attribute this to the production of inflammatory cytokines by adipositis as a possible explanation. There are reports of improved psoriasis in patients who lost weight and after gastric bypass surgery[24-26]. Nevertheless, obesity does not appear to play a role in the new onset of psoriasis or affect the efficacy of adalimumab in the treatment of psoriasis[27,28]. However, prospective data is lacking specifically to evaluate the role of weight loss in psoriasis.
Smoking and alcohol consumption
Recent studies suggest that cigarette smoking increases oxidative damage, promotes inflammatory changes, and enhances expression of genes associated with psoriasis. Several studies across countries have linked current and past smoking habits to the increased severity or new onset psoriasis[30-36]. Smoking > 20 cigarettes daily has been associated with more than two fold increased risk of severe psoriasis, whereas the association between smoking and psoriasis seems to be stronger in women[35,36]. Smoking can worsen severity of psoriasis and makes patients less responsive to therapy[33,35,37]. While non-smokers experience more frequent remissions than smokers, cessation of smoking leads to decreased severity and the excess risk of psoriasis also declines[33,36,38].
There is extensive published literature on excessive alcohol consumption among psoriasis patients in a recent systematic review. Alcohol consumption appears to trigger, exacerbate and influence the severity and the progression of psoriasis and psoriatic arthritis[30,40-42]. The amount consumed and the type of alcohol seems to trigger development and/or exacerbation of plaque psoriasis. Qureshi et al in a recent prospective study followed 82869 women for 14 years and showed that consumption of more then 2.3 alcoholic beverages weekly was an important risk factor for new onset psoriasis. They also deduced that consuming non-light beer is an independent risk factor for developing psoriasis in females. Similarly, alcohol consumption at levels higher then 100 g/d appears to be a risk factor for the development and exacerbation of psoriasis in males[40,43]. The exact pathomechanisms by which alcohol triggers or exacerbates psoriasis remain poorly understood. Immune dysfunction/immunosuppression and increased susceptibility for infections, excessive production of inflammatory cytokines, and epidermal hyperproliferation by cycle activators such as cyclin D1 and keratinocyte growth factor have been implicated[44,45]. Not the least, alcohol abuse in psoriasis patients too is associated with decreased response to treatment and has implications for interaction with antipsoriatic medication[43,46,47].
Diet and dietary supplements
Diet rich in gluten, polyunsaturated fatty acids, and alcohol has been implicated in the severity of psoriasis in a significant number of patients. An increased incidence of psoriasis in patients with celiac disease has been suggested[49-51]. A gluten-free diet is also suggested to improve psoriasis severity in celiac disease and even in patients with no celiac disease but with immunoglobulin A and/or immunoglobulin G (IgG) antigliadin antibodies[50,51]. However, the link between psoriasis and gluten-intolerance remains poorly understood due to inconsistent data. Nonetheless, all psoriasis patients with celiac disease or gluten-intolerance should have a gluten-free diet for overall wellbeing. Polyunsaturated fatty acids, through overproduction of arachidonic acid derived eicosanoids, influence several inflammatory disorders including psoriasis. The outcome from studies on effect of diet rich in omega-3 polyunsaturated fatty acids remains inconsistent. However, intake of fish rich in omega-3 and vegetarian diets may benefit psoriasis patients, as there is decreased intake of arachidonic acid and consequent reduction in inflammatory eicosanoid formation. Omega-3 fatty acids, especially eicosapentaenoic acid and docosahexanoic acid, compete with arachidonic acid as substrates for cycloxygenase and lipoxygenase, which thereby reduces downstream proinflammatory cytokines in psoriasis plaques. Most studies performed to evaluate their efficacy or fish oil rich in omega-3 fatty acids as dietary supplements in psoriasis report improvement in mean PASI scores[52-57]. However, there is no agreement concerning the dose of oral supplementation to be effective and the outcomes of randomized controlled trials are less effective[55,56]. Parenteral infusions of omega-3 fatty acids has been reported beneficial in patients with acute psoriasis. Systemetic reviews also advocates omega-3 fatty as adjuvant treatment of chronic plaque psoriasis in evidence-based clinical guidelines[58,59]
Although caffeine consumption has been observed to decrease the therapeutic benefit of methotrexate in rheumatoid arthritis, it does not appear to effect psoriasis or inhibit anti-inflammatory effect or therapeutic benefits of methotrexate in patients with psoriasis or psoriatic arthritis. Low calorie diet in a study showed a significant improvement after 4 wk as compared to controls and oral vitamin D supplementation can be recommended in psoriasis patients who are not on topical treatment with vitamin D analogues. The reported beneficial role of probiotics in psoriasis needs evaluation[62,63]. Similarly, curcumin [1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], has been shown to resolve psoriasis by lowering phosphorylase kinase levels in psoriatic epidermis and decreasing Ki-67 cells, which are capable of division[64-66]. Psoriasis patients treated with topical steroid plus oral curcumin 2 g/d achieved best PASI 50, PASI 75, PASI 90 and PASI 100 than patients treated with topical steroids plus placebo in a recent controlled trial and perhaps best used as an adjuvant to other therpies. This phytochemical is one of the curcuminoid extracted from turmeric (curcuma longa), others being demethoxycurcumin and bisdemethoxycurcumin. It exerts anti-inflammatory activity by inhibition of cyclooxygenase, 5-lipoxygenase and glutathione S-transferase and a number of other molecules but lacks clinical data to support its recommendation as a part of psoriasis treatment. In general, there is no sufficient scientific evidence that any special psoriasis diet is beneficial and the influence of diet on the course of psoriasis remains controversial. Nevertheless, avoiding foods suspected of causing inflammation or flare-ups, and eating low energy diet, will reduce risk for psoriasis comorbidities including obesity, diabetes, and cardiovascular diseases.
Infections and antimicrobial agents
Streptococcal infection and onset of guttate psoriasis and exacerbation of chronic plaque psoriasis have been repeatedly linked so much so that some workers routinely treat exacerbations with antimicrobial agents[67-71]. Saxena et al noted significant improvement in PASI score in 30 patients with chronic plaque psoriasis at 12 wk and excellent improvement at 2 years from treatment with intramuscular benzathine penicillin (1.2 million units) fortnightly for 24 wk initially and then given once a week for a 2-year study period. Later, in a single blind randomized case-control study they used oral azithromycin for 48 wk as a single 500 mg/d for 4 d with a gap of 10 d (total 24 such courses) and achieved PASI 75 in 80% patients in the treatment group. No significant change was noted in control group. However, 20% of treated patients experienced recurrence at the end of one-year study period. Polat et al used erythromycin 1000 mg/d and topical corticosteroids in 36 psoriasis patients and only topical corticosteroids in 24 controls for 4 wk. They noted statistically significant difference between the mean PASI of the two groups at the end of the treatment. The treatment used for the study group was also more effective against pruritus. However, these effects were attributed to inhibition of the production of many proinflammatory cytokines, including interleukin-6 (IL-6), IL-8 and TNF-α, perhaps by suppressing NF-κB or activator protein-1, and reduced neutrophil activity by macrolides rather than to their antibacterial properties. It has therefore been suggested that macrolides might be candidates for adjunctive treatment of psoriasis[74,75]. It is always prudent to treat appropriately any suspected coinfection to reduce overall morbidity, although, intervention by antibiotics is not considered of significant benefit by some researchers[76,77].
ANTIMETABOLITES AND OTHER IMMUNOSUPPRESSIVES
The drugs like methotrexate and cyclosporine with their proven efficacy in psoriasis remain well-established thearpies of first choice for moderate to severe psoriasis. Methotrexate (0.2-0.4 mg/kg, 7.5 mg to maximum of 30 mg/wk), alone or in combination with other drugs, is highly effective for the treatment of all forms of psoriasis. Its efficacy almost equals that of cyclosporine A or fumarates but is superior to that of hydroxycarbamide or mycophenolate mofetil (MMF)[78-83]. The efficacy and safety of combination of methotrexate and biologic therapy using adalimumab, etanercept, infliximab, or briakinumab too has been demonstrated in several uncontrolled studies and case series involving patients with psoriatic arthritis as well, and even in patients without previous methotrexate therapy[84-93]. However, methotrexate induced hepatotoxicity ranging from an asymptomatic transaminasemia to hepatic fibrosis and cirrhosis remains the most important concern in addition to vast potential for drug interactions (Tables 2 and 3). Therapeutic guidelines and recommendations have been available from time to time for monitoring methotrexate induced hepatotoxicity (Tables 4 and 5)[94-96]. Unfortunately, the potential efficacy of a topical methotrexate preparation in palmoplantar or plaque psoriasis remains unexploited[97-99]. Drugs like hydroxycarbamide, azathioprine, leflunamide, 5-fluorouracil, paclitaxel, and MMF too have been used infrequently in spite of limited therapeutic benefit vs methotrexate.
Table 3 Methotrexate drug interactions of significance.
Drugs that increase methotrexate drug levels and toxicity
Decrease renal excretion, displacement from plasma proteins
Decrease renal excretion, displacement from plasma proteins
Decrease renal excretion, displacement from plasma proteins
Increased intracellular accumulation of methotrexate
Increased intracellular accumulation of methotrexate, decreased renal tubular function
Displacement from plasma proteins
Displacement from plasma proteins
Displacement from plasma proteins
Displacement from plasma proteins
Drugs that simultaneously inhibit folate metabolic pathway-increase hematologic toxicity
Inhibition of dihyrofolate reductase
Inhibition of dihydropteroate synthetase
Inhibition of dihydropteroate synthetase
Drugs that may synergistically increase hepatotoxicity-common target organ
Common target organ for toxicity-liver
Common target organ for toxicity-liver
NSAID: Nonsteroidal anti-inflammatory drug.
Table 4 Guidelines for monitoring psoriasis patients receiving methotrexate by utilizing PIIINP levels.
Indications for considering withdrawal of methotrexate
Elevation of PIIINP above 10.0 μg/L in at least 3 samples in one 12-mo period
Indications for considering liver biopsy
Elevation of pretreatment PIIINP above 8.0 μg/L
Elevation of PIIINP above 8.0 μg/L in 2 consecutive samples
Elevation of PIIINP above the normal range (1.7-4.2 μg/L) in at least 3 samples over a 12 mo period
Remarks: Serum for PIIINP measurement should be collected prior to starting methotrexate and should subsequently be measured every 2-3 mo during continued treatment
Table 5 Grading of Liver biopsy as per Roenigk scale and recommendations for further methotrexate therapy.
Liver histopathologic findings
Normal; fatty infiltration, nuclear
May continue methotrexate
Variability and portal inflammation- mild
Fatty infiltration, nuclear variability, portal tract expansion, inflammation and necrosis- moderate to severe
May use methotrexate with caution and repeat biopsy at 6 mo
Fibrosis-moderate to severe
Should not be given except in exceptional circumstances
Hydroxycarbamide (hydroxyurea), an antimetabolite, inhibits DNA synthesis by interfering with catalytic activity of the enzyme ribonucleoside diphosphatase reductase during the S-phase of the cell cycle. It was reported to be effective in refractory psoriasis for the first time by Yarbo in 1969. Since then many reports have shown favorable but variable results[100-108]. However, it is probably difficult to evaluate efficacy of hydroxycarbamide from these studies as various workers have used different doses for varying periods of time and evaluated their patients by different criteria. For instance, Layton et al in their study of 86 patient with extensive chronic plaque psoriasis treated with hydroxycarbamide (0.5-1.5 g/d given for 3-96 mo), observed satisfactory remission in 61% patients while other 39% patients had inadequate response or significant relapse during treatment. While Sharma et al obtained 76% reduction in the mean PASI score with hydroxyurea (1-1.5 g/d) given for 12 wk. Moschella et al administered intermittent courses of hydroxycarbamide over a period of 18 mo to treat 60 patients with severe or incapacitating psoriasis and noted good to excellent response in 63% patients in first 6 wk and in 50% patients in 18 mo respectively. Boyd et al in their review summarized therapeutic experience with hydroxycarbamide as excellent in 18%-38% and poor in 15%-20% patients. Weekly doses of hydroxylcarbamide too have been tried with variable success. Hydroxycarbamide, 3.0 or 4.5 gm administered in weekly doses, was found effective in small number of patients and devoid of serious side effects as compared to its reported safety profile of daily therapy in a comparative study. Eight (53%) patients did not show adequate response (< 25% reduction in PASI) at the end of 4 wk and 8 (53%) patients had mild to moderate improvement (25%-75% reduction in PASI) at 8 wk of treatment. However, at the end of 12-wk study period only 2 (13%) patients achieved marked improvement (> 75% reduction in PASI), 11 (73%) patients had mild to moderate improvement (25%-75% reduction in PASI) and 2 (13%) patients did not respond at all. The mean percentage reduction in PASI score was 48.47% ± 26.53% at the end of 12 wk. However, methotrexate (15-20 mg/wk) was faster in clearing the lesions and associated with higher adverse effects than hydroxycarbamide. Cutaneous or nail pigmentation, diffuse reversible alopecia, gastrointestinal symptoms, hematological and liver function abnormalities are usual side effects reported in 33% and 43% patients while hematologic side effects comprised 21% and 35% after prolonged hydroxycarbamide therapy in two separate studies[102,103]. Kumar et al reported side effects in their 65.5% patients, pigmentation of nails, skin or mucosa being the commonest one seen in 58.6% patients. Sharma et al also observed post-inflammatory lesional and nail hyperpigmentation in all their 34 patients apart from hematological adverse effects and skin infections in 23.53% patients. More uncommon and severe adverse reactions necessitating discontinuation of therapy include “flu-like” syndrome, cutaneous vasculitis, leukopenia, thrombocytopenia, and fixed drug eruption[103,104]. Side effects like lesional erythema and tenderness, lesional and nail hyperpigmentation, arthralgia, dryness of mouth, periorbital swelling and diarrhea 3 d after the weekly dose of hydroxycarbamide not warranting discontinuation of treatment were observed by Ranjan et al. This low incidence of side effects and particularly absence of serious ones like hematologic toxicity was attributed to less number of doses used for short period of 1 to 2 d in a week. It is also observed that some variants of psoriasis may respond better to hydroxycarbamide than others. A good clearance in pustular psoriasis patients treated with 1-2 g/d hydroxycarbamide has been observed in 45%-63% of psoriasis patients treated[105,107]. The response is slow in erythrodermic or guttate psoriasis and palmo-plantar pustulosis[103,105,107,108]. Hydroxycarbamide and infliximab combination was more effective in treating a case of recalcitrant psoriasis who had failed therapy with acitretin, bath Psoralen ultraviolet-A (PUVA), narrow band ultraviolet B (UVB), topical tar ointment, diathranol, vitamin D analogs and steroids. However, its use in combination with other psoriasis treatment remains understudied. Despite slow response, hydroxycarbamide appears a reasonable alternative to methotrexate in patients who either develop gastrointestinal or hepatotoxic side effects due to methotrexate, or have achieved its recommended cumulative dose.
Azathioprine and 6-thioguanine
Azathioprine, an analogue of physiologic purines (adenine, hypoxanthine, guanine), is approved for use in rheumatoid arthritis and renal transplant recipients for its immunosuppressive activity. It is also used in dermatology for the treatment of blistering disorders, parthenium dermatitis, atopic dermatitis or other inflammatory dermatoses. It is rapidly absorbed after oral ingestion and nearly 30% is protein bound. After absorption, azathioprine is converted in vivo to 6-mercaptopurine and then its active metabolite, the nucleotide thioinosinic acid. Its maximum effect is on rapidly dividing cells and it may block the active enzyme and antigenic sites due to its alkylating effect on sulfhydril amino groups. It inhibits mitosis, B-cell proliferation, suppresses T lymphocyte function, and antibody formation. It requires at least 6-8 wk for its onset of action. The recommended dose of azathioprine is 100-150 mg/d (1.5-3 mg/kg per day). Sufficient perspective data from randomized trials is lacking but reports have shown its efficacy in severe psoriasis. DuVivier et al observed 75%-100% clearance of psoriasis in 13 psoriasis patients among 19 of 29 patients who had benefited from treatment with azathioprine. It was found effective in another 5 of 10 treatment-resistant psoriasis patients with ≥ 25% improvement. Hacker et al used azathioprine in a psoriasis patient who had failed conventional psoriasis therapy (methotrexate, etretinate, corticosteroids) because of inadequate response or adverse effects. Azathioprine was as effective as other drugs in the treatment of psoriatic arthritis as well in a long-term study. Remissions for > 5 years have been reported in 10 psoriasis patients following treatment with azathioprine pulse therapy in a recent study. The researcher used azathioprine “intermittent high dose” (500 mg on 3 consecutive days) repeated every month along with “continuous low dose” (100 mg daily) during the intervening period comprising “one azathioprine pulse” of treatment. The patients were treated in Phase-1 until clearance that occurred after 1-5 pulses (average 3.7 pulses). The responders were shifted to Phase-2 and received same pulse dosing for another 9 mo followed by Phase-3 of “continuous low dose therapy” for one year. The patients were followed up without any treatment (Phase-4). Additionally, patients were treated with oral methotrexate (15 mg weekly), topical tar ointment before starting azathioprine pulse therapy for faster clearance. However, gastrointestinal intolerance, and bone marrow and liver toxicity at high dose remain a major concern. Azathioprine has been used effectively to treat patients with concurrent psoriasis and bullous pemphigoid and seems to be a good choice for such patients during corticosteroid weaning[117-119].
The major adverse effects of azathioprine include myelosuppression (anemia, leukopenia, thrombocytopenia, pancytopenia) that is more common among population having inherited deficiency of thiopurine S-methyltransferase (TPMT) activity. Liver toxicity (elevation of bilirubin, transaminases and alkaline phosphatase), and gastrointestinal side effects (nausea, vomiting, diarrhoea, oral ucers, esophagitis, steatorrheoa) are less common in recommended dosed. Nevertheless, patients should be monitored weekly for 1 mo, then every 2 weekly for 2 mo, and monthly or more frequently for hematologic or hepatic toxicity when dose alteration or other therapy changes are made/planned. Measurement of thiopurine methyltransferase levels can be used for guiding dosing pattern.
Six-thioguanine is the active form of azathioprine that works by inhibition of purine synthesis. It seems suitable alternative therapy for patients of who are failures or excluded for methotrexate, retinoids, or PUVA therapy. It is as effective or perhaps more effective in treating psoriasis than its parent drug. Zackheim et al treated 48 patients having extensive plaque psoriasis with 6-thioguanine. They observed > 75% improvement as an initial response in 79%, > 50% improvement in 8% (including two patients with palmoplantar pustular psoriasis) while 13% had < 50% improvement. Almost 50% improvement continued in 65% patients during follow-up of 21 years (median 13 mo). The therapy was more effective, and better tolerated than methotrexate in majority of the patients who had changed from methotrexate due to inadequate response or side effects. Zackheim et al made similar observations in their retrospective study of 81 patients with plaque psoriasis and five of palmoplantar pustular psorasis. A pulse-dosing schedule of 2 or 3 times per week showed marked improvement in 10 (71%) of 14 patients studied and maintenance dose varied from 120 mg twice a week to 160 mg 3 times a week. Pulse dosing schedule of 6-thioguanine is recommended to minimize its more serious adverse effects like myelosuppression, pancytopenia, and acute hepatitis but requires regular clinical and laboratory follow up. Nausea, headache and fatigue occur less frequently.
Leflunomide is an immunosuppressive disease-modifying antirheumatic drug. It is a prodrug and 70% of the drug administered converts into its active metabolite teriflunomide that inhibits mitochondrial enzyme dihydro orotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis). It is primarily indicated for treating rheumatoid arthritis and is found beneficial for the treatment of psoriasis with concurrent psoriatic arthritis. Kaltwasser et al in a double blind, randomized placebo controlled study comprising 182 patients with psoriasis and psoriatic arthritis achieved a PASI 75 response at 24 wk in 17% patients in leflunomide group. While only 8% patients in placebo group had similar response. Similarly, psoriatic arthritis responded in 59% patients in leflunomide and systemic corticosteroids group vs 30% patients in placebo group.
Gastrointestinal irritation, elevated liver enzymes, leukopenia, drug eruption, headache, increased risk of infections, anaphylaxis, angiooedema, anaemia, agranulocytosis, eosinophilia, leucopenia, pancytopenia, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, oral ulcers, cutaneous lupus erythematosus, severe infection, interstitial lung disease, cirrhosis and liver failure, and teratogenicity are usual adverse effects. Adequate contraception is recommended during leflunomide and additionally for 3 mo in males and 2 years in females after stopping the drug. Although combination of methotrexate and leflunamide is apparently more effective than either drug used alone (in rheumatoid arthritis), care should also be taken for concomitant use of methotrexate as combination may lead to severe or fatal hepatotoxicity. Similarly, concurrent vaccination with live vaccines (like haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential of severe infection because of immunosuppression from leflunamide.
Fluorouracil (5FU), an antimetabolite, acts principally by inhibiting thymidylate synthase leading to inhibition of pyrimidine thymidine synthesis. This anucleoside is important for deoxyribonucleic acid (DNA) replication. Thymidylate synthase catalyses methylation of deoxyuridine monophosphate to form thymidine monophosphate that is inhibited by 5FU therapy leading to cell death of rapidly dividing tumor cells and decreases epidermal proliferation. Systemic fluorouracil is used for breast, anal, colorectal esophageal, pancreatic, gastric, and head and neck cancers. It is available as a solution, cream or a sustained-release preparation in various concentrations (0.5%, 1%, and 5%) for topical/intralesional use in actinic keratoses and Bowen’s disease.
Due to its inhibitory effect on epidermal cell proliferation 5FU has been used topically, intralesionally or orally for treating plaque psoriasis[128-134]. As early as 1972, Tsuji et al treated 13 patients with psoriasis using topical fluorouracil 5% ointment under occlusion. The treated lesions became necrotic followed by re-epithelization after stopping the ointment and complete clearance. Pearlman et al[129,130] used intralesional 1 mL fluorouracil (50 mg/mL) for 1-3 injections at 1- to 2-wk intervals (average 2 injections/patient) in 11 patients with psoriasis. The lesions improved in 2 wk and cleared completely in 4 wk. Subsequently, long remissions were observed in both the studies without significant systemic toxicity. Combining it with epinephrine for intralesional treatment showed improved response requiring single-dose treatment in 53 patients[132,133]. The combination was superior in improvement of psoriatic plaques than pulsed dye laser or betamethasone in a comparative study. In a recent open-randomized-controlled study, 40 patients were treated with intralesional 5FU (0.1 mL/cm2) weekly for three injections. Total or near total clearance of lesions occurred in 35 patients at 12 wk. It was also effective for treating acrodermatitis continua of Hallopeau. Gastrointestinal upsets, persistent hiccups, mucositis, headache, myelosuppression, photosensitivity, cardio toxicity, and mood alterations are common adverse effects of oral 5FU while pain, necrosis, and hyperpigmentation occurs from intralesional therapy.
Paclitaxel, a complex diterpene, is synthetic or derived from the bark of the Pacific yew tree (Taxus baccata). This chemotherapeutic agent demonstrates substantial anti-tumor effect in carcinoma of the breast, ovary, and lung, head and neck, bladder, testes, esophagus and endometrium. It has modest effect in Kaposi’s sarcoma, lymphoma and carcinoma of the stomach and cervix. It has shown antiproliferative, antiangiogenic, and anti-inflammatory properties prompting a phase II pilot study for its efficacy in 12 patients with severe psoriasis. A dose-dependent decrease in PASI scores varying from 15% to 80% in different patients was observed. Higher dose (75 mg/m2 every 4 wk for 6 doses) produced more significant results than lower dose at more frequent intervals; 37.5 mg/m2 every 2 wk for 3 doses and 50 mg/m2 for additional 6 doses. No patient had myelosuppression (usual with doses > 100 mg/m2 every 3 wk), but hypersensitivity reactions occurred in two patients and another patient had flare up of Crhon’s disease. A new oral formulation, nanoemulsion of paclitaxel, has increased bioavailability in experimental animal models but needs evaluation for its clinical efficacy and safety among psoriasis patients.
MMF is an immunosuppressive drug used extensively in organ transplant recipients to prevent graft rejection prior to its usage for treating autoimmune blistering dermatoses (bullous pemphigoid, pemphigus vulgaris). It metabolizes to mycophenolic acid that inhibits de novo purine synthesis in B and T cells by inhibition of inosine monophosphate dehydrogenase enzyme for selective lymphocyte immunosuppressive effect. Haufs et al reported first use of MMF for psoriasis leading to several case reports and uncontrolled studies demonstrating variable and beneficial effect of MMF for treating psoriasis[139-145]. Subsequent studies found MMF less effective as compared to methotrexate or cyclosporine but reported less nausea than methotrexate and renal toxicity than cyclosporine[82,146]. Beissert et al observed a superior efficacy of cyclosporine as compared to that of MMF in a prospective, multicenter, randomized trial to treat chronic plaque-type psoriasis. However, there was no difference in time to relapse, side effects, and psoriasis disability index. As monotherapy, its overall PASI 75 achievement rate is less than 20% and PASI 50 is nearly 50%[144-146]. MMF also appears a reasonable alternative for patients with cyclosporine induced nephrotoxicity. Although PASI score increased in each patient treated with MMF after a 2-4 wk washout period of cyclosporine, the cyclosporine induced deranged renal function was significantly improved in a study evaluating switching from cyclosporine to MMF. Regression of erythema, induration and scaling of psoriasis plaques has been reported from topical MMF but further evaluation is needed.
MMF has been also used successfully with cyclosporine minimizing toxicity of both drugs. Ameen et al reported moderate to good improvement with cyclosporin (2.5 mg/kg per day) and MMF (3 g/d) in 3-11 mo among 78% patients with severe recalcitrant psoriasis. It also appear good choice in psoriasis patients having concurrent immunobullous disorders or HIV infection[150,151].
Severe gastrointestinal side effects (nausea, diarrhoea) and reversible hematologic toxicity are common. Hematologic malignancies, progressive multifocal leukoencephalopathy and serious infections have been reported in transplant recipients receiving MMF but are uncommon in psoriasis patients treated with MMF[152,153]. Nevertheless, all patients under treatment with MMF will routinely require evaluation for therapy-related complications by complete blood counts, hepatorenal function tests, and electrolyte estimation, and serious infections or neoplasia as per guidelines. Despite unavailability of high-quality clinical trials, MMF in recommended doses of 1-1.5 g twice daily (maximum dose 3 g/d) appears a good alternative for the treatment of psoriasis in patients who are unable to take other drugs due to contraindication or toxicity or for maintaining disease control achieved from other therapies.
RETINOIDS AND RETINOID ACID METABOLISM BLOCKING AGENTS
Retinoids are synthetic and natural compounds that have biologic activity like that of vitamin A. Tretinoin and isotretinoin are the first generation retinoids while etretinate and acitretin are the second generation retinoids which are aromatic retinoids and supposed to be more effective in psoriasis and other keratinization disorders than first generation retinoids. Bexarotene and alitretinoin belong to third generation. The systemic retinoids, alone or in combination with other systemic (methotrexate, cyclosporine, hydroxyurea, PUVA) or topical agents (calcipotriene, coal tar ointment, steroids), or in rotational and sequential therapy constitute an important form of therapy in severe and resistant psoriasis. Retinoids are effective even as monotherapy particularly in exfoliative erythrodermic psoriasis and pustular psoriasis. However, clinical data suggest that retinoid monotherapy may be less effective than other systemic agents in short term treatment of chronic plaque and guttate psoriasis. The advantage lies in their being not associated with immunosuppression or limitation of cumulative dose, and having no significant hepatic or renal toxicity. Therefore, they can be used alone or in combination with conventional therapies for psoriasis or biologic agents for treatment and maintenance therapy as well as in HIV affected patients with psoriasis. The exact mechanism of action of retinoids in psoriasis is not understood comprehensively. There are two families of retinoid receptors, a retinoic acid receptor (RAR) family and retinoid X receptor (RXR) family, each having three isoforms: α, β and γ. They perhaps exert their therapeutic effect by modulating three major pathogenic features of psoriasis, abnormal keratinocyte differentiation, keratinocyte hyperproliferation and tissue infiltration by inflammatory cells thus decreasing scaling, erythema and thickness of the plaques. They induce hypergranulosis and decrease number of tonofilaments and desmosomes, and widening of intracellular space causing a keratolytic effect. They inhibit neutrophil migration, alter cytokine production by T lymphocyte, interfere with keratinocyte responsiveness to cytokines or abolish resistance of keratinocytes to apoptosis. However, isotretinoin has no clearly identified affinity for any retinoid acid receptor. Acitretin, an active metabolite of etretinate, is the most frequently used oral retinoid to treat psoriasis despite its lower efficacy as monotherapy vs methotrexate or cyclosporine. Its combination with UVB (reUVB) or PUVA (rePUVA) increases the responses of both modalities reducing the number and duration of therapy sessions needed to achieve clearance and decrease the cumulative adverse effects of ultraviolet (UV) radiation. It can also be combined with other systemic agents like methotrexate, cyclosporine and hydroxyurea, biological therapies or with topical agents like calcipotriene and steroids in rotational and sequential therapy. The efficacy of retinoids in combination with biological therapies has been reported in several uncontrolled studies and case reports[158-167]. Ontheotherhand, other retinoids remain under evaluated for treating psoriasis.
Isotretinoin up to 2 mg/kg per day has been used in treating psoriasis. Isotretinoin was first used in the treatment of psoriasis in 1973. Hotard et al analyzed the medication prescribed to patients with a primary and only diagnosis of psoriasis spanning a period of 5 years. Out of 8.5 million visits, only 39% of the patients receiving systemic treatments were women. With respect to retinoids, it was observed that women received less etretinate (35% women among 100 patients on etretinate) than men but more isotretinoin (100% women) than men were, as all 9 patients who received isotretinoin were young females. Isotretinoin is considered more effective in pustular psoriasis than in chronic plaque psoriasis[170-173]. Moy et al successfully treated 10 of 11 patients with pustular psoriasis using isotretinoin. Pustulation ceased after 3 to 5 d of treatment with daily dose of 1.5-2 mg/kg per day but recurrences were frequent on reduction of the dose. The pustulation subsided when the dose was increased again or most patients required additional agents to control their disease. Similarly, Al-Shobaili et al found excellent outcome in a 16-year-old girl treated with isotretinoin for pustular psoriasis. Isotretinoin can be administered safely in patients who have developed adverse effects to etretinate. Marhold et al reported a case of 29 years old female patient suffering from severe pustular psoriasis and had increased liver enzymes while on etretinate. Liver biopsy revealed changes of drug induced hepatitis. After normalization of the liver parameters following withdrawal of etretinate, isotretinoin was administered during a severe relapse. Contrarily, isotretinoin was well tolerated and resulted in a good therapeutic response. Vahlquist et al also used isotretinoin in a patient of pustular psoriasis of palms and soles, who developed hepatitis after treatment with etretinate. However, they found it only marginally effective. Patients with plaque psoriasis can be treated with isotretinoin in a dose up to 1.5-2 mg/kg per day. Increasing small doses of isotretinoin are recommended initially while treating erythrodermic psoriasis in order not to provoke the disease[177,178]. Etretinate and acitretin has been shown to control chronic plaque psoriasis more effectively than isotretinoin when used as a single agent. Moy et al compared isotretinoin with etretinate in chronic plaque psoriasis. Ten patients who had psoriasis affecting 20%-50% of their body surface area were treated with isotretinoin 1.5 mg/kg per day for at least 8 wk, and other 19 patients who had psoriasis affecting 40%-90% of their body surface area were treated with etretinate 0.75 mg/kg per day for the same period. Eighteen out of 19 patients treated with etretinate had either a complete or a moderate response, while only 4 of 10 patients treated with isotretinoin were moderate or complete responders. It showed a significant difference in efficacy in favour of etretinate. However, isotretinoin has shown equal efficacy to other retinoids when combined with psoralen photochemotherapy[179,180]. Combination of isotretinoin with PUVAsol was clinically more effective in clearing lesions of chronic plaque psoriasis and improved quality of life than PUVAsol alone in a recent study. The mean percentage reduction in PASI score at the end of 12 wk was 51.92 ± 23.83 and 3 (27.27%) patients achieved marked to complete remission in a recent study comparing it with methotrexate. Isotretinoin appeared less effective than methotrexate and only 4 (36.36%) patients had either mild improvement or were non responder in the first 8 wk.
Adverse effects of retinoids
Diffuse interstitial skeleton hyperostosis, premature epiphyseal closure, pseudotumour cerebri, severe headache and hepatotoxicity are potential important adverse effects. Musculoskeletal (arthralgia, myalgia, fatigue, muscle weakness, tendonitis), neuropsychiatric (mild depression, headache) and gastrointestinal (nausea, vomiting, abdominal pain) abnormalities may also occur. The retinoid tretogenecity remains the major concern and limitation for their use. When taken in the first trimester, they cause severe embryonic abnormalities in up to 50% and spontaneous abortion in up to one third of pregnancies. Malformations occur even with short periods of use, therefore no systemic dose of retinoids is considered safe during pregnancy. The most frequently described congenital malformation from isotretinoin is “the isotretinoin dysmorphic syndrome”. It includes facial malformations (rudimentary external ears, absent or imperforate auditory canals, triangular microcephalic skull with large occiput and narrowing of the frontal bone, cleft palate, microphthalmia, depressed mid face), central nervous system anomalies (hydrocephalus, cranial nerve dysfunction), and cardiac malformations (over riding aorta, interrupted or hypoplastic aortic arch, atrioventricular septal defects, abnormal origin of the subclavian arteries). Limb reduction defects and thymic aplasia too have been described. Hersh et al reported that 10% of live birth records examined showed malformations of pregnancies occurring within 30 d after isotretinoin discontinuation. However, women who conceive one cycle after discontinuing isotretinoin are advised that their teratogenic risk is not higher than baseline. The risk of retinoid embryopathy in fetuses fathered by men taking isotretinoin is minimal, if any.
Retinoids also adversely affect the skin (xerosis, palmoplantar and digital desquamation, retinoid dermatitis, photosensitivity, pyogenic granuloma, staphylococcus infections), the hair and nails (telogen effluvium, abnormal hair texture, dryness, fragility, paronychia, onycholysis), the eye (dry eyes with visual blurring, blephrocunjunctivitis, photophobia), and mucous membranes (chelitis, dry mouth, sore mouth and tongue, nasal mucosa dryness, epistaxis). The majority of case control and other epidemiological studies have shown no association between mood change, depression, psychosis and suicide ideation, and isotretinoin use. Nevertheless, individual idiosyncratic psychological adverse response to the drug cannot be excluded. Similarly, the current evidence is insufficient to establish a causal association between isotretinoin and inflammatory bowel disease.
New generation retinoids
Because of high selectivity for the β and γ subtypes of RARs the new generation retinoids have targeted action on psoriatic keratinocytes with minimum risk of adverse effects. They have better pharmacokinetics, and half-life of active metabolite of tazarotene (tazarotenic acid) is only 7-12 h. This imparts the advantage of contraception just being necessary for a few days after the last dose. The efficacy, safety and tolerability of tazarotene for psoriasis patients have been reported in phase III trials. It has been used safely for up to 52 wk without any significant increase in retinoid toxicities like hypertriglyceridemia, hypercholesterolemia, altered liver function tests, alopecia or conjunctival dryness. Several studies have also examined the safety and tolerability of topical tazarotene (0.1% and 0.05% gels), alone or in combination with topical corticosteroids (clobetasole, mometasone, flucinonide), calcipotriene or phototherapy for treating psoriasis[188-193]. Tazarotene 0.1% is generally more effective than the 0.05% cream. Tazarotene gel is non-sensitizer, non-phototoxic or non-photosensitizing, and treatment-related adverse effects like mild-to-moderate local skin irritation occur mainly from tazarotene 0.1% but systemic adverse effects do not occur.
Bexarotene, a synthetic RXR-selective retinoid, is an available treatment for cutaneous T-cell lymphoma. Antipsoriatic effect of oral bexarotene in doses up to 3.0 mg/kg per day during 12 wk of treatment has been evaluated on proliferation, differentiation, and inflammation parameters[194,195]. Smit et al observed > 50% improvement in modified PASI, plaque elevation, and physician’s global assessment in 22%, 52%, and 36% of patients, respectively, in a phase II multicentric trial. No serious treatment related adverse events occurred. However, studies for the optimal dose and its potential as a new therapeutic modality are warranted. Similarly, therapeutic potential of topical bexarotene gel 1% in psoriasis needs further evaluation. Oral Alitretinoin (9-cis-retinoic acid) 30 mg/d, alone or in combination with etanercept is another promising therapy for recalcitrant palmoplantar pustulosis or hyperkeratotic palmoplantar psoriasis but warrants confirmation of its efficacy and safety by controlled studies[197,198].
Contraindications, drug interactions and monitoring guidelines
Absolute contraindications for the use of retinoids are pregnancy or woman who is likely to become pregnant, non-compliance with contraception, nursing mothers, or individuals with known hypersensitivity. Relative contraindications include leukopenia, moderate to severe cholesterol or triglyceride elevation, and significant hepatic or renal dysfunction. Monitoring of concomitant medications that may interact with retinoids is required (Table 6). Pregnancy test in women of childbearing age, complete blood count, liver and renal function tests, complete lipid profile and urinalysis if indicated should be performed at baseline and repeated monthly for the first 3-6 mo, and then every 3 monthly. X-ray of wrist, ankle or thoracic spine at baseline and periodically are needed if retinoids are required for a long duration. Ophthalmologic examination is done as and when required.
Drugs that may synergistically increase hepatotoxicity
Common target organ for toxicity-liver
Common target organ for toxicity-liver
Drugs whose levels are changed by retinoids
Cyclosporine A levels are increased via competition for CYP 3A4
According to iPLEGE program, the patient is advised to have a negative pregnancy test before isotretinoin use, every month during treatment, at the end of treatment and 1 mo after stopping treatment. The women must use two form of contraception for at least 1 mo prior to initiation of isotretinoin, during and one month after discontinuing therapy. Women of childbearing potential must access the iPLEDGE system at the time of first prescription and then at each subsequent prescription.
Retinoid acid metabolism blocking agents
Retinoid acid metabolism blocking agents, liarazole and talarozole, are retinoid mimetic drugs that act by blocking cytochrome P-450 dependent 4-hydroxylation of all-trans-retinoic acid. They modulate intracellular levels of endogenous retinoids and in turn normalize aberrant epithelial growth and differentiation. As the plasma all-trans-retinoic acid levels do not increase beyond physiologic levels, the retinoid-associated adverse effects are less frequent despite their efficacy similar to that of retinoids. Talarozole is a more selective inhibitor of the enzyme retinoic acid 4-hydroxylase and is effective in lower doses causing less side effects. Due to their rapid metabolism and clearance unlike synthetic retinoids, these drugs are safer for women and children. Liarazole was found effective for both palmoplantar pustular psoriasis and chronic plaque psoriasis in double-blind, randomized, placebo-controlled trials[199,200]. In a small pilot study, a noticeable improvement was observed in 4 of 7 patients with palmplantar pustular psoriasis treated with liarazole (75 mg, twice daily) as compared to 1 in 8 patients receiving placebo. The lowest effective dose was 75 mg twice daily in a dose ranging, randomized, placebo controlled trial. A marked improvement occurred in 18% in liarozole 50 mg, 11% in 75 mg, 38% in 150 mg and 6% subjects in placebo group subjects, respectively. Verfaille et al treated 19 patients of psoriasis with talarozole (1 mg) for 8 wk and observed significant reduction in PASI. No formal announcement has been made for the results of phase II clinical trial for of its oral formulation, and phase I clinical trial for topical formulation.
FUMARIC ACID ESTERS
Althoguh fumaric acid was found effective in systemic treatment of psoriasis as early as 1959, the drug is licensed only in Germany and Netherlands for short-term (< 6 mo) use in patients with severe psoriasis when topical therapy is not indicated. However, successful completion of a phase 3 study for use of its improved formulation in psoriasis has greatly renewed worldwide interest for this drug. The commercial preparations Fumaderm® initial and Fumaderm® have mixture of dimethylfumarate and three salts of ethyl hydrogen fumarate. (Fumaderm® initial contains dimethylfumarate 30 mg per tablet; Fumaderm® has dimethylfumarate 120 mg per tab).
The esters are used as fumaric acid itself is poorly absorbed after oral intake. They have almost complete absorption in the small intestines. The dimethylfumarate is rapidly hydrolyzed to more active metabolite monomethylfumarate by esterases. Dimethylfumarate and its metabolite monomethylfumarate are the principal active ingredients. Its interaction with intra- and extra-cellular thiols (glutathione) is considered the primary mechanism of action. This inhibits NF-κB-mediated transcription of intracellular mediators (TNF-α or IL-8) and adhesion molecules (E-selectin, ICAM-1, VCAM-1). Other work suggests their therapeutic benefit by shift of the Th1-cytokines pattern towards Th2-type cytokine pattern associated with reduction in peripheral lymphocytes (primary T cells) inhibiting proliferation of epidermal keratinocytes in psoriasis patients[203,204]. Fumarates at higher concentrations inhibit induction of apoptosis and maturation of dendritic cells, which have an important role in immunologic reaction, and development and maintenance of an inflammatory response. These effects have been also demonstrated to be mediated by interference of the intracellular redox system.
Clinical studies from 1990s have reported a substantial reduction in PASI score following treatment with fumaric acid. Its efficacy and safety have been reported frequently and reviewed comprehensively[205-215]. Altmeyer et al[208,209] in two separate studies noted nearly 50% reduction in PASI in 50 patients with severe psoriasis and 80% in 83 patients respectively after 16 wk of treatment with Fumaderm®. Mrowietz et al also reported 80% reduction in PASI after a 16-wk open-label multicenter study. The efficacy of fumarates is also confirmed in recent years. Litjens et al reported nearly 53% reduction in PASI in 20 psoriasis patients while substantial improvement or clearance was observed by Carboni et al in 71% of 40 psoriasis patients after 12-wk treatment with fumarates. Twenty percent patients achieved a statistically significant reduction in PASI from 13.9 ± 9.0 to 11.3 ± 9.2 in a single center study from United Kingdom. The efficacy of fumaric acid ester in treating mild psoriasis too has been documented in a recent Italian study. Reich et al retrospectively analyzed the data of 984 patients with psoriasis for the long-term safety and efficacy of fumaric acid ester. Either the patients were on 24 mo of continuous treatment or at least 36 mo of intermittent treatment (mean duration 44 mo). Overall, 31%, 67%, 76%, 78% and 82% of the patients showed a substantial improvement or were clear of symptoms after 3, 6, 12, 24 and 36 mo, respectively, without significant laboratory abnormality or serious adverse effects. Although the efficacy of fumarates has been also demonstrated in psoriatic arthritis, nail psoriasis, and palmoplantar pustulosis, they are not recommended to treat psoriatic arthritis currently for lack of significant activity in arthritis, dactylitis, and enthesitis[216-219].
The therapy is usually initiated with low dose and escalated weekly until clinical response (usually observed in 4-6 wk) or a maximum dose of 1.2 g/d is achieved. Treatment with fumaric acid esters can be maintained for up to 2 years. Short-term intermittent therapy until major improvement followed by drug withdrawal is another mode of therapy. Although no rebound phenomenon or pustular exacerbation occurs, gradual tapering to minimal threshold dose is recommended to prevent relapse in patients with high disease activity.
The comparative efficacy of fumaric acid esters vs other systemic therapies remains understudied and so is that of their combination with other systemic therapies. Methotrexate and fumarates were equally effective without significant adverse events in the treatment of patients with psoriasis in a small, short-term study. Fallah Arani et al in a first ever randomized controlled trial treated 60 patients with moderate to severe psoriasis vulgaris either with methotrexate (30 patients; 15 mg/Wk) or fumarates (30 patients; 30 mg, followed by 120 mg) for 16 wk. They reported 50% reduction in PASI at 12 wk of 42% and 60% patients in fumaric acid esters and methotrexate group, respectively. PASI 75% was observed in 19% of fumaric acid esters and 24% of methotrexate group, respectively. Two patients in fumaric acid esters and 4 in methotrexate group dropped out due to adverse effects. Gollnick et al found combination of oral fumaric acid esters and topical calcipotriol significantly more effective and faster acting than monotherapy with slight fumaric acid esters-sparing effect imparting a superior benefit/risk ratio. Combination produced higher and early mean reduction in PASI (76% vs 52%) and PASI 50 in 3 wk vs 9 wk. Fumarates can be combined with UVA or UVB during initial 3 wk of therapy. There are reports of successful use in combination with methotrexate, acitretin, hydroxyurea or ciclosporin but combining retinoids have no additional benefit. However, their combination with other systemic therapies is not recommended currently.
The fumaric acid esters are safe in inducing remission in a reasonable time and retain it through extended periods. Gastrointestinal complaints (nausea, abdominal cramps, or diarrhea) occur in up to 60% of patients in first few weeks of therapy. These symptoms can be reduced by dose reduction, taking the drug with milk, or addition of aluminium hydroxide, metoclopramide, ranitidine or pentoxifylline[222,223]. Flushing is seen in 30%-50% as feeling of warmth, facial flushing, and headache lasting for minutes to hours, and may be severe. It can be ameliorated with administration of acetylsalicylic acid. Leukocytopenia, lymphopenia, and eosinophilia can occur. The development of progressive multifocal leukoencephalopathy in two patients treated with Fumaderm® has been attributed to therapy associated prolonged severe lymphopenia[224,225]. Leukopenia below 3000/μL and lymphopenia below 500/μL, thus, need drug withdrawal or reduced doses. Eosinophilia is transient, seen in 4-10 wk of therapy, and improves after the drug withdrawal/reduction. Occasional renal toxicity is observed and proteinuria when occurs will disappear following drug cessation or dose reduction[227,228]. Isolated elevation of serum bilirubin, hepatic enzymes, serum creatinine or potassium, and dyslipidemia may occur but increased susceptibility for infections or development of malignancies is not observed. Progressive multifocal leukoencephalopathy is a potentially severe toxicity. Discontinuation of therapy from adverse effects may be needed in 30%-40% cases.
Calcineurin or protein phosphatase 3, a calcium-dependent serine-threonine phosphatase, activates the T cells of the immune system and can be blocked by drugs called calcineurin inhibitors that include cyclosporine, tacrolimus, pimecrolimus and voclosporine. Both cyclosporine and tacrolimus are chemically distinct molecules. They bind to the intracellular immunophilins cyclophilin and FKBP-12 respectively. Both inhibit the phosphatase action of calcineurin required for the movement of nuclear factors in activated T cells to the chromosomes where subsequent cytokine synthesis occurs. They prevent IL-2 production in T cells and decreased secretion of IL-2 prevents proliferation of the inflammatory response via B cells and T cells. This attenuated inflammatory response greatly reduces the overall function of the immune system producing clinical response. Cyclosporine (cyclosporine A), a neutral cyclic undecapeptide, is derived from fungus Tolypocladium inflatum gams. It has been approved in the United States for 1-year and in Europe for 2-year of continuous therapy. Cyclosporine (2.5 to 5 mg/kg per day) has efficacy comparable to that of biologics in rapid control of severe, widespread, intensely inflammatory and erythrodermic psoriasis, cases resistant to other treatments, and nail psoriasis. Several studies have noted that 80%-90% of patients improve significantly after 12-16 wk of cyclosporine therapy[229,230]. The drug is also useful in treating childhood psoriasis with results and adverse effect profile similar to that is seen in adults[231-233]. However, early rebound flare up of psoriasis occurs after stopping the drug. Headache, tremors, and paresthesia/hyperesthesia are common adverse effects with short-term therapy. An irreversible nephrotoxicity and/or hypertension following long-term therapy especially in patients treated continuously with cyclosporine for > 2 years is of serious concern. Another major concern is almost six fold increased incidence of non-melanoma skin cancers like squamous cell carcinomas with long-term low-dose cyclosporine therapy especially when it is used in combination with PUVA (psoralen + UVA) therapy.
This relatively new member of calcineurin inhibitors has higher affinity for calcineurin, faster clearance of metabolites from the body, high efficacy and a better safety profile as compared to cyclosporine. Nearly 67% patients receiving 1.5 mg/kg per day of voclosporine achieved PASI 75 in phase II trial. Similarly, 16%, 25% and 47% patients achieved PASI 75 response at 12 wk after voclosporine 0.2, 0.3, and 0.4 mg/kg, respectively, in a phase III dose-finding placebo-controlled study comprising 451 patients with chronic plaque psoriasis as compared to 4% patients in the placebo group. No significant adverse events or alterations in blood pressure, lipids or triglycerides were observed.
Topical calcineurin inhibitors
After noticing incidental improvement of psoriasis following systemic tacrolimus to prevent rejection in one heart and three liver transplant recipients, the researchers reported good response to the drug in other three patients with severe, recalcitrant and treatment resistant psoriasis. Subsequently, European FK 506 multicenter psoriasis study group in a double-blind, placebo-controlled study comprising 50 patients with severe recalcitrant plaque-type psoriasis randomized to receive treatment with either oral tacrolimus (FK 506) (n = 27) or placebo (n = 23) reported 83% PASI reduction in 27 psoriasis patients at the end of 9 wk. Similarly, Rappersberger et al used oral pimecrolimus with high clinical efficacy and good tolerability. The drug was well tolerated without clinically relevant laboratory abnormalities in a large, double-blind, dose-finding study. Oral pimecrolimus, given as 20 and 30 mg twice daily in psoriasis patients, demonstrated a mean percentage reduction in PASI by 51.3% and 54%, respectively, at week 7 from the baseline. However, availability of topical formulations of tacrolimus and pimecrolimus (approved for atopic dermatitis) renewed interest for their use in the treatment of psoriasis as an alternative to topical corticosteroids. Mrowietz et al used pimecrolimus (0.3% or 1%) to treat 10 patients with chronic plaque psoriasis in double-blind randomized-controlled study. Total scores decreased by 92% for clobetasol, by 82% for pimecrolimus (0.1%), by 63% for pimecrolimus (0.3%), and by 18% for control. They are most effective in recalcitrant psoriasis affecting the face, genitals, and intertriginous areas[241-245]. Tacrolimus (0.1%) ointment completely cleared psoriasis of face, intertriginous skin or both in 81% of 21 patients at end of study period of 57 d. It also demonstrated complete clearing (24.8% vs 5.8%) in another randomized-controlled study at day 8, and 65.2% vs 31.5% at 8 wk in 80% of 167 patients with facial and intertriginous psoriasis. Other researchers also made similar observations for efficacy and safety of topical tacrolimus with nearly 80% of patients having complete clearance of psoriasis on the face, genitalia, intertriginous areas, and corporal plaques. Tacrolimus ointment improved plaque psorisis in a microplaque assay. It has been also used with equal efficacy and safety in pediatric patients. Brune et al evaluated tacrolimus 0.1% ointment in a single-centre open-label trial by treating 11 children aged between 6 and 15 years having psoriasis of face, folds or both. All patients had clearance or achieved excellent response within first 30 d itself. However, it is less effective for hyperkeratotic plaques involving back, trunk, elbows, and knees, perhaps from poor penetration. Combining tacrolimus (0.1%) with salicylic acid (6%), or calcipotriene (0.005%) improves outcome in such cases[249,250]. Using tacrolimus or pimecrolimus under occlusion is also associated with improved efficacy in treatment of psoriasis. Changing formulations for tacrolimus or pimecrolimus to improve its penetration and cutaneous bioavailability is another promising area for research. Topical liposomal tacrolimus was found nine times more effective than tacrolimus ointment in experimental studies. Polymeric micelles- methoxy-polyethylene glycol-dihexyl substituted polylactide (MPEG-dihexPLA), a biodegradable and biocompatible diblock copolymer, as a nanocarrier was highly efficient for selective cutaneous delivery of tacrolimus experimentally.
Burning sensation and/or pruritus, usually in first few days of application of tacrolimus or pimecrolimus, is considered secondary to release of neuropeptides such as substance P. Although United States FDA has issued “black-box” warning considering the risk for lymphoma and skin cancer, there is no convincing data for enhanced risk for the development of either cutaneous or systemic malignancy after topical use in large number of patients with atopic dermatitis for up to 4 years[255,256].
THIAZOLIDINEDIONES AND STATINS
Thiazolidinediones, pioglitazone, troglitazone, and rosiglitazone, are used for the treatment of non-insulin-dependent diabetes mellitus. They lower insulin resistance in peripheral adipose and muscle tissues, and decrease hepatic gluconeogenesis by binding to peroxisome proliferator-activated receptors (PPAR) γ. They also have cardiovascular benefits because of their property of lowering blood pressure, improving endothelial cell function/fibrinolysis, and increasing high-density lipoprotein. Increased expression of PPAR β/δ has been observed in activated T cells in human psoriatic lesions while experimental studies have shown that activation of PPAR β/δ in the epidermis could sustain a psoriasiform inflammation with keratinocyte hyperproliferation, accumulation of dendritic cells and endothelial activation[257,258]. Experimentally, topical PPAR β/δ antagonists effectively reversed PPAR β/δ activation triggered psoriasis-like changes. The PPARγ agonists said to act via modulating anti-inflammatory actions by decreasing inflammatory cytokines like IL-2, TNF-α and IFN-γ, and down regulating the expression of adhesion molecules like VCAM-1. They also inhibit the production of IL-17 by CD4+ cells, and neoangiogenesis/angiogenesis both in vitro and in vivo[261,262]. Shafiq et al in a double-blind randomized placebo-controlled clinical trial evaluated pioglitazone monotherapy in 70 patients with moderate to severe psoriasis. Three groups of patients received placebo, pioglitazone 15 or 30 mg/d, respectively for 10 wk. Psoriasis cleared or almost cleared in 40% of treated patients compared to 12.5% of patients in placebo group at end of the study period. The results were better with higher dose of pioglitazone and mean percentage reduction in mean PASI score was 21.6%, 41.1% and 47.5% in the pioglitazone 15 mg, 30 mg, and placebo groups, respectively. Adverse events like decreased hemoglobin in one patient and elevation of liver enzymes in two patients did not warrant withdrawal from study. In another open-label study, Bongartz et al reported statistically significant reduction with pioglitazone 60 mg/d and non-steroidal anti-inflammatory drugs in average number of painful and/or swollen joints and a 38% reduction of PASI score in 10 patients after 12 wk of treatment. A 3-mo treatment period appears appropriate for any significant clinical response as most improvement occurred between 6 and 12 wk. The pioglitazone in combination with methotrexate or acetretin seems more effective in improving plaque psoriasis in two recent studies than control groups receiving methotrexate or acetretin alone. Lajevardi et al in a randomized controlled, assessor-blinded study compared the efficacy of methotrexate and combination of methotrexate and pioglitazone in 22 patients in each group. The PASI 75 was achieved in 63.6% with combination treatment as compared to 9.1% with methotrexate alone at end of 16 wk study period. Mean percentage reduction was 70.3% vs 60.2% in combination vs methotrexate alone group. Mittal et al reported mean percentage reduction in PASI score of 64.2% in acetretin plus pioglitazone group as compared to 52.7% in acetretin plus placebo group after 12-wk study period. Its combination with other systemic therapy remains unevaluated. Troglitazone also normalized histological changes of psoriasis and reduced hyperplasia in experimental murine and human skin models. A substantial efficacy of troglitazone in psoriasis too has been reported in similar studies[267,268]. However, rosiglitazone was no more effective than placebo in a recent study. Moreover, the drug has been withdrawn because of idiosyncratic hepatotoxicity.
Thiazolidinediones, due to their effect on lipid and glucose metabolism, appear to be therapy of choice for psoriasis associated with metabolic comorbidities like insulin resistance, obesity, dyslipidemia, or cardiovascular diseases. Pioglitazone 150 mg/d also led to complete remission of psoriasis in a 65-year-old man with non-alcoholic steatohepatitis and diabetes who had not responded to treatment with ursodeoxycholic acid. However, topical formulations of these agents need further evaluation as no change was observed in PASI scores in a study comprising 8 patients with plaque psoriasis treated with topical 0.5% rosiglitazone. Apparently, thiazolidinediones make useful therapeutic options for psoriasis and pioglitazone remains the most studied drug among its peers. Although more evaluation is needed for pioglitazone, alone or its combination with methotrexate, acetretin or other antipsoriatic drugs, it appears a relatively safe, convenient, and effective therapeutic option for psoriasis.
Statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. They were developed originally to treat lipid disorders in patients with hypercholesterolemia. They have significant immuno-modulating properties and studies have shown that they modify Th1/Th2 response to Th1 response, inhibit MHC-II induction, cytokine release, inhibit mast cells degranulation, and induce apoptosis. CCL20/CCR6 interaction also plays an important role in the pathogenesis of psoriasis. Kim et al investigated an inhibitory effect of statins on CCL20/CCR6 interaction and could demonstrate that IL-1β, TNF-α, and IL-17A significantly increased CCL20 production from HaCaT cells. Fluvastatin and simvastatin, but not pravastatin seemed to reduce this effect. Statins have shown to reduce inflammatory markers and when added to standard psoriasis therapy may improve disease severity. Statins show a hierarchy in their anti-inflammatory activity (cerivastatin > atorvastatin > simvastatin > pravastatin > lovastatin > fluvastatin). However, studies on their potential role in preventing psoriasis have yielded conflicting results. A decreased progression of psoriasis is shown to be associated with statin intake in several studies[274-279]. Contrarily, statins have been implicated for deterioration of skin lesions as well[280-283]. Shirinsky et al in an 8-wk pilot study for the efficacy of simvastatin (40 mg/d) observed beneficial effects in seven patients with plaque psoriasis. Brauchli et al observed no link between long-term use of statins and the decreased risk of psoriasis diagnosis in a case-control retrospective analysis of 36702 cases of psoriasis identified between 1994 and 2005 from United Kingdom based General Practice Research Database. However, they observed a reduced psoriasis risk for short-term statin users. Whereas, another retrospective cohort study assessed the relationship between adherence with statins and the risk of psoriasis among 205820 health plan enrollees in Israel (mean age 55 years; 54.1% female) and found that high and long-term adherence with statins is not associated with a meaningful reduction in the risk of psoriasis. Another aspect of statins use is their combination with other antipsoriasis therapy. It showed a trend toward greater improvements in psoriasis severity in a study comprising 232 patients using topical corticosteroids, topical vitamin D, and some anti-ischemic treatments. The patients on statins (n = 66) had more severe disease (BSA of 13.26%) before starting new psoriasis medication as compared with 12.25% for the patients in nonstatin (n = 166) group. Interestingly, the trend reversed after initiating medication, with a BSA of 5.21% vs 7.43% for the statin vs nonstatin users. There was overall 64% reduction in psoriasis severity in statin group as compared with 45% reduction in the nonstatin group. Although the difference was not statistical significance, trend for those treated with statins was toward greater improvement. Combined treatment with simvastatin and topical betamethasone also provided better clinical outcome in a double-blind study comprising 30 subjects with plaque-type psoriasis randomized to two groups. Oral simvastatin (40 mg/d) combined with topical betamethasone (50% in pet) ointment in first group, whereas the second group received topical betamethasone (50% in pet) ointment and oral placebo. PASI score decreased significantly in both groups after study period of 8 wk. However, the reduction in PASI score was more expressed in simvastatin group patients. The potential efficacy of adding topical simvastatin to topical calcipotriol in plaque psoriasis also needs confirmatation. Effects of combined treatment with atorvastatin (40 mg/d) vs placebo and keratolytics and/or corticosteroids were studied by Faghihi et al in a prospective, randomized, double-blind, placebo-controlled study. Oral atorvastatin was not associated with therapeutic benefit in patients with PASI scores < 12 points prior to addition of statin and the differences in mean PASI score were not statistically significant in two groups. Statins associated adverse effects like myopathy, proteinuria, elevated transaminases, or haemorrhagic stroke were not noted by these studies. Simvastatin presents the highest risk of toxicity via mechanism of CYP3A4 inhibition. It is not uncommon to find statins triggering/aggravating psoriasis. Cozzani et al reported worsening of psoriasis in a patient 3 mo after atorvastatin and considerable improvement after discontinuation of atorvastatin. There is also report of exacerbation of psoriasis following pravastatin use. Despite reduction in all-cause mortality among people without evidence of cardiovascular disease treated with statins, the major concern from wide use of statins in psoriasis is possible drug interactions between concomitant antipsoriatic or other therapies (methotrexate, cyclosporine, fibrates, macrolides, warfarin, digoxin, and azole antifungals)[285,286]. Potential interaction between fluvastatin and cyclosporine, primarily metabolized by CYP2C9 and not CYP3A4, is low.
It is perhaps too early to recommend use of statins in psoriasis as stand alone therapy as sufficient perspective data is lacking. The misinterpretation of available data is also possible as patients using statin are likely to change towards a healthier lifestyle as has been suggested by Brauchli et al. Nonetheless, statins seems reasonable adjuncts to psoriasis therapy in view of the fact that psoriasis patients have a significant risk for metabolic disturbances and cardiovascular diseases.
ANTI-INFLAMMATORY AND OTHER DISEASE MODIFYING DRUGS
The utility of anti-inflammatory drugs as monotherapy is limited. While some of these agents like sulfasalazine have well identified advantage especially in psoriatic arthritis, others may perhaps have just more than a placebo effect. Nevertheless, their significance is perhaps in “add-on” therapy to ameliorate accompanying symptoms of inflammation and being sick.
Sulfasalazine, a sulfa drug, is a derivative of mesalazine formed by combining sulfapyridine and salicylate with an azo bond. Sulfasalazine is primarily used for the treatment of inflammatory bowl disease including Crohn’s disease and ulcerative colitis. It is also indicated for the treatment of rheumatoid arthritis or other inflammatory arthritis such as psoriatic arthritis. The recommended dose is 500 mg three times daily and increased as needed/tolerated. Sulfasalazine metabolizes to sulfapyridine that is responsible for some of the anti-arthritic effects and side effects of sulfasalazine from high serum concentrations of sulfapyridine and poor acetylation of the drug. Its other metabolite, 5-aminosalicylic acid (5-ASA), is considered responsible for its major therapeutic effect. However, its exact mechanism of action is not understood well but its anti-inflammatory effect is attributed to inhibition of dihydrofolate reductase and folate absorption. Sulfasalazine has been found effective in the treatment of psoriasis, spondyloarthropathy and psoriatic arthritis[287-299]. In a double-blind, randomized, controlled trial of sulfasalazine, intolerable adverse effects warranted discontinuation of treatment in 8 of 25 patients while other 7 of 17 patients, who continued treatment, showed 60%-89% improvement in their psoriasis. In a small study, 3 of 8 patients in sulfasalazine group had moderate (50% to 70%) improvement of PASI score as compared 70% (very good response) improvement in PASI score in 6 of 7 patients in methotrexate group. Significant improvement was observed in morning stiffness, number of painful joints, articular index, clinical score, and pain score, with the favourable response more pronounced in the polyarticular group and response became visible as early as 4 wk[289,297]. In a large double blind, placebo-controlled study 58% of 221 patients with moderate to severe psoriasis improved with sulfasalazine (2 g/d) over 36 wk and showed improvement in their psoriatic arthritis compared with 45% in the placebo group. Rahman et al treated 36 patients with sulfasalazine (3 g/d). One or more side effects warranted discontinuation of drug in 14 of 16 patients within 3 mo. A 50% reduction in actively inflamed joint count was noted in 7/20 patients at 6 mo and 11/15 patients at 12 mo as compared to 7/19 patients in the control group at 6 mo and 10/20 patients at 12 mo. Combe et al also noted significant improvement in their study of 120 patients. Overall, the benefit remains marginal with no halt in radiographic progression in psoriatic arthritis and significant number of patients experience adverse effects. The axial disease also does not appear to improve significantly. Comparatively, cyclosporine was more effective than sulfasalzine in the treatment of psoriatic arthritis in an open trial.
Although adverse effects are not serious, may occur in about 60% of patients requiring withdrawal from study in 15% patients. Gastrointestinal intolerance (nausea, heartburn, vomiting, and diarrhea), malaise, headache, arthralgia, drug fever, and reversible oligospermia are common while leukopenia and agranulocytosis, and haemolytic anemia in G6PD deficient individuals are more serious adverse effects. Skin eruptions can also occur and caused 4 of 23 patients receiving drug to drop out in a trial. As the effect of sulfasalazine remains variable, its usage must be weighed against risk vs benefit of the drug. It must not be combined with methotrexate due to enhanced hepatorenal toxicity.
Colchicine, an alkaloid extracted from the plant Colchicum species (C. autumale), has anti-inflammatory response by interfering neutrophil chemotaxis and inhibition of cell-mediated immune responses. It is mostly used to treat acute gout in a dose of 0.6 to 1.2 mg once or twice daily while its efficacy in psoriasis varies from being effective to having no effect on skin lesions. Wahba et al observed significant clearing of skin lesions in 11 of 22 patients treated with colchicine (0.02 mg/kg per day) with symptomatic improvement observed in four patients with arthralgias. No significant difference was reported in 25 patients treated with colchicine (0.6-1.8 mg/d) or placebo at 23 wk in a subsequent placebo controlled study while colchicine was also associated with more adverse effects necessitating withdrawal from study in three patients. Seideman et al in a double blind, placebo controlled, and cross over study found significant improvement in joint pain and swelling, and grip strength in 10 of 12 patients after 16 wk treatment with colchicine (1.5 mg/d). Complete remission of pustular psoriasis occurred in 3 of 4 patients after colchicine treatment. Palmoplantar pustulosis too has been treated successfully with some exceptions[304-306]. However, the potential efficacy of topical colchicine needs further evaluation. Colchicine associated gastrointestinal adverse effects at doses above 2-3 mg/d are the major concern and may occur in 80% of patients and can be an indicator of maximum therapeutic dose. Myopathy and neuropathy may occur in long-term therapy while pancytopenia and renal failure results from overdose of the drug. Colchicine may be more useful in psoriatic arthritis, pustular psoriasis and palmoplantar psoriasis in a subset of patients, but more perspective data will be required to establish the role of colchicine in the management of psoriasis.
Therapeutic efficacy of this well-known antileprosy drug was first reported in a patient of generalized pustular psoriasis who was managed on a regimen of long-term systemic triamcinolone and dapsone. Subsequently, several reports of its successful use in the treatment of childhood pustular psoriasis appeared[309-311]. An excellent response from dapsone was noted in 19 of 26 children while other five children had moderate response when treated with dapsone. The response improved further when dapsone was combined with triptolide (the active ingredient in a Chinese herb) and erythromycin. Dapsone (100 mg/d) was also effective in treating inverse psoriasis involving genital skin fold. The usual dose for pustular psoriasis in children is 1 mg/kg per day or 50-300 mg/d in adults and decreased to a low maintenance dose after effective control. The mechanism of its action in psoriasis has been postulated to be due to its anti-inflammatory effects by virtue of interference with neutrophil chemotaxis, blockage of prostaglandin-and leukotriene-mediated inflammation, and inhibition of myeloperoxidase in neutrophils and eosinophils, preventing tissue injury from oxygen radicals. Woolly headedness, anemia, dose-related methemoglobinemia, hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients, agranulocytosis, hepatitis, dapsone hypersensitivity syndrome, peripheral neuropathy are some of its potential adverse effects requiring periodic evaluation. The utility of dapsone appears exciting but few well-controlled clinical studies are highly desirable to evaluate efficacy of this very versatile low-cost treatment in psoriasis.
Pentoxifylline, a methylxanthine derivative, is a non-selective inhibitor that moderates the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanisine monophosphate by decreasing their hydrolysis and augments cyclic nucleotide-dependant signal transduction leading to variable effects on inflammation[313,314]. It reduces blood viscosity, inhibits aggregation of platelets, erythrocytes and leukocytes, inhibits thrombus formation and improves microcirculation and tissue perfusion because of hemorheologic actions. It also suppresses TNFα gene transcription, expression of TNF mRNA and secretion of TNF protein in macrophages and monocytes. The anti-TNF effect and antiproliferative effect of pentoxifylline is speculated to be responsible for its efficacy in psoriasis[293,316]. Magela Magalhães et al in a randomized, placebo-controlled trial treated 61 patients with active psoriasis with pentoxifylline 400 mg/d or placebo. Clinicopathologic evaluation 8 wk after treatment showed no statistically significant differences from pre-treatment features between the two groups. el-Mofty et al in a randomized controlled trial studied efficacy of sulfasalazine and pentoxifylline. They divided 32 patients in four groups treated either with sulfasalazine (group A), pentoxifylline (group B), both drugs (group C), or methotrexate (group D), respectively. Combination of sulfasalazine and pentoxifylline produced a better response than either drug used alone but methotrexate was superior in clearing the psoriasis at weeks 0, 2, 4, 6 and 8 of follow up. Its combination with fumaric acid esters is also said to reduce the severity and incidence of fumaric acid esters associated flushing and gastrointestinal side effects. Similarly, use of pentoxifylline with cyclosporine might reduce later’s nephrotoxicity. Overall, its usefulness as monotherapy appears limited as compared to its combination with other antipsoriatic therapy. It is perhaps better to use it as only “add-on” therapy in the treatment of psoriasis.
PHOTOTHERAPY RELATED PROCEDURES
Phototherapy using UV light from sun or artificial source is a well-established treatment option in psoriasis of moderate severity, palmoplantar psoriasis, guttate and small plaque variety. UV light of both, broadband (BB) UV-B (290-320 nm) and narrowband (NB) UV-B (311-313 nm), and UV-A (320-400 nm) wavelength is predominantly used in psoriasis therapy. Comparatively, NBUV-B phototherapy is superior to BBUV-B in efficacy and remission periods but is equal or less effective than PUVA therapy[320-325]. PUVA is useful in thick plaque psoriasis, palmoplantar psoriasis (particularly with topical psoralene), and for UVB phototherapy non-responders. However, UV-B phototherapy has added advantage of ease of administration and no psoralene toxicity (gastrointestinal intolerance, hepatotoxicity, phototoxicity, photodamage, premature aging, cataract, risk of skin cancers). Combination of PUVA or UV-B phototherapy has been used along with various topical (corticosteroids, calcipotriene, anthralin, tazarotene) or systemic treatments (methotrexate, retinoids) for enhanced therapeutic effect even at lower than recommended doses[326-329]. A combination of PUVA and UV-B has cleared psoriasis more effectively with an average of 11.3 treatments at doses much lower than needed for monotherapy. The overall objective is to maintain minimum perceptible erythema for optimal dosing until 20-25 treatments, total or near total remission, or no further improvement is noticeable. The treatment is continued with reduced frequency to maintenance therapy once the remission is achieved. Nevertheless, the limitation is its contraindication in patients with erythrodermic or photo aggravated psoriasis, photosensitive disorders (systemic lupus erythematosus), personal or family history of melanoma or other skin cancers, and severe actinic damage. Eye protection is essential during UV phototherapy and ingestion of psoralene is contraindicated in children aged < 12 years.
Photodynamic therapy or photochemotherapy using topical aminolevulinic acid has been tried in psoriasis with inadequate clinical response in a randomized study comprising 29 patients. Results have been discouraging in a recent randomized double-blind trial of this modality in 12 patients with psoriasis. The therapy is frequently associated with severe pain and burning during and after treatment warranting its discontinuation. Topical hypericin, methylene blue, and systemic ALA and verteporfin are perhaps better tolerated photosensitizers for photodynamic therapy. Like photodynamic therapy, photopheresis and extracorporeal photochemotherapy are ineffective for skin lesions or psoriatic arthritis[334,335] and not prefered.
Grenz ray therapy
Grenz rays are essentially short-wavelength X rays with a wavelength of 0.07 to 0.4 nm, which is also in the range of long-wavelength ultraviolet radiation. They are produced at low kilovoltages with very limited penetration ability; up to the first half millimeter of the skin. Grenz ray therapy has been used effectively in many inflammatory dermatoses (eczemas, lichen planus, acne, Hailey- Hailey disease, mycosis fungoides) perhaps for their anti inflammatory effect and ability to decrease Langerhans cells in the epidermis. Many researchers have reported good response from grenz rays (4 Gy weekly for 6 wk) therapy in psoriasis as well. Grenz rays therapy was effective in 14 of 16 patients with scalp psoriasis in a double-blind bilateral trial leading to complete clearing of scalp lesions treated with grenz rays for 6 wk and the remission lasted for 3 mo in 9 of these patients. Grenz rays combined with topical corticosteroids cleared scalp psoriasis faster than topical corticosteroids alone in 17 patients with symmetrical scalp psoriasis lesions in a double-blind study. The remission also lasted longer with combination therapy than when grenz rays were used alone. Lindelöf et al compared grenz ray therapy alone with combination of grenz rays and topical betamethasone dipropionate in 40 patients with scalp psoriasis randomized into two groups. One group received 4 Gy of Grenz rays administered on six occasions at intervals of 1 wk and the other group was given the same Grenz ray treatment plus topical corticosteroid. The patients were assessed before and after Grenz ray therapy. Psoriasis cleared significantly in 16 out of 19 (84%) of the patients in the Grenz ray group, and I3 out of I8 (72%) of the patients in the combination group but the remission did not differ significantly between the two groups at end of follow-up of 6 mo. Remissions were longer with combination of grenz rays and selenium sulphide shampoo in combination as compared to placebo shampoo and Grenz rays. Grenz ray therapy was also effective in a limited manner and appears to be a useful adjunct to other therapies for palmoplantar psoriasis and nail psoriasis particularly for nails with normal thickness[341,342]. The grenz ray therapy (4 Gy weekly for 6 wk) showed moderated but significant improvement of palmoplantar pustulosis in 15 patients in a randomized placebo controlled bilateral study. The efficacy of grenz ray therapy was assessed in 22 patients with nail psoriasis in a randomized, bilateral controlled study. One hand was allocated to treatment group receiving 5 Gy of grenz rays at weekly interval on 10 occasions. The placebo group received simulated therapy. The patients receiving active treatment showed moderate but significant improvement when psoriatic nails of normal thickness as compared to the control group. Overall, current evidence on its efficacy for psoriasis remains limited and development of non-melanoma skin cancers is a concern in the long term in addition to reported adverse effects of erythema and pigmentation[336,343].
The monochromatic excimer laser used 308 nm xenon chloride light source and can deliver supra-erythemogenic doses up to 6 MED (2-6 MEDs) focally to the individual skin lesion for targeted phototherapy to minimize radiation and number of treatments. Initially used as three times weekly with an average of 10-12 treatments needed normally for improvement. Asawanonda et al reported at least 75% clearing of psoriasis in 72% of 124 patients after an average 6.2 treatments with excimer laser delivered twice weekly. Higher response was noted with excimer laser in comparison with pulse-dye laser in a recent comparative study; few patients also responded better with the pulse-dye laser. Patients in both the groups had remissions lasting more than 3 mo to 1 year. Blistering, burning and pain, and postinflammatory hyperpigmentation are potential side effects of excimer laser.
Climatotherapy and balneophototherapy
Exposure to sunlight is well known to improve psoriasis in majority. Daily bathing in Dead Sea water followed by exposure to sunlight perhaps remains the most studied mode of climatotherapy. The efficacy of Dead Sea climatotherapy has been attributed to the, high mineral contents, climatic conditions, and its location at about 400 m below sea level. Exposure to UV light through a mineral haze surrounding the beaches for 15 min daily to begin with is increased gradually depending on skin type to a maximum of 3 h/d for 3-4 wk. A 2 wk therapy is also considered optimal by some workers. The therapy has been found effective in psoriasis decreasing PASI scores by 75% or more with long remissions[348-350]. Harari et al observed 95.5% improvement of pre-treatment mean PASI score that decreased from 31.7 to 1.42 in 64 patients after 4-wk Dead Sea climatotherapy. All patients achieved PASI 50 and 75.9% of them reached PASI 75 during the same period. The median time of remission was 23 wk after a median duration of 33.6 wk. However, no long-term changes in psoriasis severity and quality of life were observed following Dead Sea climatotherapy in an earlier study. Nevertheless, improvement is considered comparable to that from NB-UVB or PUVA therapy and other treatment modalities[351,353]. It was effective in psoriatic arthritis and has been used safely in pediatric patients[354-357]. Although considered expensive and time consuming, Shani et al found it cost-effective considering the cost involved in travel, hotel accommodations, medical and laboratory charges, loss of productive days, adverse effects, and time taken for recovery of inpatient treatment. It has been combined safely and effectively with acitretin for psoriasis therapy.
Balneophototherapy involves salt-water baths and artificial ultraviolet radiation as an alternative to climatotherapy at the Dead Sea. Although high clearance rates have been reported with balneophototherapy[358,359], combination of Dead Sea bathing and sun exposure was more effective with 83% improvement as compared to 73% improvement with sun exposure alone and 28% improvement in psoriatics who only soaked in Dead Sea salts. Climatotherapy is considered safe and adverse effects of this non-drug therapy such as sunburn, pruritus, folliculitis, solar elasotsis, solar lentigens, poikiloderma and wrinkles may occur[349,350,361]. Photodamage, malignant melanoma and non-melanoma skin cancer are other potential risks associated with long-term therapy.
Phototherapy for treating psoriasis, as standalone therapy or in combination with other modalities, remains as good an option as it was before therapies that were more effective became available. NBUV-B phototherapy is preferred being simpler and cheaper than all these procedures, virtually safer and free of adverse effects associated with psoralene ingestion.
Because of inherent complications, these physical treatment modalities should not be preferred to other therapeutic modalities or biologicals even in resistant debilitating disease.
Dialysis and related procedures
A report on incidental clearance of psoriasis lesions following haemodialysis in 1976 lead several small studies reporting a variable response[362-367]. Twardowski also performed hemodyliasis for psoriasis in a non-uremic patient. A review of these reports reveals that peritoneal dialysis was more effective than hemodialysis. With 3-4 continuous ambulatory peritoneal dialyses per day, the psoriasis cleared completely in the two patients with renal failure and improved in the other two patients with normal renal function. However, continuous treatment is perhaps required to prevent relapse. In a randomized double-blind crossover study treatment with sham and real peritoneal dialysis was performed in severe chronic plaque psoriasis unresponsive to conventional therapies including methotrexate. Two patients cleared completely, two patients had more than 75% clearance and one patient had no significant response in peritoneal dialysis group while none of the 5 patients in the control group had any response. Sobh et al treated 40 patients with severe psoriasis after their random grouping for haemodialysis (group-1), peritoneal dialysis (group-2), and treatment with modified Goeckerman (group-3). Ten dialysis sessions showed better response in peritoneal than haemodialysis, and both were better than Goeckerman treatment. There were no significant changes in plasma, or tissue zinc and copper levels while there was a significant decrease in IgG deposits after treatment in the three groups. Contrarily, Nissenson et al in a randomized controlled trial of haemodialysis in seven patients with severe psoriasis observed no significant objective improvement. They performed a 24 h course of haemodialysis in three patients once daily for 4 d and repeat haemodialysis after 4 wk. Sham dialysis was performed in similar manner in four patients. In another study, 4/8 (50%) patients in haemodialysis group and 6/10 (60%) patients in peritoneal dialysis group, respectively, improved at the end of six months. The benefit was temporary and one patient developed exfoliative dermatitis 11 d after haemodialysis. Three patients of Llewellyn et al neither tolerated nor benefited from peritoneal dialysis. The exact mechanism of action of this procedure is poorly understood and is postulated to be from decreased IgG, increased fibronectin level, and postulated removal (from bloodstream) of growth-promoting substances, psoriasis-related factors, activated polymorphonuclear leukocytes, interference with neutrophil migration[371,372].
While some psoriasis patients with renal disease may benefit from dialysis, the severe psoriasis itself independently predicts chronic kidney disease. Haemodialysis may also cause relapse, worsening of pre existing psoriasis or trigger de novo psoriasis during chronic hemodialysis for renal disease. New-onset psoriasis may occur during both haemodialysis and peritoneal dialysis and factors implicated include dialysis-induced growth factor, cytokines, and chemokines in psoriasis development[375-377].
The outcome of hemofiltration, leukopheresis, cardiopulmonary bypass, and exchange with fresh frozen plasma in psoriasis treatment has been variable[378-381]. Plasma exchange gave no or only partial remissions but no controlled studies are available[382,383]. However, a controlled study noted no beneficial effect from sham and true plasma pheresis and leucopheresis. Forced osmotic diuresis simply does not work. Among all, peritoneal dialysis may favourably influence psoriasis outcome but never preferred unless it is required for its well-defined indications.
Exacerbation, persistence or new onset of chronic plaques psoriasis within a subset of psoriatics is often attributed to hyper-reactivity to super-antigens, usually viral or bacterial proteins. Streptococcal infection has been the most implicated trigger in such instances. It has been suggested that some auto-reactive T cells primed against streptococcal proteins may cross react with keratinocytes (molecular mimicry) causing exacerbation of psoriasis. Molecular studies have suggested that auto-reactive T cells from tonsils can enter the circulation with homing to the skin triggering exacerbations/persistence of psoriasis. Tonsillectomy perhaps offer a valuable treatment option for such patients However, most reports in the literature on tonsillectomy comprise small case series or case reports pertaining to Japanese patients with acute guttate psoriasis, chronic plaque psoriasis or palmoplantar pustulosis. A complete clearance of guttate psoriasis and proteinuria was reported 2 and 6 mo after tonsillectomy in two patients, respectively. Similarly, complete clearance of recurrent guttate psoriasis with remissions lasting for 16 mo was observed in two patients 1-2 mo after tonsillectomy. Hone et al reported complete clearance in 5 (83%) patients in a retrospective study comprising six patients with guttate psoriasis. However, the effect of tonsillectomy in guttate psoriasis remains poorly studied despite strong suggestion for its association with streptococcal pharyngitis. The clinical improvement in plaque psoriasis and reduction of circulating streptococcal and keratin peptide-reactive IFN-γ-positive CD8-positive skin-homing T cells is closely related. However, the benefit of tonsillectomy in chronic plaque psoriasis remains ambiguous at best. In a questionnaire based retrospective study of 74 Danish patients with plaque psoriasis, 32% patients each reported complete or significant clearance of recalcitrant psoriasis vulgaris while 39% patients had some improvement. Worsening of disease was reported by 7% and 22% experienced no improvement. There was also no statistical difference in the benefit of tonsillectomy for patients who reported flare up of their skin disease and who reported no effect from tonsillitis. Hone et al reported complete or partial clearance of psoriasis plaques after tonsillectomy in 29% patients each, respectively; three of seven (42%) patients did not benefit at all. Recently, Thorleifsdottir et al noted a significant reduction in PASI score ranging from 30%-90% in 86% of 29 patients vs 0% in controls in a randomized clinical trial of tonsillectomy in chronic plaque psoriasis. Nearly, 60% patients achieved PASI 50 and the improvement was apparent 2 mo after tonsillectomy that lasted for over 2 years. Rachakonda et al also made similar observations in a recent systematic review of 20 publications of last 53 years comprising 545 patients with psoriasis who were evaluated for or underwent tonsillectomy.
The therapeutic efficacy of tonsillectomy was also analysed in 12 patients among 385 patients with generalize pustular psoriasis in a 1999 report by Ozawa et al. The disease decreased in approximately 50% but only 2 (16.7%) patients showed clear-cut benefit. The exacerbation of palmoplantar pustulosis too has been imputed to acute tonsillitis pioneering its treatment with tonsillectomy[393-399]. Subjective marked or complete remission after tonsillectomy was reported by 89% of respondents to a questionnaire who had been treated for palmoplantar pustulosis by tonsillectomy. Thirteen of 15 patients with palmoplantar pustulosis in another study reported effective to complete response 3 mo after tonsillectomy, no or partial response was also observed in one patient each. Takahara et al[394,399] in two separate studies noted subjective improvement after tonsillectomy in 87% and 94% patients with palmoplantar pustulosis, respectively. Wu et al have recently reviewed available evidence for the benefit of tonsillectomy in treatment of psoriasis. Overall, tonsillectomy may be useful for a subset of these patients in view of high rates of reported response to the procedure. However, additional well-designed studies including patients of diverse ethnicities will be needed for any recommendations. Moreover, the benefit must outweigh the risk associated with the procedure as disease remission after tonsillectomy was only for over two years or so in the reviewed reports. Long-term antimicrobial therapy will perhaps be more useful in such cases unless tonsillectomy is required due to its well-established indications.
Ichthyotherapy (Ichthys-Fish, Greek) means treatment for skin by using fish Garra rufa, commonly known as “nibble fish” or “doctor fish of Kangal”, which is a natural inhabitant of river basins in Central Eurasia. It is widely used in beauty and foot spas, and for the treatment of wounds or skin disorders like psoriasis and dermatitis that has made Kangal (Turkey) a popular health resort. The treatment involves lying in the ponds/spas and let the fish nibble on the scales and loose skin on the affected areas. Although the utility of Garra rufa in the treatment of psoriasis was identified as early as 1989 by Turkish researchers[403,404], no controlled studies have been carried out for its efficacy. The two recent short-term, uncontrolled studies report beneficial effects of ichthyotherapy in psoriasis. Ozçelik et al followed up 14 of 87 patients with chronic plaque psoriasis having prolonged immersion (mean 7.4 ± 1.1 h/d, mean 11.5 ± 6.6 d) in warm spring spas of Kangal containing Garra rufa. They reported complete clearance at 21 d in 8 (57.14%) and partial clearance in 6 (42.85%) patients, respectively. Two patients with erythrodermic or pustular psoriasis could not use this mode of therapy due to pain. Thirty-five of 87 patients experienced significantly longer remissions as compared to patients treated with topical corticosteroids alone. The overall beneficial effect was attributed to de-scaling of skin lesions by the fish, high selenium content and jacuzzi effect in spa water, natural sunlight, and reverse Koebner’s phenomenon. Grassberger et al used ichthyotherapy in a controlled medical setting to eliminate potential risk of infections associated with this mode of therapy. They evaluated its efficacy in 67 Austrian patients with moderate to severe chronic psoriasis who had undergone fish spa therapy for 2 h/d for three weeks in a tub containing garra rufa combined with short-term UV-A exposure and emollient application after each session. The tub and the fish were used exclusively for one individual patient. The bath water temperature was maintained at 36 °C-37 °C, filtered and disinfected constantly, and changed every 3-4 times a day. Overall, there was 71.7% reduction in PASI score and 87.5% patients reported a more favourable response vs other therapies. PASI ≥ 75 and PASI ≥ 50 were noted in 31 (46.3%) and 61 (91%) patients, respectively. Mean remission period was 8.58 mo and 65% patients reported decreased severity of relapse. They attributed beneficial effects to the relaxing effect of baths, decreased stress and psychological wellbeing contrary to the earlier belief.
Although no significant side effects were noted in these studies, pain, bleeding from nibbled skin lesions or transmission of viral and bacterial infections remains a potential risk[406,407]. The main concern about the use of fish spas involves the transmission of infectious agents such as Mycobacterium marinum, M. fortuitum and M. chelonae, Aeromonas spp. (Aeromonas folliculitis), Streptocococcus spp., Salmonellae (soft tissue infections, pustular dermatitis), Vibrio cholerae, V. vulinficus, or Klebsiella spp (wound infections) particularly among patients with diabetes, a common psoriasis co-morbidity, causing significant morbidity.
The usefulness of various therapies, systemic (methotrexate, cyclosporine, acitretin or various biological therapeutic agents) or topical (tar, anthralin, corticosteroids or vitamin D analog ointments, phototherapy with or without psoralens) has been well established. The utility of vitamin D analogs (calcipotriol, calcitriol, tacalcitol, maxacalcitol, becocalcidiol) in psoriasis needs a mention here since these are important in sequential therapy as monotherapy or in combination with topical corticosteroids (halobetasol, clobetasol, betamethasone dipropionate) for added benefit and steroid-sparing effect. Over the years several clinical studies across the regions have demonstrated efficacy and safety of topical calcipotriene without tachyphylaxis or skin atrophy observed with topical corticosteroids[408-412]. Calcitriol is as effective as betamethsone propionate or short-contact dithranol therapy, and significantly more effective than calcipotriene for the treatment of facial, hairline, and flexural psoriasis with better tolerability. While several studies have demonstrated efficacy of tacalcitol in the treatment of mild to moderate plaque psoriasis, nail psoriasis and scalp psoriasis, maxacalcitol (25 μg/g) is considered more effective than once-daily calcipotriol[413-418]. However, noncompliance for vitamin D analogs reported in 12%-20% patients is due to lesional and perilesional irritation with accompanying perilesional erythema, stinging, itching, and/or burning following topical application[419-423]. Hypercalcemia, hypercalciuria and parathyroid hormone suppression are rare but potential systemic adverse effects and occur because of using more than recommended dose of 100 g/wk or in the presence of impaired calcium metabolism or underlying renal disease[424-428]. Relatively high cost of therapy is another reason for noncompliance.
Emollients, especially petrolatum-containing products, remain a main stay of any treatment. They retain moisture in the stratum corneum and increase local penetration of topical medications. Petrolatum ointment has an antipsoriatic effect while combination with salicylic acid (3%-6%) will have descaling effect on psoriasis plaques and enhance penetration of corticosteroid. Ichthyol pale (4% sodium shale oil sulfonate), a substitute for coal tar with conventional moisturizing properties, also offers anti inflammatory, antipruritic and antimicrobial actions because of high sulphur content[429,430]. All these can be used alternating with gradual withdrawal of topical steroids for the maintenance stage. Anecdotal efficacy of topical aminophylline 4% ointment could not be substantiated[431,432]. Changing topical formulations for improved drug delivery and cutaneous bioavailability appears another area for for future researchers.
Apremilast is recently FDA approved oral therapy of active psoriatic arthritis in adult patients. It was found superior over placebo in phase 3 randomised, placebo-controlled trial (PALACE 1-4 study) comprising patients with active psoriatic arthritis. Overall, it was also equally effective as monotherapy as in combination with existing DMARDs. There was also improvement in the PASI 50 (51% vs 19%) and PASI 75 (21% vs 5%) compared with placebo. Headache, nausea, and diarrhea were the only significant adverse effects reported. Apremilast 30 mg twice daily was also effective in chronic plaque psoriasis in a phaes 3 multicenter, randomized, placebo-controlled trial (ESTEEM 1 study). Its exact mechanism of action needs elucidation but said to regulate inflammatory mediators by inhibition of phosphosphodiesterase 4 enzyme in immune cells leading to increase in intracellular cAMP levels.
Peptide-T, tyrosine kinase inhibitors (Erlotinib), p38 mitogen activated protein kinase inhibitors, protein kinase-C inhibitors, nerve growth factor receptor blocker, rapamycin inhibitors (sirolimus, everolimus) constitute experimental therapies[435-441]. Alternative approaches (acupuncture, ayurvedic medicine, traditional Chinese medicine, homeopathic medicine, naturopathic medicine, etc.), and immunotherapy (heat-killed delipidated, deglycolipidated Mycobacterium vaccae, Mycobacterium w or anti-leishmania vaccines) forms other interesting area of research despite variable results[442-445].
It is also interesting to note the evolution of psoriasis and its therapeutic modalities. The concept of keratinocyte dysfunction led to treatment with phototherapy, methotrexate, and retinoids before 1980s, whereas, cyclosporine was introduced after it was considered an immunologic disease during 1980s. Alefacept, efalizumab, and TNF-α blockers were developed during 1990-2005 as psoriasis evolved as a disease of altered cytokine profile (IL-12/Th1-mediated). In recent years, ustekinumab and secukinumab have been developed in view of IL-23/Th17-mediated cytokine profile in psoriasis. Normalization of angiogenesis, an important pathologic component of psoriasis lesions, appears emerging concept for novel antiangiogenic agents for more targeted therapy; may be in combination or as an alternative to conventional therapies. Calcium dobesilate inhibits VEGF and interferes with fibroblast growth factor-induced neoangiogenesis; the efficacy of topical 5% cream in limited plaque psoriasis appears promising[446-448]. Neovastat, also a VEGF antagonist with anti-angiogenic and anti-inflammatory properties, has shown statistically significant reduction in PASI score in randomized phase I/II dose-comparison clinical trials comprising 29 patients with psoriasis. More well designed studies are required before these drugs are approved for the treatment of psoriasis. Finally yet importantly, the clinicians must be apprised of all available antipsoriasis therapies in view of variable therapeutic outcome(s) that may test one’s ingenuity in managing some of the “difficult to treat” patients. It seems that nonstandard and off-label therapies will remain an important alternative in rotational/intermittent treatment(s) or to more widely used and evidence based treatments until a therapy that is affordable, safe, effective, and more importantly, remittiv becomes available.
P- Reviewer: Ayroldi E, Denadai R, Farkas A, Guslandi M S- Editor: Ji FF L- Editor: A E- Editor: Wu HL
Gudjonsson JE, Elder JT. Psoriasis: epidemiology.Clin Dermatol. 2007;25:535-546.
Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey.Arch Dermatol. 2001;137:280-284.
Christophers E, Griffiths CE, Gaitanis G, van de Kerkhof P. The unmet treatment need for moderate to severe psoriasis: results of a survey and chart review.J Eur Acad Dermatol Venereol. 2006;20:921-925.
Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis.J Am Acad Dermatol. 2004;50:859-866.
Reimus JL, Vingerhoets AJ, Soons PH, Korstanje MJ. Suffering in psoriasis patients: its relation with illness severity and subjective well-being.Int J Dermatol. 2007;46:1042-1045.
Mahajan VK, Khatri G, Prabha N, Abhinav C, Sharma V. Clopidogrel: a possible exacerbating factor for psoriasis.Indian J Pharmacol. 2014;46:123-124.
Yamamoto T, Katayama I, Nishioka K. Clinical analysis of staphylococcal superantigen hyper-reactive patients with psoriasis vulgaris.Eur J Dermatol. 1998;8:325-329.
Balci DD, Duran N, Ozer B, Gunesacar R, Onlen Y, Yenin JZ. High prevalence of Staphylococcus aureus cultivation and superantigen production in patients with psoriasis.Eur J Dermatol. 1998;19:238-242.
Skinner RB, Rosenberg EW, Noah PW. Psoriasis of the palms and soles is frequently associated with oropharyngeal Candida albicans.Acta Derm Venereol Suppl (Stockh). 1994;186:149-150.
Squiquera L, Galimberti R, Morelli L, Plotkin L, Milicich R, Kowalckzuk A, Leoni J. Antibodies to proteins from Pityrosporum ovale in the sera from patients with psoriasis.Clin Exp Dermatol. 1994;19:289-293.
Reveille JD, Conant MA, Duvic M. Human immunodeficiency virus-associated psoriasis, psoriatic arthritis, and Reiter’s syndrome: a disease continuum?Arthritis Rheum. 1990;33:1574-1578.
Townsend BL, Cohen PR, Duvic M. Zidovudine for the treatment of HIV-negative patients with psoriasis: a pilot study.J Am Acad Dermatol. 1995;32:994-999.
Duvic M, Crane MM, Conant M, Mahoney SE, Reveille JD, Lehrman SN. Zidovudine improves psoriasis in human immunodeficiency virus-positive males.Arch Dermatol. 1994;130:447-451.
Mahajan VK, Sharma NL, Sarin S, Bansal A, Sud N. Triple antiretroviral therapy improves psoriasis associated with human immunodeficiency virus infection: a clinico-therapeutic experience.J Eur Acad Dermatol Venereol. 2008;22:1017-1018.
Favre M, Orth G, Majewski S, Baloul S, Pura A, Jablonska S. Psoriasis: A possible reservoir for human papillomavirus type 5, the virus associated with skin carcinomas of epidermodysplasia verruciformis.J Invest Dermatol. 1998;110:311-317.
Ashkevari SSH, Maboodi A. Acute generalized pustular psoriasis and idiopathic hypoparathyroidism in an adolescent girl.Acta Medica Iranica. 2004;42:300-302.
Kawamura A, Kinoshita MT, Suzuki H. Generalized pustular psoriasis with hypoparathyroidism.Eur J Dermatol. 1999;9:574-576.
Tercedor J, Ródenas JM, Muñoz M, Céspedes S, Naranjo R. Generalized pustular psoriasis and idiopathic hypoparathyroidism.Arch Dermatol. 1991;127:1418-1419.
Boisseau-Garsaud AM, Legrain V, Hehunstre JP, Maleville J, Taïeb A. Treatment of psoriasis by oral calcitriol. A study of 5 cases and review of the literature.Ann Dermatol Venereol. 1993;120:669-674.
Duarte GV, Oliveira Mde F, Cardoso TM, Follador I, Silva TS, Cavalheiro CM, Nonato W, Carvalho EM. Association between obesity measured by different parameters and severity of psoriasis.Int J Dermatol. 2013;52:177-181.
Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II.Arch Intern Med. 2007;167:1670-1675.
Kumar S, Han J, Li T, Qureshi AA. Obesity, waist circumference, weight change and the risk of psoriasis in US women.J Eur Acad Dermatol Venereol. 2013;27:1293-1298.
Debbaneh M, Millsop JW, Bhatia BK, Koo J, Liao W. Diet and psoriasis, part I: Impact of weight loss interventions.J Am Acad Dermatol. 2014;71:133-140.
Higa-Sansone G, Szomstein S, Soto F, Brasecsco O, Cohen C, Rosenthal RJ. Psoriasis remission after laparoscopic Roux-en-Y gastric bypass for morbid obesity.Obes Surg. 2004;14:1132-1134.
de Menezes Ettinger JE, Azaro E, de Souza CA, dos Santos Filho PV, Mello CA, Neves M, de Amaral PC, Fahel E. Remission of psoriasis after open gastric bypass.Obes Surg. 2006;16:94-97.
Herron MD, Hinckley M, Hoffman MS, Papenfuss J, Hansen CB, Callis KP, Krueger GG. Impact of obesity and smoking on psoriasis presentation and management.Arch Dermatol. 2005;141:1527-1534.
Lafuente-Urrez RF, Pérez-Pelegay J. Impact of obesity on the effectiveness of adalimumab for the treatment of psoriasis: a retrospective study of 30 patients in daily practice.Eur J Dermatol. 2014;24:217-223.
Armstrong AW, Armstrong EJ, Fuller EN, Sockolov ME, Voyles SV. Smoking and pathogenesis of psoriasis: a review of oxidative, inflammatory and genetic mechanisms.Br J Dermatol. 2011;165:1162-1168.
Higgins E. Alcohol, smoking and psoriasis.Clin Exp Dermatol. 2000;25:107-110.
Jankovic S, Raznatovic M, Marinkovic J, Jankovic J, Maksimovic N. Risk factors for psoriasis: A case-control study.J Dermatol. 2009;36:328-334.
Naldi L, Chatenoud L, Linder D, Belloni Fortina A, Peserico A, Virgili AR, Bruni PL, Ingordo V, Lo Scocco G, Solaroli C. Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study.J Invest Dermatol. 2005;125:61-67.
Raychaudhuri SP, Gross J. Psoriasis risk factors: role of lifestyle practices.Cutis. 2000;66:348-352.
Zhang X, Wang H, Te-Shao H, Yang S, Wang F. Frequent use of tobacco and alcohol in Chinese psoriasis patients.Int J Dermatol. 2002;41:659-662.
Fortes C, Mastroeni S, Leffondré K, Sampogna F, Melchi F, Mazzotti E, Pasquini P, Abeni D. Relationship between smoking and the clinical severity of psoriasis.Arch Dermatol. 2005;141:1580-1584.
Setty AR, Curhan G, Choi HK. Smoking and the risk of psoriasis in women: Nurses’ Health Study II.Am J Med. 2007;120:953-959.
Gupta MA, Gupta AK, Watteel GN. Cigarette smoking in men may be a risk factor for increased severity of psoriasis of the extremities.Br J Dermatol. 1996;135:859-860.
Michaëlsson G, Gustafsson K, Hagforsen E. The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking.J Am Acad Dermatol. 2006;54:737-738.
Brenaut E, Horreau C, Pouplard C, Barnetche T, Paul C, Richard MA, Joly P, Le Maître M, Aractingi S, Aubin F. Alcohol consumption and psoriasis: a systematic literature review.J Eur Acad Dermatol Venereol. 2013;27 Suppl 3:30-35.
Poikolainen K, Reunala T, Karvonen J, Lauharanta J, Kärkkäinen P. Alcohol intake: a risk factor for psoriasis in young and middle aged men?BMJ. 1990;300:780-783.
Qureshi AA, Dominguez PL, Choi HK, Han J, Curhan G. Alcohol intake and risk of incident psoriasis in US women: a prospective study.Arch Dermatol. 2010;146:1364-1369.
Wu S, Cho E, Li WQ, Han J, Qureshi AA. Alcohol intake and risk of incident psoriatic arthritis in women.J Rheumatol. 2015;42:835-840.
Gupta MA, Schork NJ, Gupta AK, Ellis CN. Alcohol intake and treatment responsiveness of psoriasis: a prospective study.J Am Acad Dermatol. 1993;28:730-732.
Farkas A, Kemény L, Széll M, Dobozy A, Bata-Csörgo Z. Ethanol and acetone stimulate the proliferation of HaCaT keratinocytes: the possible role of alcohol in exacerbating psoriasis.Arch Dermatol Res. 2003;295:56-62.
Ockenfels HM, Keim-Maas C, Funk R, Nussbaum G, Goos M. Ethanol enhances the IFN-gamma, TGF-alpha and IL-6 secretion in psoriatic co-cultures.Br J Dermatol. 1996;135:746-751.
Higgins EM, du Vivier AW. Alcohol abuse and treatment resistance in skin disease.J Am Acad Dermatol. 1994;30:1048.
Shelling ML, Kirsner RS. Failure to counsel patients with psoriasis to decrease alcohol consumption (and smoking).Arch Dermatol. 2010;146:1370.
Wolters M. Diet and psoriasis: experimental data and clinical evidence.Br J Dermatol. 2005;153:706-714.
Chalmers RJ, Kirby B. Gluten and psoriasis.Br J Dermatol. 2000;142:5-7.
Addolorato G, Parente A, de Lorenzi G, D’angelo Di Paola ME, Abenavoli L, Leggio L, Capristo E, De Simone C, Rotoli M, Rapaccini GL. Rapid regression of psoriasis in a coeliac patient after gluten-free diet. A case report and review of the literature.Digestion. 2003;68:9-12.
Michaëlsson G, Gerdén B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W, Hjelmquist G, Lööf L. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet.Br J Dermatol. 2000;142:44-51.
Balbás GM, Regaña MS, Millet PU. Study on the use of omega-3 fatty acids as a therapeutic supplement in treatment of psoriasis.Clin Cosmet Investig Dermatol. 2011;4:73-77.
Lassus A, Dahlgren AL, Halpern MJ, Santalahti J, Happonen HP. Effects of dietary supplementation with polyunsaturated ethyl ester lipids (Angiosan) in patients with psoriasis and psoriatic arthritis.J Int Med Res. 1990;18:68-73.
Kojima T, Terano T, Tanabe E, Okamoto S, Tamura Y, Yoshida S. Long-term administration of highly purified eicosapentaenoic acid provides improvement of psoriasis.Dermatologica. 1991;182:225-230.
Danno K, Sugie N. Combination therapy with low-dose etretinate and eicosapentaenoic acid for psoriasis vulgaris.J Dermatol. 1998;25:703-705.
Mayser P, Grimm H, Grimminger F. n-3 fatty acids in psoriasis.Br J Nutr. 2002;87 Suppl 1:S77-S82.
Mayser P, Mrowietz U, Arenberger P, Bartak P, Buchvald J, Christophers E, Jablonska S, Salmhofer W, Schill WB, Krämer HJ. Omega-3 fatty acid-based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial.J Am Acad Dermatol. 1998;38:539-547.
Maringer B, Zietemann V, Ratzinger , G , Siebert U. Effectiveness of omega-3-fatty acids in psoriasis: a systematic review.Aktuelle Ernährungsmedizin. 2009;34:195-200.
Millsop JW, Bhatia BK, Debbaneh M, Koo J, Liao W. Diet and psoriasis, part III: role of nutritional supplements.J Am Acad Dermatol. 2014;71:561-569.
Nesher G, Mates M, Zevin S. Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis.Arthritis Rheum. 2003;48:571-572.
Swanson DL, Barnes SA, Mengden Koon SJ, el-Azhary RA. Caffeine consumption and methotrexate dosing requirement in psoriasis and psoriatic arthritis.Int J Dermatol. 2007;46:157-159.
Rucević I, Perl A, Barisić-Drusko V, Adam-Perl M. The role of the low energy diet in psoriasis vulgaris treatment.Coll Antropol. 2003;27 Suppl 1:41-48.
Vijayashankar M, Raghunath N. Pustular psoriasis responding to probiotics-a new insight.Our Dermatol Online. 2012;3:326-328.
Heng MC, Song MK, Harker J, Heng MK. Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters.Br J Dermatol. 2000;143:937-949.
Antiga E, Bonciolini V, Volpi W, Del Bianco E, Caproni M. Oral Curcumin (Meriva) Is Effective as an Adjuvant Treatment and Is Able to Reduce IL-22 Serum Levels in Patients with Psoriasis Vulgaris.Biomed Res Int. 2015;2015:283634.
Kurd SK, Smith N, VanVoorhees A, Troxel AB, Badmaev V, Seykora JT, Gelfand JM. Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective clinical trial.J Am Acad Dermatol. 2008;58:625-631.
Valdimarsson H, Baker BS, Jónsdóttir I, Powles A, Fry L. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens?Immunol Today. 1995;16:145-149.
Villeda-Gabriel G, Santamaría-Cogollos LC, Pérez-Lorenzo R, Reyes-Maldonado E, Saúl A, Jurado-Santacruz F, Jiménez-Zamudio L, García-Latorre E. Recognition of Streptococcus pyogenes and skin autoantigens in guttate psoriasis.Arch Med Res. 1998;29:143-148.
Pérez-Lorenzo R, Zambrano-Zaragoza JF, Moo-Castillo K, Luna-Vázquez DL, Ruiz-Guillermo L, García-Latorre E. IgG class antibodies to heat shock-induced streptococcal antigens in psoriatic patients.Int J Dermatol. 2003;42:110-115.
Dogan B, Karabudak O, Harmanyeri Y. Antistreptococcal treatment of guttate psoriasis: a controlled study.Int J Dermatol. 2008;47:950-952.
Vincent F, Ross JB, Dalton M, Wort AJ. A therapeutic trial of the use of penicillin V or erythromycin with or without rifampin in the treatment of psoriasis.J Am Acad Dermatol. 1992;26:458-461.
Saxena VN, Dogra J. Long-term use of penicillin for the treatment of chronic plaque psoriasis.Eur J Dermatol. 2005;15:359-362.
Saxena VN, Dogra J. Long-term oral azithromycin in chronic plaque psoriasis: a controlled trial.Eur J Dermatol. 2010;20:329-333.
Polat M, Lenk N, Yalcin B, Gür G, Tamer E, Artuz F, Alli N. Efficacy of erythromycin for psoriasis vulgaris.Clin Exp Dermatol. 2007;32:295-297.
Komine M, Tamaki K. An open trial of oral macrolide treatment for psoriasis vulgaris.J Dermatol. 2000;27:508-512.
Owen CM, Chalmers RJ, O’Sullivan T, Griffiths CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis.Br J Dermatol. 2001;145:886-890.
Wilson JK, Al-Suwaidan SN, Krowchuk D, Feldman SR. Treatment of psoriasis in children: is there a role for antibiotic therapy and tonsillectomy?Pediatr Dermatol. 2003;20:11-15.
Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD, de Rie MA. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis.N Engl J Med. 2003;349:658-665.
Sandhu K, Kaur I, Kumar B, Saraswat A. Efficacy and safety of cyclosporine versus methotrexate in severe psoriasis: a study from north India.J Dermatol. 2003;30:458-463.
Flytström I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial.Br J Dermatol. 2008;158:116-121.
Ranjan N, Sharma NL, Shanker V, Mahajan VK, Tegta GR. Methotrexate versus hydroxycarbamide (hydroxyurea) as a weekly dose to treat moderate-to-severe chronic plaque psoriasis: a comparative study.J Dermatolog Treat. 2007;18:295-300.
Akhyani M, Chams-Davatchi C, Hemami MR, Fateh S. Efficacy and safety of mycophenolate mofetil vs. methotrexate for the treatment of chronic plaque psoriasis.J Eur Acad Dermatol Venereol. 2010;24:1447-1451.
Fallah Arani S, Neumann H, Hop WC, Thio HB. Fumarates vs. methotrexate in moderate to severe chronic plaque psoriasis: a multicentre prospective randomized controlled clinical trial.Br J Dermatol. 2011;164:855-861.
Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, Unnebrink K, Kaul M, Camez A. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).Br J Dermatol. 2008;158:558-566.
van den Reek JM, van Lümig PP, Kievit W, Zweegers J, van de Kerkhof PC, Seyger MM, de Jong EM. Effectiveness of adalimumab dose escalation, combination therapy of adalimumab with methotrexate, or both in patients with psoriasis in daily practice.J Dermatolog Treat. 2013;24:361-368.
Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, Thompson EH, Hooper M, Kricorian G. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis.Br J Dermatol. 2012;167:649-657.
Driessen RJ, van de Kerkhof PC, de Jong EM. Etanercept combined with methotrexate for high-need psoriasis.Br J Dermatol. 2008;159:460-463.
Yamauchi PS, Lowe NJ. Etanercept therapy allows the tapering of methotrexate and sustained clinical responses in patients with moderate to severe psoriasis.Int J Dermatol. 2008;47:202-204.
Strober BE. Successful treatment of psoriasis and psoriatic arthritis with etanercept and methotrexate in a patient newly unresponsive to infliximab.Arch Dermatol. 2004;140:366.
Wee JS, Petrof G, Jackson K, Barker JN, Smith CH. Infliximab for the treatment of psoriasis in the U.K.: 9 years’ experience of infusion reactions at a single centre.Br J Dermatol. 2012;167:411-416.
Baranauskaite A, Raffayová H, Kungurov NV, Kubanova A, Venalis A, Helmle L, Srinivasan S, Nasonov E, Vastesaeger N. Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study.Ann Rheum Dis. 2012;71:541-548.
Dalaker M, Bonesrønning JH. Long-term maintenance treatment of moderate-to-severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort.J Eur Acad Dermatol Venereol. 2009;23:277-282.
Reich K, Langley RG, Papp KA, Ortonne JP, Unnebrink K, Kaul M, Valdes JM. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis.N Engl J Med. 2011;365:1586-1596.
Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference.J Am Acad Dermatol. 2009;60:824-837.
Carretero G, Puig L, Dehesa L, Carrascosa JM, Ribera M, Sánchez-Regaña M, Daudén E, Vidal D, Alsina M, Muñoz-Santos C. [Guidelines on the use of methotrexate in psoriasis].Actas Dermosifiliogr. 2010;101:600-613.
Berends MA, van Oijen MG, Snoek J, van de Kerkhof PC, Drenth JP, Han van Krieken J, de Jong EM. Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens.Arch Dermatol. 2007;143:1515-1519.
Ravi Kumar BC, Kaur I, Kumar B. Topical methotrexate therapy in palmoplantar psoriasis.Indian J Dermatol Venereol Leprol. 1999;65:270-272.
Kumar B, Sandhu K, Kaur I. Topical 0.25% methotrexate gel in a hydrogel base for palmoplantar psoriasis.J Dermatol. 2004;31:798-801.
Syed TA, Hadi SM, Qureshi ZA, Nordstrom CG, Ali SM. Management of psoriasis vulgaris with methotrexate 0.25% in a hydrophilic gel: a placebo-controlled, double-blind study.J Cutan Med Surg. 2001;5:299-302.
Leavell UW, Yarbro JW. Hydroxyurea. A new treatment for psoriasis.Arch Dermatol. 1970;102:144-150.
Sharma VK, Dutta B, Ramam M. Hydroxyurea as an alternative therapy for psoriasis.Indian J Dermatol Venereol Leprol. 2004;70:13-17.
Stein KM, Shelley WB, Weinberg RA. Hydroxyurea in the treatment of pustular psoriasis.Br J Dermatol. 1971;85:81-85.
Smith CH. Use of hydroxyurea in psoriasis.Clin Exp Dermatol. 1999;24:2-6.
Hattel T, Sondergaard J. Pustulosis palmaris et plantaris treated with hydroxyurea.Acta Derm Venereol. 1974;54:152-154.
Chuah SY, Oon HHB, Theng CTS, Chong WS, Pan JY. Hydroxyurea in the treatment of severe psoriasis: a retrospective review from Singapore.Hong Kong J Dermatol Venereol. 2014;22:169-173.
Leavell UW, Mersack IP, Smith C. Survey of the treatment of psoriasis with hydroxyurea.Arch Dermatol. 1973;107:467.
Kumar B, Saraswat A, Kaur I. Rediscovering hydroxyurea: its role in recalcitrant psoriasis.Int J Dermatol. 2001;40:530-534.
Gach JE, Berth-Jones J. Successful treatment of recalcitrant psoriasis with a combination of infliximab and hydroxyurea.J Dermatolog Treat. 2003;14:226-228.
Du Vivier A, Munro DD, Verbov J. Treatment of psoriasis with azathioprine.Br Med J. 1974;1:49-51.
Greaves MW, Dawber R. Azathioprine in psoriasis.Br Med J. 1970;2:237-238.
Hacker SM, Ramos-Caro FA, Ford MJ, Flowers FP. Azathioprine: a forgotten alternative for treatment of severe psoriasis.Int J Dermatol. 1992;31:873-874.
Lee JC, Gladman DD, Schentag CT, Cook RJ. The long-term use of azathioprine in patients with psoriatic arthritis.J Clin Rheumatol. 2001;7:160-165.
Gupta R. Prolonged Remission of Psoriasis with Azathioprine Pulse Therapy.Indian J Dermatol. 2015;60:360-363.
Burnett PE. Bullous pemphigoid and psoriasis vulgaris.Dermatol Online J. 2003;9:19.
Primka EJ, Camisa C. Psoriasis and bullous pemphigoid treated with azathioprine.J Am Acad Dermatol. 1998;39:121-123.
Roeder C, Driesch PV. Psoriatic erythroderma and bullous pemphigoid treated successfully with acitretin and azathioprine.Eur J Dermatol. 1999;9:537-539.
Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients.Arch Dermatol. 1995;131:193-197.
Zackheim HS, Maibach HI. Treatment of psoriasis with 6-thioguanine.Australas J Dermatol. 1988;29:163-167.
Zackheim HS, Glogau RG, Fisher DA, Maibach HI. 6-Thioguanine treatment of psoriasis: experience in 81 patients.J Am Acad Dermatol. 1994;30:452-458.
Silvis NG, Levine N. Pulse dosing of thioguanine in recalcitrant psoriasis.Arch Dermatol. 1999;135:433-437.
Kaltwasser JP, Nash P, Gladman D, Rosen CF, Behrens F, Jones P, Wollenhaupt J, Falk FG, Mease P. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial.Arthritis Rheum. 2004;50:1939-1950.
Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatoid arthritis.Drugs. 1999;58:1137-1164.
Lee SS, Park YW, Park JJ, Kang YM, Nam EJ, Kim SI, Lee JH, Yoo WH, Lee SI. Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.Scand J Rheumatol. 2009;38:11-14.
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies.Nat Rev Cancer. 2003;3:330-338.
Tsuji T, Sugai T. Topically administered fluorouracil in psoriasis.Arch Dermatol. 1972;105:208-212.
Pearlman DL, Youngberg B, Engelhard C. Weekly pulse dosing schedule of fluorouracil: a new topical therapy for psoriasis.J Am Acad Dermatol. 1986;15:1247-1252.
Pearlman DL, Youngberg B, Engelhard C. Weekly psoriasis therapy using intralesional fluorouracil.J Am Acad Dermatol. 1987;17:78-82.
Abernethy DR, Alper JC, Wiemann MC, McDonald CJ, Calabresi P. Oral 5-fluorouracil in psoriasis: pharmacokinetic-pharmacodynamic relationships.Pharmacology. 1989;39:78-88.
Lowe NJ, Nychay S, Orenberg EK, Korey A. Intradermal fluorouracil and epinephrine injectable gel for treatment of psoriatic plaques.Arch Dermatol. 1995;131:1340-1341.
Taheri S, Asilian A, Faghihi G. Efficacy of 5-fluorouracil plus epinephrine, pulsed dye laser and betamethasone on the improvement of psoriatic plaques (a comparative study).Iranian J Dermatol. 2009;12:36-41.
Mahajan BB, Singla M. Evaluation of intralesional 5% 5-fluorouracil in resistant localized plaque psoriasis.Indian Dermatol Online J. 2014;5:287-290.
Sehgal VN, Verma P, Sharma S, Srivastava G, Aggarwal AK, Rasool F, Chatterjee K. Acrodermatitis continua of Hallopeau: evolution of treatment options.Int J Dermatol. 2011;50:1195-1211.
Ehrlich A, Booher S, Becerra Y, Borris DL, Figg WD, Turner ML, Blauvelt A. Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot study.J Am Acad Dermatol. 2004;50:533-540.
Khandavilli S, Panchagnula R. Nanoemulsions as versatile formulations for paclitaxel delivery: peroral and dermal delivery studies in rats.J Invest Dermatol. 2007;127:154-162.
Gomez EC, Menendez L, Frost P. Efficacy of mycophenolic acid for the treatment of psoriasis.J Am Acad Dermatol. 1979;1:531-537.
Grundmann-Kollmann M, Mooser G, Schraeder P, Zollner T, Kaskel P, Ochsendorf F, Boehncke WH, Kerscher M, Kaufmann R, Peter RU. Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil.J Am Acad Dermatol. 2000;42:835-837.
Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients.Br J Dermatol. 2001;144:583-586.
Zhou Y, Rosenthal D, Dutz J, Ho V. Mycophenolate mofetil (CellCept) for psoriasis: a two-center, prospective, open-label clinical trial.J Cutan Med Surg. 2003;7:193-197.
Fallah Arani S, Waalboer Spuij R, Nijsten T, Neumann HA, Thio B. Enteric-coated mycophenolate sodium in psoriasis vulgaris: an open pilot study.J Dermatolog Treat. 2014;25:46-49.
Beissert S, Pauser S, Sticherling M, Frieling U, Loske KD, Frosch PJ, Haase I, Luger TA. A comparison of mycophenolate mofetil with ciclosporine for the treatment of chronic plaque-type psoriasis.Dermatology. 2009;219:126-132.
Davison SC, Morris-Jones R, Powles AV, Fry L. Change of treatment from cyclosporin to mycophenolate mofetil in severe psoriasis.Br J Dermatol. 2000;143:405-407.
Wohlrab J, Jahn K, Plaetzer M, Neubert R, Marsch WC. Topical application of mycophenolate mofetil in plaque-type psoriasis.Br J Dermatol. 2001;144:1263-1264.
Ameen M, Smith HR, Barker JN. Combined mycophenolate mofetil and cyclosporin therapy for severe recalcitrant psoriasis.Clin Exp Dermatol. 2001;26:480-483.
Rallis E, Anyfantakis V. Coexistent psoriasis and bullous pemphigoid responding to mycophenolate mofetil monotherapy.Skinmed. 2008;7:101-102.
Forman SB, Higginson R, Garrett AB. Psoriasis and psoriatic arthritis in a patient with HIV: response to mycophenolate mofetil treatment.J Drugs Dermatol. 2008;7:972-973.
Kaltenborn A, Schrem H. Mycophenolate mofetil in liver transplantation: a review.Ann Transplant. 2013;18:685-696.
Epinette WW, Parker CM, Jones EL, Greist MC. Mycophenolic acid for psoriasis. A review of pharmacology, long-term efficacy, and safety.J Am Acad Dermatol. 1987;17:962-971.
van de Kerkhof PC. Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology.Dermatol Ther. 2006;19:252-263.
Arechalde A, Saurat JH. Management of psoriasis: the position of retinoid drugs.BioDrugs. 2000;13:327-333.
Lebwohl M, Drake L, Menter A, Koo J, Gottlieb AB, Zanolli M, Young M, McClelland P. Consensus conference: acitretin in combination with UVB or PUVA in the treatment of psoriasis.J Am Acad Dermatol. 2001;45:544-553.
Lebwohl M, Menter A, Koo J, Feldman SR. Combination therapy to treat moderate to severe psoriasis.J Am Acad Dermatol. 2004;50:416-430.
Heinecke GM, Luber AJ, Levitt JO, Lebwohl MG. Combination use of ustekinumab with other systemic therapies: a retrospective study in a tertiary referral center.J Drugs Dermatol. 2013;12:1098-1102.
Strober BE, Clarke S. Etanercept for the treatment of psoriasis: combination therapy with other modalities.J Drugs Dermatol. 2004;3:270-272.
Langewouters AM, Van Erp PE, De Jong EM, Van De Kerkhof PC. The added therapeutic efficacy and safety of alefacept in combination with other (systemic) anti-psoriatics in refractory psoriasis.J Dermatolog Treat. 2006;17:362-369.
Krueger GG, Gottlieb AB, Sterry W, Korman N, Van De Kerkhof P. A multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis.J Dermatolog Treat. 2008;19:146-155.
Conley J, Nanton J, Dhawan S, Pearce DJ, Feldman SR. Novel combination regimens: biologics and acitretin for the treatment of psoriasis-- a case series.J Dermatolog Treat. 2006;17:86-89.
Adişen E, Karaca F, Gürer MA. When there is no single best biological agent: psoriasis and psoriatic arthritis in the same patient responding to two different biological agents.Clin Exp Dermatol. 2008;33:164-166.
Smith EC, Riddle C, Menter MA, Lebwohl M. Combining systemic retinoids with biologic agents for moderate to severe psoriasis.Int J Dermatol. 2008;47:514-518.
Gisondi P, Girolomoni G. Combination of efalizumab and acitretin in chronic plaque psoriasis.J Eur Acad Dermatol Venereol. 2008;22:247-248.
Ingram JR, Anstey AV, Piguet V. Combination treatment with a tumour necrosis factor antagonist and an oral retinoid: efficacy in severe acral psoriasis?Br J Dermatol. 2012;167:949-951.
Gallo E, Llamas-Velasco M, Daudén E, García-Diez A. Refractory generalized pustular psoriasis responsive to a combination of adalimumab and acitretin.Int J Dermatol. 2013;52:1610-1611.
Li W, Liu Y, Luo Q, Li XM, Zhang XB. Off-label uses of retinoids in dermatology.Our Dermatol Online. 2012;3:S259-278.
Hotard RS, Feldman SR, Fleischer AB. Sex-specific differences in the treatment of severe psoriasis.J Am Acad Dermatol. 2000;42:620-623.
Sofen HL, Moy RL, Lowe NJ. Treatment of generalised pustular psoriasis with isotretinoin.Lancet. 1984;1:40.
Moy RL, Kingston TP, Lowe NJ. Isotretinoin vs etretinate therapy in generalized pustular and chronic psoriasis.Arch Dermatol. 1985;121:1297-1301.
Fry L. Psoriasis.Br J Dermatol. 1988;119:445-461.
Griffiths CE, Clark CM, Chalmers RJ, Li Wan Po A, Williams HC. A systematic review of treatments for severe psoriasis.Health Technol Assess. 2000;4:1-125.
Al-Shobaili H, Al-Khenaizan S. Childhood generalized pustular psoriasis: successful treatment with isotretinoin.Pediatr Dermatol. 2007;24:563-564.
Marhold I, Duschet P, Schwarz T, Gschnait F. Successful use of isotretinoin in type Zumbusch generalized pustular psoriasis following recovered etretinate-induced hepatitis.Hautarzt. 1991;42:580-583.
Vahlquist A, Lööf L, Nordlinder H, Rollman O, Vahlquist C. Differential hepatotoxicity of two oral retinoids (etretinate and isotretinoin) in a patient with palmoplantar psoriasis.Acta Derm Venereol. 1985;65:359-362.
Wiegand UW, Chou RC. Pharmacokinetics of oral isotretinoin.J Am Acad Dermatol. 1998;39:S8-12.
Gollnick HP. Oral retinoids--efficacy and toxicity in psoriasis.Br J Dermatol. 1996;135 Suppl 49:6-17.
Halverstam CP, Lebwohl M. Nonstandard and off-label therapies for psoriasis.Clin Dermatol. 2008;26:546-553.
Gahalaut P, Soodan PS, Mishra N, Rastogi MK, Soodan HS, Chauhan S. Clinical efficacy of psoralen + sunlight vs. combination of isotretinoin and psoralen + sunlight for the treatment of chronic plaque-type psoriasis vulgaris: a randomized hospital-based study.Photodermatol Photoimmunol Photomed. 2014;30:294-301.
Abhinav C, Mahajan VK, Mehta KS, Chauhan PS, Gupta M. Weekly methotrexate versus daily isotretinoin to treat moderate-to-severe chronic plaque psoriasis: a comparative study.Our Dermatol Online J. 2015;6:392-398.
Hersh JH, Danhauer DE, Hand ME, Weisskopf B. Retinoic acid embryopathy: timing of exposure and effects on fetal development.JAMA. 1985;254:909-910.
Lee SM, Kim HM, Lee JS, Yoon CS, Park MS, Park KI, Namgung R, Lee C. A case of suspected isotretinoin-induced malformation in a baby of a mother who became pregnant one month after discontinuation of the drug.Yonsei Med J. 2009;50:445-447.
Rademaker M. Adverse effects of isotretinoin: A retrospective review of 1743 patients started on isotretinoin.Australas J Dermatol. 2010;51:248-253.
Crockett SD, Gulati A, Sandler RS, Kappelman MD. A causal association between isotretinoin and inflammatory bowel disease has yet to be established.Am J Gastroenterol. 2009;104:2387-2393.
Krueger GG, Drake LA, Elias PM, Lowe NJ, Guzzo C, Weinstein GD, Lew-Kaya DA, Lue JC, Sefton J, Chandraratna RA. The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis.Arch Dermatol. 1998;134:57-60.
Weinstein GD, Koo JY, Krueger GG, Lebwohl MG, Lowe NJ, Menter MA, Lew-Kaya DA, Sefton J, Gibson JR, Walker PS. Tazarotene cream in the treatment of psoriasis: Two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks.J Am Acad Dermatol. 2003;48:760-767.
Koo J, Behnam SE, Behnam SM. The efficacy of topical tazarotene monotherapy and combination therapies in psoriasis.Expert Opin Pharmacother. 2003;4:2347-2354.
Guenther LC, Poulin YP, Pariser DM. A comparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene 0.005% ointment twice daily in the treatment of plaque psoriasis.Clin Ther. 2000;22:1225-1238.
Angelo JS, Kar BR, Thomas J. Comparison of clinical efficacy of topical tazarotene 0.1% cream with topical clobetasol propionate 0.05% cream in chronic plaque psoriasis: a double-blind, randomized, right-left comparison study.Indian J Dermatol Venereol Leprol. 2007;73:65.
Lebwohl M, Ast E, Callen JP, Cullen SI, Hong SR, Kulp-Shorten CL, Lowe NJ, Phillips TJ, Rosen T, Wolf DI. Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis.J Am Acad Dermatol. 1998;38:705-711.
Smit JV, Franssen ME, de Jong EM, Lambert J, Roseeuw DI, De Weert J, Yocum RC, Stevens VJ, van De Kerkhof PC. A phase II multicenter clinical trial of systemic bexarotene in psoriasis.J Am Acad Dermatol. 2004;51:249-256.
Smit JV, de Jong EM, van Hooijdonk CA, Otero ME, Boezeman JB, van de Kerkhof PC. Systemic treatment of psoriatic patients with bexarotene decreases epidermal proliferation and parameters for inflammation, and improves differentiation in lesional skin.J Am Acad Dermatol. 2004;51:257-264.
Breneman D, Sheth P, Berger V, Naini V, Stevens V. Phase II clinical trial of bexarotene gel 1% in psoriasis.J Drugs Dermatol. 2007;6:501-506.
Irla N, Navarini AA, Yawalkar N. Alitretinoin abrogates innate inflammation in palmoplantar pustular psoriasis.Br J Dermatol. 2012;167:1170-1174.
Meyer V, Goerge T, Luger TA, Beissert S. Successful treatment of palmoplantar hyperkeratotic psoriasis with a combination of etanercept and alitretinoin.J Clin Aesthet Dermatol. 2011;4:45-46.
Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths CE. Oral liarozole in the treatment of palmoplantar pustular psoriasis: a randomized, double-blind, placebo-controlled study.Br J Dermatol. 2001;145:546-553.
Berth-Jones J, Todd G, Hutchinson PE, Thestrup-Pedersen K, Vanhoutte FP. Treatment of psoriasis with oral liarozole: a dose-ranging study.Br J Dermatol. 2000;143:1170-1176.
Verfaille CJ, Thissen CA, Bovenschen HJ, Mertens J, Steijlen PM, van de Kerkhof PC. Oral R115866 in the treatment of moderate to severe plaque-type psoriasis.J Eur Acad Dermatol Venereol. 2007;21:1038-1046.
Geria AN, Scheinfeld NS. Talarozole, a selective inhibitor of P450-mediated all-trans retinoic acid for the treatment of psoriasis and acne.Curr Opin Investig Drugs. 2008;9:1228-1237.
Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference.Br J Dermatol. 1999;141:424-429.
Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, Barker J, Bos JD, Burmester GR, Chimenti S. European S3-guidelines on the systemic treatment of psoriasis vulgaris.J Eur Acad Dermatol Venereol. 2009;23 Suppl 2:1-70.
Treumer F, Zhu K, Gläser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells.J Invest Dermatol. 2003;121:1383-1388.
Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity.Trends Mol Med. 2005;11:43-48.
Kolbach DN, Nieboer C. Fumaric acid therapy in psoriasis: results and side effects of 2 years of treatment.J Am Acad Dermatol. 1992;27:769-771.
Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, Wassilew SW, Horn T, Kreysel HW, Lutz G. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients.J Am Acad Dermatol. 1994;30:977-981.
Altmeyer P, Hartwig R, Matthes U. Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients.Hautarzt. 1996;47:190-196.
Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study.Br J Dermatol. 1998;138:456-460.
Litjens NH, Nibbering PH, Barrois AJ, Zomerdijk TP, Van Den Oudenrijn AC, Noz KC, Rademaker M, Van De Meide PH, Van Dissel JT, Thio B. Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines.Br J Dermatol. 2003;148:444-451.
Carboni I, De Felice C, De Simoni I, Soda R, Chimenti S. Fumaric acid esters in the treatment of psoriasis: an Italian experience.J Dermatolog Treat. 2004;15:23-26.
Brewer L, Rogers S. Fumaric acid esters in the management of severe psoriasis.Clin Exp Dermatol. 2007;32:246-249.
Kokelj F, Plozzer C, Avian A, Trevisan G. Fumaric acid and its derivatives in the treatment of psoriasis vulgaris: our experience in forty-one patients.Acta Dermatovenerol Croat. 2009;17:170-175.
Reich K, Thaci D, Mrowietz U, Kamps A, Neureither M, Luger T. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis--a retrospective study (FUTURE).J Dtsch Dermatol Ges. 2009;7:603-611.
Wain EM, Darling MI, Pleass RD, Barker JN, Smith CH. Treatment of severe, recalcitrant, chronic plaque psoriasis with fumaric acid esters: a prospective study.Br J Dermatol. 2010;162:427-434.
Peeters AJ, Dijkmans BA, van der Schroeff JG. Fumaric acid therapy for psoriatic arthritis. A randomized, double-blind, placebo-controlled study.Br J Rheumatol. 1992;31:502-504.
Vlachou C, Berth-Jones J. Nail psoriasis improvement in a patient treated with fumaric acid esters.J Dermatolog Treat. 2007;18:175-177.
Ständer H, Stadelmann A, Luger T, Traupe H. Efficacy of fumaric acid ester monotherapy in psoriasis pustulosa palmoplantaris.Br J Dermatol. 2003;149:220-222.
Gollnick H, Altmeyer P, Kaufmann R, Ring J, Christophers E, Pavel S, Ziegler J. Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.Dermatology. 2002;205:46-53.
Balasubramaniam P, Stevenson O, Berth-Jones J. Fumaric acid esters in severe psoriasis, including experience of use in combination with other systemic modalities.Br J Dermatol. 2004;150:741-746.
Skaria AM, Schmid U. Antipsoriatic effect of fumaric acid derivates.J Am Acad Dermatol. 1996;34:323-324.
Friedrich M, Sterry W, Klein A, Rückert R, Döcke WD, Asadullah K. Addition of pentoxifylline could reduce the side effects of fumaric acid esters in the treatment of psoriasis.Acta Derm Venereol. 2001;81:429-430.
Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid.N Engl J Med. 2013;368:1657-1658.
van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy.N Engl J Med. 2013;368:1658-1659.
Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis.Br J Dermatol. 2003;149:363-369.
Raschka C, Koch HJ. Longterm treatment of psoriasis using fumaric acid preparations can be associated with severe proximal tubular damage.Hum Exp Toxicol. 1999;18:738-739.
Ogilvie S, Lewis Jones S, Dawe R, Foerster J. Proteinuria with fumaric acid ester treatment for psoriasis.Clin Exp Dermatol. 2011;36:632-634.
Ho VC, Griffiths CE, Berth-Jones J, Papp KA, Vanaclocha F, Dauden E, Beard A, Puvanarajan L, Paul C. Intermittent short courses of cyclosporine microemulsion for the long-term management of psoriasis: a 2-year cohort study.J Am Acad Dermatol. 2001;44:643-651.
Berth-Jones J, Henderson CA, Munro CS, Rogers S, Chalmers RJ, Boffa MJ, Norris PG, Friedmann PS, Graham-Brown RA, Dowd PM. Treatment of psoriasis with intermittent short course cyclosporin (Neoral). A multicentre study.Br J Dermatol. 1997;136:527-530.
Mahé E, Bodemer C, Pruszkowski A, Teillac-Hamel D, de Prost Y. Cyclosporine in childhood psoriasis.Arch Dermatol. 2001;137:1532-1533.
Perrett CM, Ilchyshyn A, Berth-Jones J. Cyclosporin in childhood psoriasis.J Dermatolog Treat. 2003;14:113-118.
Dadlani C, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporine, and etanercept: review of the dermatologic and rheumatologic literature.J Am Acad Dermatol. 2005;52:316-340.
Paul CF, Ho VC, McGeown C, Christophers E, Schmidtmann B, Guillaume JC, Lamarque V, Dubertret L. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study.J Invest Dermatol. 2003;120:211-216.
Bissonnette R, Papp K, Poulin Y, Lauzon G, Aspeslet L, Huizinga R, Mayo P, Foster RT, Yatscoff RW, Maksymowych WP. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis.J Am Acad Dermatol. 2006;54:472-478.
Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506)--a new therapeutic agent for severe recalcitrant psoriasis.Arch Dermatol. 1992;128:781-785.
Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebo-controlled study. The European FK 506 Multicentre Psoriasis Study Group.Arch Dermatol. 1996;132:419-423.
Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Greig G, Kehren J, Chibout SD, Cordier A, Holter W. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated.J Invest Dermatol. 2002;119:876-887.
Gottlieb AB, Griffiths CE, Ho VC, Lahfa M, Mrowietz U, Murrell DF, Ortonne JP, Todd G, Cherill R, Marks I. Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial.Br J Dermatol. 2005;152:1219-1227.
Mrowietz U, Wustlich S, Hoexter G, Graeber M, Bräutigam M, Luger T. An experimental ointment formulation of pimecrolimus is effective in psoriasis without occlusion.Acta Derm Venereol. 2003;83:351-353.
Yamamoto T, Nishioka K. Topical tacrolimus: an effective therapy for facial psoriasis.Eur J Dermatol. 2003;13:471-473.
Freeman AK, Linowski GJ, Brady C, Lind L, Vanveldhuisen P, Singer G, Lebwohl M. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas.J Am Acad Dermatol. 2003;48:564-568.
Lebwohl M, Freeman AK, Chapman MS, Feldman SR, Hartle JE, Henning A. Tacrolimus ointment is effective for facial and intertriginous psoriasis.J Am Acad Dermatol. 2004;51:723-730.
Martín Ezquerra G, Sánchez Regaña M, Herrera Acosta E, Umbert Millet P. Topical tacrolimus for the treatment of psoriasis on the face, genitalia, intertriginous areas and corporal plaques.J Drugs Dermatol. 2006;5:334-336.
Gribetz C, Ling M, Lebwohl M, Pariser D, Draelos Z, Gottlieb AB, Zaias N, Chen DM, Parneix-Spake A, Hultsch T. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study.J Am Acad Dermatol. 2004;51:731-738.
Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI. Tacrolimus ointment improves psoriasis in a microplaque assay.Br J Dermatol. 1999;141:103-107.
Brune A, Miller DW, Lin P, Cotrim-Russi D, Paller AS. Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pediatric patients.Pediatr Dermatol. 2007;24:76-80.
Zonneveld IM, Rubins A, Jablonska S, Dobozy A, Ruzicka T, Kind P, Dubertret L, Bos JD. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study.Arch Dermatol. 1998;134:1101-1102.
Carroll CL, Clarke J, Camacho F, Balkrishnan R, Feldman SR. Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment.Arch Dermatol. 2005;141:43-46.
Tirado-Sánchez A, Ponce-Olivera RM. Preliminary study of the efficacy and tolerability of combination therapy with calcipotriene ointment 0.005% and tacrolimus ointment 0.1% in the treatment of stable plaque psoriasis.Cutis. 2012;90:140-144.
Mrowietz U, Graeber M, Bräutigam M, Thurston M, Wagenaar A, Weidinger G, Christophers E. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion.Br J Dermatol. 1998;139:992-996.
Erdogan M, Wright JR, McAlister VC. Liposomal tacrolimus lotion as a novel topical agent for treatment of immune-mediated skin disorders: experimental studies in a murine model.Br J Dermatol. 2002;146:964-967.
Lapteva M, Mondon K, Möller M, Gurny R, Kalia YN. Polymeric micelle nanocarriers for the cutaneous delivery of tacrolimus: a targeted approach for the treatment of psoriasis.Mol Pharm. 2014;11:2989-3001.
Ständer S, Ständer H, Seeliger S, Luger TA, Steinhoff M. Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin.Br J Dermatol. 2007;156:1020-1026.
Koo JY, Fleischer AB, Abramovits W, Pariser DM, McCall CO, Horn TD, Gottlieb AB, Jaracz E, Rico MJ. Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: results in 8000 patients.J Am Acad Dermatol. 2005;53:S195-S205.
Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ. Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis.J Am Acad Dermatol. 2005;53:S186-S194.
Montagner A, Wahli W. Contributions of peroxisome proliferator-activated receptor β/δ to skin health and disease.Biomol Concepts. 2013;4:53-64.
Romanowska M, Reilly L, Palmer CN, Gustafsson MC, Foerster J. Activation of PPARbeta/delta causes a psoriasis-like skin disease in vivo.PLoS One. 2010;5:e9701.
Hack K, Reilly L, Palmer C, Read KD, Norval S, Kime R, Booth K, Foerster J. Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.PLoS One. 2012;7:e37097.
Marx N, Kehrle B, Kohlhammer K, Grüb M, Koenig W, Hombach V, Libby P, Plutzky J. PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis.Circ Res. 2002;90:703-710.
Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators.Circulation. 2000;101:235-238.
Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo.J Biol Chem. 1999;274:9116-9121.
Shafiq N, Malhotra S, Pandhi P, Gupta M, Kumar B, Sandhu K. Pilot trial: Pioglitazone versus placebo in patients with plaque psoriasis (the P6).Int J Dermatol. 2005;44:328-333.
Bongartz T, Coras B, Vogt T, Schölmerich J, Müller-Ladner U. Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study.Rheumatology (Oxford). 2005;44:126-129.
Lajevardi V, Hallaji Z, Daklan S, Abedini R, Goodarzi A, Abdolreza M. The efficacy of methotrexate plus pioglitazone vs. methotrexate alone in the management of patients with plaque-type psoriasis: a single-blinded randomized controlled trial.Int J Dermatol. 2015;54:95-101.
Mittal R, Malhotra S, Pandhi P, Kaur I, Dogra S. Efficacy and safety of combination Acitretin and Pioglitazone therapy in patients with moderate to severe chronic plaque-type psoriasis: a randomized, double-blind, placebo-controlled clinical trial.Arch Dermatol. 2009;145:387-393.
Ellis CN, Varani J, Fisher GJ, Zeigler ME, Pershadsingh HA, Benson SC, Chi Y, Kurtz TW. Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.Arch Dermatol. 2000;136:609-616.
Pershadsingh HA, Sproul JA, Benjamin E, Finnegan J, Amin NM. Treatment of psoriasis with troglitazone therapy.Arch Dermatol. 1998;134:1304-1305.
Ellis CN, Barker JN, Haig AE, Parker CA, Daly S, Jayawardene DA. Placebo response in two long-term randomized psoriasis studies that were negative for rosiglitazone.Am J Clin Dermatol. 2007;8:93-102.
Itoh S, Kanazuka A, Akimoto T. Combined treatment with ursodeoxycholic acid and pioglitazone in a patient with NASH associated with type 2 diabetes and psoriasis.Dig Dis Sci. 2003;48:2182-2186.
Kuenzli S, Saurat JH. Effect of topical PPARbeta/delta and PPARgamma agonists on plaque psoriasis. A pilot study.Dermatology. 2003;206:252-256.
Kim TG, Byamba D, Wu WH, Lee MG. Statins inhibit chemotactic interaction between CCL20 and CCR6 in vitro: possible relevance to psoriasis treatment.Exp Dermatol. 2011;20:855-857.
Hilgendorff A, Muth H, Parviz B, Staubitz A, Haberbosch W, Tillmanns H, Hölschermann H. Statins differ in their ability to block NF-kappaB activation in human blood monocytes.Int J Clin Pharmacol Ther. 2003;41:397-401.
Brauser D. Statins added to standard psoriasis therapy may improve disease severity. American Academy of Dermatology (AAD) 68th Annual Meeting: Abstract P3309. Presented on March 7 2010; .
Brauchli YB, Jick SS, Meier CR. Statin use and risk of first-time psoriasis diagnosis.J Am Acad Dermatol. 2011;65:77-83.
Faghihi T, Radfar M, Mehrabian Z, Ehsani AH, Rezaei Hemami M. Atorvastatin for the treatment of plaque-type psoriasis.Pharmacotherapy. 2011;31:1045-1050.
Ghazizadeh R, Tosa M, Ghazizadeh M. Clinical improvement in psoriasis with treatment of associated hyperlipidemia.Am J Med Sci. 2011;341:394-398.
Naseri M, Hadipour A, Sepaskhah M, Namazi MR. The remarkable beneficial effect of adding oral simvastatin to topical betamethasone for treatment of psoriasis: a double-blind, randomized, placebo-controlled study.Niger J Med. 2010;19:58-61.
Shirinsky IV, Shirinsky VS. Efficacy of simvastatin in plaque psoriasis: A pilot study.J Am Acad Dermatol. 2007;57:529-531.
Chodick G, Weitzman D, Shalev V, Weil C, Amital H. Adherence to statins and the risk of psoriasis: a population-based cohort study.Br J Dermatol. 2015;173:480-487.
Cozzani E, Scaparro M, Parodi A. A case of psoriasis worsened by atorvastatin.J Dermatol Case Rep. 2009;3:60-61.
Jacobi TC, Highet A. A clinical dilemma while treating hypercholesterolaemia in psoriasis.Br J Dermatol. 2003;149:1305-1306.
Yamamoto M, Ikeda M, Kodama H, Sano S. Transition of psoriasiform drug eruption to psoriasis de novo evidenced by histopathology.J Dermatol. 2008;35:732-736.
Iraji F, Tajmirriahi N, Siadat AH, Momeni I, Nilforoushzadeh MA. Efficacy of adding topical simvastatin to topical calcipotriol on improvement of cutaneous plaque psoriasis.Adv Biomed Res. 2014;3:11.
Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease.Cochrane Database Syst Rev. 2013;1:CD004816.
Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions.Circulation. 2004;109:III50-III57.
Halasz CL. Sulfasalazine as folic acid inhibitor in psoriasis.Arch Dermatol. 1990;126:1516-1517.
Gupta AK, Ellis CN, Siegel MT, Duell EA, Griffiths CE, Hamilton TA, Nickoloff BJ, Voorhees JJ. Sulfasalazine improves psoriasis. A double-blind analysis.Arch Dermatol. 1990;126:487-493.
Gupta AK, Grober JS, Hamilton TA, Ellis CN, Siegel MT, Voorhees JJ, McCune WJ. Sulfasalazine therapy for psoriatic arthritis: a double blind, placebo controlled trial.J Rheumatol. 1995;22:894-898.
Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, Budiman-Mak E, Blackburn WD, Vasey FB, Mahowald ML. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.Arthritis Rheum. 1996;39:2013-2020.
Dougados M, vam der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin R, Veys E, Zeidler H, Kvien TK, Olivieri I, Dijkmans B. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study.Arthritis Rheum. 1995;38:618-627.
Farr M, Kitas GD, Waterhouse L, Jubb R, Felix-Davies D, Bacon PA. Sulphasalazine in psoriatic arthritis: a double-blind placebo-controlled study.Br J Rheumatol. 1990;29:46-49.
el-Mofty M, el-Darouti M, Rasheed H, Bassiouny DA, Abdel-Halim M, Zaki NS, el-Hanafy G, el-Hadidi H, Azzam O, el-Ramly A. Sulfasalazine and pentoxifylline in psoriasis: a possible safe alternative.J Dermatolog Treat. 2011;22:31-37.
Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study.Arthritis Rheum. 1999;42:2325-2329.
Rahman P, Gladman DD, Cook RJ, Zhou Y, Young G. The use of sulfasalazine in psoriatic arthritis: a clinic experience.J Rheumatol. 1998;25:1957-1961.
Watkinson G. Sulphasalazine: a review of 40 years’ experience.Drugs. 1986;32 Suppl 1:1-11.
Fraser SM, Hopkins R, Hunter JA, Neumann V, Capell HA, Bird HA. Sulphasalazine in the management of psoriatic arthritis.Br J Rheumatol. 1993;32:923-925.
Salvarani C, Macchioni P, Olivieri I, Marchesoni A, Cutolo M, Ferraccioli G, Cantini F, Salaffi F, Padula A, Lovino C. A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis.J Rheumatol. 2001;28:2274-2282.
Combe B, Goupille P, Kuntz JL, Tebib J, Lioté F, Bregeon C. Sulphasalazine in psoriatic arthritis: a randomized, multicentre, placebo-controlled study.Br J Rheumatol. 1996;35:664-668.
Wahba A, Cohen H. Therapeutic trials with oral colchicine in psoriasis.Acta Derm Venereol. 1980;60:515-520.
McKendry RJ, Kraag G, Seigel S, al-Awadhi A. Therapeutic value of colchicine in the treatment of patients with psoriatic arthritis.Ann Rheum Dis. 1993;52:826-828.
Seideman P, Fjellner B, Johannesson A. Psoriatic arthritis treated with oral colchicine.J Rheumatol. 1987;14:777-779.
Zachariae H, Kragballe K, Herlin T. Colchicine in generalized pustular psoriasis: clinical response and antibody-dependent cytotoxicity by monocytes and neutrophils.Arch Dermatol Res. 1982;274:327-333.
Wong SS, Tan KC, Goh CL. Long-term colchicine for recalcitrant palmoplantar pustulosis: treatment outcome in 3 patients.Cutis. 2001;68:216-218.
Takigawa M, Miyachi Y, Uehara M, Tagami H. Treatment of pustulosis palmaris et plantaris with oral doses of colchicine.Arch Dermatol. 1982;118:458-460.
Thestrup-Pedersen K, Reymann F. Treatment of pustulosis palmaris et plantaris with colchicine. A double-blind cross-over trial.Acta Derm Venereol. 1984;64:76-78.
Juanqin G, Zhiqiang C, Zijia H. Evaluation of the effectiveness of childhood generalized pustular psoriasis treatment in 30 cases.Pediatr Dermatol. 1998;15:144-146.
Mazzatenta C, Martini P, Luti L, Domenici R. Diffuse sterile pustular eruption with changing clinical features in a 2-year old.Pediatr Dermatol. 2005;22:250-253.
Guglielmetti A, Conlledo R, Bedoya J, Ianiszewski F, Correa J. Inverse psoriasis involving genital skin folds: successful therapy with dapsone.Dermatol Ther (Heidelb). 2012;2:15.
Zargari O. Pentoxifylline: a drug with wide spectrum applications in dermatology.Dermatol Online J. 2008;14:2.
Bruynzeel I, Stoof TJ, Willemze R. Pentoxifylline and skin inflammation.Clin Exp Dermatol. 1998;23:168-172.
Çakmak SK, Çakmak A, Gönül M, Kiliç A, Gül Ü. Pentoxifylline use in dermatology.Inflamm Allergy Drug Targets. 2012;11:422-432.
Gilhar A, Grossman N, Kahanovicz S, Reuveni H, Cohen S, Eitan A. Antiproliferative effect of pentoxifylline on psoriatic and normal epidermis. In vitro and in vivo studies.Acta Derm Venereol. 1996;76:437-441.
Magela Magalhães G, Coelho da Silva Carneiro S, Peisino do Amaral K, de Freire Cássia F, Machado-Pinto J, Cuzzi T. Psoriasis and pentoxifylline: a clinical, histopathologic, and immunohistochemical evaluation.Skinmed. 2006;5:278-284.
Shifow AA, Naidu MU, Kumar KV, Prayag A, Ratnakar KS. Effect of pentoxifylline on cyclosporine-induced nephrotoxicity in rats.Indian J Exp Biol. 2000;38:347-352.
Tanetsakunwatana T, Tovanabutra N, Kanchanarattanakorn K, Chiewchanvit S. Pentoxifylline as add-on therapy in the treatment of moderate to severe psoriasis.Chiang Mai Medical J. 2013;52:43-50.
van Weelden H, De La Faille HB, Young E, van der Leun JC. A new development in UVB phototherapy of psoriasis.Br J Dermatol. 1988;119:11-19.
Green C, Ferguson J, Lakshmipathi T, Johnson BE. 311 nm UVB phototherapy--an effective treatment for psoriasis.Br J Dermatol. 1988;119:691-696.
Coven TR, Burack LH, Gilleaudeau R, Keogh M, Ozawa M, Krueger JG. Narrowband UV-B produces superior clinical and histopathological resolution of moderate-to-severe psoriasis in patients compared with broadband UV-B.Arch Dermatol. 1997;133:1514-1522.
Tanew A, Radakovic-Fijan S, Schemper M, Hönigsmann H. Narrowband UV-B phototherapy vs photochemotherapy in the treatment of chronic plaque-type psoriasis: a paired comparison study.Arch Dermatol. 1999;135:519-524.
Yones SS, Palmer RA, Garibaldinos TT, Hawk JL. Randomized double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralen-UV-A therapy vs narrowband UV-B therapy.Arch Dermatol. 2006;142:836-842.
Gordon PM, Diffey BL, Matthews JN, Farr PM. A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis.J Am Acad Dermatol. 1999;41:728-732.
Iest J, Boer J. Combined treatment of psoriasis with acitretin and UVB phototherapy compared with acitretin alone and UVB alone.Br J Dermatol. 1989;120:665-670.
Green C, Lakshmipathi T, Johnson BE, Ferguson J. A comparison of the efficacy and relapse rates of narrowband UVB (TL-01) monotherapy vs. etretinate (re-TL-01) vs. etretinate-PUVA (re-PUVA) in the treatment of psoriasis patients.Br J Dermatol. 1992;127:5-9.
Ozdemir M, Engin B, Baysal I, Mevlitoğlu I. A randomized comparison of acitretin-narrow-band TL-01 phototherapy and acitretin-psoralen plus ultraviolet A for psoriasis.Acta Derm Venereol. 2008;88:589-593.
Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy.J Am Acad Dermatol. 2001;45:487-498; quiz 499-502.
Momtaz-T K, Parrish JA. Combination of psoralens and ultraviolet A and ultraviolet B in the treatment of psoriasis vulgaris: a bilateral comparison study.J Am Acad Dermatol. 1984;10:481-486.
Radakovic-Fijan S, Blecha-Thalhammer U, Schleyer V, Szeimies RM, Zwingers T, Hönigsmann H, Tanew A. Topical aminolaevulinic acid-based photodynamic therapy as a treatment option for psoriasis? Results of a randomized, observer-blinded study.Br J Dermatol. 2005;152:279-283.
Schleyer V, Radakovic-Fijan S, Karrer S, Zwingers T, Tanew A, Landthaler M, Szeimies RM. Disappointing results and low tolerability of photodynamic therapy with topical 5-aminolaevulinic acid in psoriasis. A randomized, double-blind phase I/II study.J Eur Acad Dermatol Venereol. 2006;20:823-828.
Vahlquist C, Larsson M, Ernerudh J, Berlin G, Skogh T, Vahlquist A. Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralen-ultraviolet A irradiation.Arthritis Rheum. 1996;39:1519-1523.
Wilfert H, Hönigsmann H, Steiner G, Smolen J, Wolff K. Treatment of psoriatic arthritis by extracorporeal photochemotherapy.Br J Dermatol. 1990;122:225-232.
Lindelöf B. Grenz ray therapy in dermatology. An experimental, clinical and epidemiological study.Acta Derm Venereol Suppl (Stockh). 1987;132:1-67.
Johannesson A, Lindelöf B. The effect of grenz rays on psoriasis lesions of the scalp: a double blind bilateral trial.Photodermatol. 1985;2:388-391.
Johannesson A, Lindelöf B. Additional effect of grenz rays on psoriasis lesions of the scalp treated with topical corticosteroids.Dermatologica. 1987;175:290-292.
Lindelöf B, Johannesson A. Psoriasis of the scalp treated with Grenz rays or topical corticosteroid combined with Grenz rays. A comparative randomized trial.Br J Dermatol. 1988;119:241-244.
Lindelöf B, Johannesson A. Treatment of scalp psoriasis with topical selenium sulphide alone or in combination with Grenz rays.J Dermatol Treatment. 1991;2:47-49.
Lindelöf B, Beitner H. The effect of grenz ray therapy on pustulosis palmoplantaris. A double-blind bilateral trial.Acta Derm Venereol. 1990;70:529-531.
Lindelöf B. Psoriasis of the nails treated with grenz rays: a double-blind bilateral trial.Acta Derm Venereol. 1989;69:80-82.
Lindelöf B, Eklund G. Incidence of malignant skin tumors in 14,140 patients after grenz-ray treatment for benign skin disorders.Arch Dermatol. 1986;122:1391-1395.
Kemény L, Bónis B, Dobozy A, Bor Z, Szabó G, Ignácz F. 308-nm excimer laser therapy for psoriasis.Arch Dermatol. 2001;137:95-96.
Asawanonda P, Anderson RR, Chang Y, Taylor CR. 308-nm excimer laser for the treatment of psoriasis: a dose-response study.Arch Dermatol. 2000;136:619-624.
Taibjee SM, Cheung ST, Laube S, Lanigan SW. Controlled study of excimer and pulsed dye lasers in the treatment of psoriasis.Br J Dermatol. 2005;153:960-966.
Cohen AD, Shapiro J, Michael D, Hodak E, Van-Dijk D, Naggan L, Vardy DA. Outcome of “short-term” Dead Sea climatotherapy for psoriasis.Acta Derm Venereol. 2008;88:90-91.
Cohen AD, Van-Dijk D, Naggan L, Vardy DA. Effectiveness of climatotherapy at the Dead Sea for psoriasis vulgaris: A community-oriented study introducing the ‘Beer Sheva Psoriasis Severity Score’.J Dermatolog Treat. 2005;16:308-313.
Hodak E, Gottlieb AB, Segal T, Politi Y, Maron L, Sulkes J, David M. Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: combined effects on epidermal and immunologic activation.J Am Acad Dermatol. 2003;49:451-457.
Shani J, Harari M, Hristakieva E, Seidl V, Bar-Giyora J. Dead-Sea climatotherapy versus other modalities of treatment for psoriasis: comparative cost-effectiveness.Int J Dermatol. 1999;38:252-262.
Harari M, Novack L, Barth J, David M, Friger M, Moses SW. The percentage of patients achieving PASI 75 after 1 month and remission time after climatotherapy at the Dead Sea.Int J Dermatol. 2007;46:1087-1091.
Wahl AK, Mørk C, Cooper BA, Padilla G. No long-term changes in psoriasis severity and quality of life following climate therapy.J Am Acad Dermatol. 2005;52:699-701.
Halevy S, Sukenik S. Different modalities of spa therapy for skin diseases at the Dead Sea area.Arch Dermatol. 1998;134:1416-1420.
Elkayam O, Ophir J, Brener S, Paran D, Wigler I, Efron D, Even-Paz Z, Politi Y, Yaron M. Immediate and delayed effects of treatment at the Dead Sea in patients with psoriatic arthritis.Rheumatol Int. 2000;19:77-82.
Sukenik S, Giryes H, Halevy S, Neumann L, Flusser D, Buskila D. Treatment of psoriatic arthritis at the Dead Sea.J Rheumatol. 1994;21:1305-1309.
Shiri J, Amichai B, Grunwald MH. Re-climatotherapy: a combination of acitretin and climatotherapy at the Dead Sea.J Am Acad Dermatol. 2005;52:541-542.
Ben-Amitai D, David M. Climatotherapy at the dead sea for pediatric-onset psoriasis vulgaris.Pediatr Dermatol. 2009;26:103-104.
Gambichler T, Altmeyer P, Hoffmann K. Cost-effectiveness of Dead-Sea climatotherapy and balneophototherapy of psoriasis.Int J Dermatol. 2001;40:158-159.
Gambichler T, Küster W, Kreuter A, Altmeyer P, Hoffmann K. Balneophototherapy-combined treatment of psoriasis vulgaris and atopic dermatitis with salt water baths and artificial ultraviolet radiation.J Eur Acad Dermatol Venereol. 2000;14:425-428.
Even-Paz Z, Gumon R, Kipnis V, Abels D, Efron D. Dead Sea sun versus Dead Sea water in the treatment of psoriasis.J Dermatolog Treat. 1996;7:83-86.
David M, Tsukrov B, Adler B, Hershko K, Pavlotski F, Rozenman D, Hodak E, Paltiel O. Actinic damage among patients with psoriasis treated by climatotherapy at the Dead Sea.J Am Acad Dermatol. 2005;52:445-450.
McEvoy J, Kelly AM. Psoriatic clearance during haemodialysis.Ulster Med J. 1976;45:76-78.
Twardowski ZJ. Abatement of psoriasis and repeated dialysis.Ann intern Med. 1977;86:509-510.
Twardowski ZJ, Nolph KD, Rubin J, Anderson PC. Peritoneal dialysis for psoriasis. An uncontrolled study.Ann Intern Med. 1978;88:349-351.
Glinski W, Zarebska Z, Jabłonska S, Imiela J, Nosarzewski J. The activity of polymorphonuclear leukocyte neutral proteinases and their inhibitors in patients with psoriasis treated with a continuous peritoneal dialysis.J Invest Dermatol. 1980;75:481-487.
Halevy S, Halevy J, Boner G, Rosenfeld JB, Feuerman EJ. Dialysis therapy for psoriasis. Report of three cases and review of the literature.Arch Dermatol. 1981;117:69-72.
Anderson PC. Dialysis treatment of psoriasis.Arch Dermatol. 1981;117:67-68.
Twardowski ZJ, Lempert KD, Lankhorst BJ, Welton WA, Whittier FC, Anderson PC, Nolph KD, Khanna R, Prowant BF, Schmidt LM. Continuous ambulatory peritoneal dialysis for psoriasis. A report of four cases.Arch Intern Med. 1986;146:1177-1179.
Whittier FC, Evans DH, Anderson PC, Nolph KD. Peritoneal dialysis for psoriasis: a controlled study.Ann Intern Med. 1983;99:165-168.
Sobh MA, Abdel Rasik MM, Moustafa FE, el-Sharabasy MM, Rezk RA, el-Shamy SI. Dialysis therapy of severe psoriasis: a random study of forty cases.Nephrol Dial Transplant. 1987;2:351-358.
Nissenson AR, Rapaport M, Gordon A, Narins RG. Hemodialysis in the treatment of psoriasis. A controlled trial.Ann Intern Med. 1979;91:218-220.
Kuruvila M, Mathew T, Sugathan P, Nair LV. Effect of dialysis on psoriasis : A clinical study.Indian J Dermatol Venereol Leprol. 1998;64:146-149.
Llewellyn M, Nethercott JR, Bear RA. Peritoneal dialysis in the treatment of psoriasis.Can Med Assoc J. 1980;122:13-14.
Wan J, Wang S, Haynes K, Denburg MR, Shin DB, Gelfand JM. Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study.BMJ. 2013;347:f5961.
Triga K, Dousdampanis P, Aggelakou-Vaitis S, Gellner K. New-onset psoriasis in a maintenance hemodialysis patient.Hemodial Int. 2012;16:109-112.
Geerse DA, Suijkerbuijk J, van Poppelen KM, Litjens EJ, Cornelis T. New-onset psoriasis during peritoneal dialysis.Perit Dial Int. 2014;34:802-803.
Yamamoto T, Yokozeki H, Nishioka K. Psoriasis under haemodialysis.J Eur Acad Dermatol Venereol. 2006;20:1139-1140.
Steck WD, Nakamoto S, Bailin PL, Paganini E, Chang K, Becker JM, Matkaluk RM, Vidt DG. Hemofiltration treatment of psoriasis.J Am Acad Dermatol. 1982;6:346-349.
Jupe DM, Nightingale RF. Leukapheresis for the treatment of psoriasis.Arch Dermatol. 1983;119:629-630.
Gliński W, Barszcz D, Jabłońska S, Zarebska Z, Tigałonowa M, Janczura E. Leukopheresis for treatment of psoriasis: is therapeutical benefit related to reduced activities of neutral proteinases of polymorphonuclear leukocytes?Arch Dermatol Res. 1985;278:6-12.
Buselmeier TJ, Cantieri JS, Dahl MV, Nelson RS, Baumgaertner JC, Bentley CR, Goltz RW. Clearing of psoriasis after cardiac surgery requiring cardiopulmonary bypass oxygenation: a corollary to clearance after dialysis?Br J Dermatol. 1979;100:311-313.
Maeda K, Shinzato T, Naotsuka M, Usuda M, Sezaki R, Niwa T, Kawaguchi S, Saito A, Yamanaka N, Ohta K. Plasma exchange for treatment of intractable psoriasis.Artif Organs. 1983;7:450-453.
Liedén G, Skogh M. Plasma exchange and leukapheresis in psoriasis--no effect?Arch Dermatol Res. 1986;278:437-440.
Guillot B. Extracorporeal systems for the treatment of psoriasis.Plasma Therapy and Transfusion Technology. 1987;8:143-146.
Wolf R, Feuerman FJ. Failure of osmotic diuresis as therapy for psoriasis.Arch Dermatol. 1983;119:95.
Saita B, Ishii Y, Ogata K, Inoue S, Naritomi K. [Two sisters with guttate psoriasis responsive to tonsillectomy: case reports with HLA studies (author’s transl)].Nihon Hifuka Gakkai Zasshi. 1979;89:339-343.
McMillin BD, Maddern BR, Graham WR. A role for tonsillectomy in the treatment of psoriasis?Ear Nose Throat J. 1999;78:155-158.
Hone SW, Donnelly MJ, Powell F, Blayney AW. Clearance of recalcitrant psoriasis after tonsillectomy.Clin Otolaryngol Allied Sci. 1996;21:546-547.
Thorleifsdottir RH, Sigurdardottir SL, Sigurgeirsson B, Olafsson JH, Sigurdsson MI, Petersen H, Arnadottir S, Gudjonsson JE, Johnston A, Valdimarsson H. Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants.J Immunol. 2012;188:5160-5165.
Nyfors A, Rasmussen PA, Lemholt K, Eriksen B. Improvement of recalcitrant psoriasis vulgaris after tonsillectomy.J Laryngol Otol. 1976;90:789-794.
Rachakonda TD, Dhillon JS, Florek AG, Armstrong AW. Effect of tonsillectomy on psoriasis: a systematic review.J Am Acad Dermatol. 2015;72:261-275.
Ozawa A, Ohkido M, Haruki Y, Kobayashi H, Ohkawara A, Ohno Y, Inaba Y, Ogawa H. Treatments of generalized pustular psoriasis: a multicenter study in Japan.J Dermatol. 1999;26:141-149.
Yokoyama M, Hashigucci K, Yamasaki Y. Effect of tonsillectomy in patients with pustulosis palmaris et plantaris.Acta Otolaryngol. 2004;124:1109-1110.
Takahara M, Kishibe K, Nozawa H, Harabuchi Y. Increase of activated T-cells and up-regulation of Smad7 without elevation of TGF-beta expression in tonsils from patients with pustulosis palmaris et plantaris.Clin Immunol. 2005;115:192-199.
Tsuboi H, Katsuoka K. Pustulosis palmaris et plantaris with prominent hyperkeratosis of the soles.J Dermatol. 2006;33:892-895.
Noda K, Kodama S, Suenaga S, Suzuki M. Tonsillar focal infectious disease involving IgA nephropathy, pustulosis, and ossification.Clin Exp Nephrol. 2007;11:97-101.
Yoshizaki T, Bandoh N, Ueda S, Nozawa H, Goto T, Kishibe K, Takahara M, Harabuchi Y. Up-regulation of CC chemokine receptor 6 on tonsillar T cells and its induction by in vitro stimulation with alpha-streptococci in patients with pustulosis palmaris et plantaris.Clin Exp Immunol. 2009;157:71-82.
Ueda S, Takahara M, Tohtani T, Yoshizaki T, Kishibe K, Harabuchi Y. Up-regulation of ß1 integrin on tonsillar T cells and its induction by in vitro stimulation with α-streptococci in patients with pustulosis Palmaris et Plantaris.J Clin Immunol. 2010;30:861-871.
Takahara M. Clinical outcome of tonsillectomy for palmoplantar pustulosis and etiological relationship between palmoplantar pustulosis and tonsils.Adv Otorhinolaryngol. 2011;72:86-88.
Wu W, Debbaneh M, Moslehi H, Koo J, Liao W. Tonsillectomy as a treatment for psoriasis: a review.J Dermatolog Treat. 2014;25:482-486.
Hoddeson EK, Gourin CG. Adult tonsillectomy: current indications and outcomes.Otolaryngol Head Neck Surg. 2009;140:19-22.
Sayili M, Akca H, Duman T, Esengun K. Psoriasis treatment via doctor fishes as part of health tourism: a case study of Kangal Fish Spring.School of Tourism and Hotel Management. 2007;28:625-629.
Kürkçüoğlu N, Oz G. Psoriasis and the doctor fish.Lancet. 1989;2:1394.
Undar L, Akpinar MA, Yanikoglu A. “Doctor fish” and psoriasis.Lancet. 1990;335:470-471.
Ozçelik S, Polat HH, Akyol M, Yalçin AN, Ozçelik D, Marufihah M. Kangal hot spring with fish and psoriasis treatment.J Dermatol. 2000;27:386-390.
Grassberger M, Hoch W. Ichthyotherapy as alternative treatment for patients with psoriasis: a pilot study.Evid Based Complement Alternat Med. 2006;3:483-488.
Verner-Jeffreys DW, Baker-Austin C, Pond MJ, Rimmer GS, Kerr R, Stone D, Griffin R, White P, Stinton N, Denham K. Zoonotic disease pathogens in fish used for pedicure.Emerg Infect Dis. 2012;18:1006-1008.
Scott LJ, Dunn CJ, Goa KL. Calcipotriol ointment. A review of its use in the management of psoriasis.Am J Clin Dermatol. 2001;2:95-120.
Cullen SI. Long-term effectiveness and safety of topical calcipotriene for psoriasis. Calcipotriene Study Group.South Med J. 1996;89:1053-1056.
Ellis JP, Griffiths WAD, Klaber MR. Long term treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short contact dithranol.Eur J Clin Res. 1995;7:247-257.
Poyner T, Hughes IW, Dass BK, Adnitt PI. Long-term treatment of chronic plaque psoriasis with calcipotriol.J Dermatolog Treat. 1993;4:173-177.
Ramsay CA, Berth-Jones J, Brundin G, Cunliffe WJ, Dubertret L, van de Kerkhof PC, Menne T, Wegmann E. Long-term use of topical calcipotriol in chronic plaque psoriasis.Dermatology. 1994;189:260-264.
Lebwohl M, Menter A, Weiss J, Clark SD, Flores J, Powers J, Balin AK, Kempers S, Glinert RJ, Fleming T. Calcitriol 3 microg/g ointment in the management of mild to moderate plaque type psoriasis: results from 2 placebo-controlled, multicenter, randomized double-blind, clinical studies.J Drugs Dermatol. 2007;6:428-435.
Lecha M, Mirada A, López S, Artés M. Tacalcitol in the treatment of psoriasis vulgaris: the Spanish experience.J Eur Acad Dermatol Venereol. 2005;19:414-417.
Lambert J, Trompke C. Tacalcitol ointment for long-term control of chronic plaque psoriasis in dermatological practice.Dermatology. 2002;204:321-324.
van de Kerkhof PC, Berth-Jones J, Griffiths CE, Harrison PV, Hönigsmann H, Marks R, Roelandts R, Schöpf E, Trompke C. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis.Br J Dermatol. 2002;146:414-422.
Márquez Balbás G, Sánchez Regaña M, Umbert Millet P. Tacalcitol ointment for the treatment of nail psoriasis.J Dermatolog Treat. 2009;20:308-310.
Ruzicka T, Trompke C. Treatment of scalp psoriasis. An effective and safe tacalcitol emulsion.Hautarzt. 2004;55:165-170.
Ashcroft DM, Po AL, Williams HC, Griffiths CE. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis.BMJ. 2000;320:963-967.
Cunliffe WJ, Berth-Jones J, Claudy A, Fairiss G, Goldin D, Gratton D, Henderson CA, Holden CA, Maddin WS, Ortonne JP. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris.J Am Acad Dermatol. 1992;26:736-743.
Giannotti B, Carli P, Varotti C, Neri I. Treatment of psoriasis with calcipotriol: time of onset and healing relapses.Eur J Dermatol. 1997;7:275-278.
Highton A, Quell J. Calcipotriene ointment 0.005% for psoriasis: a safety and efficacy study. Calcipotriene Study Group.J Am Acad Dermatol. 1995;32:67-72.
Katz HI. Combined topical calcipotriene ointment 0.005% and various systemic therapies in the treatment of plaque-type psoriasis vulgaris: review of the literature and results of a survey sent to 100 dermatologists.J Am Acad Dermatol. 1997;37:S62-S68.
Mortensen L, Kragballe K, Wegmann E, Schifter S, Risteli J, Charles P. Treatment of psoriasis vulgaris with topical calcipotriol has no short-term effect on calcium or bone metabolism. A randomized, double-blind, placebo-controlled study.Acta Derm Venereol. 1993;73:300-304.
Berth-Jones J, Bourke JF, Iqbal SJ, Hutchinson PE. Urine calcium excretion during treatment of psoriasis with topical calcipotriol.Br J Dermatol. 1993;129:411-414.
Gumowski-Sunek D, Rizzoli R, Saurat JH. Effects of topical calcipotriol on calcium metabolism in psoriatic patients: comparison with oral calcitriol.Dermatologica. 1991;183:275-279.
Bourke JF, Mumford R, Whittaker P, Iqbal SJ, Le Van LW, Trevellyan A, Hutchinson PE. The effects of topical calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis.J Am Acad Dermatol. 1997;37:929-934.
Topical calcipotriol and hypercalcaemia. Lancet. 1991;337:1287-1288.
Warnecke J, Wendt A. Anti-inflammatory action of pale sulfonated shale oil (ICHTHYOL pale) in UVB erythema test.Inflamm Res. 1998;47:75-78.
Schmid MH, Korting HC. Coal tar, pine tar and sulfonated shale oil preparations: comparative activity, efficacy and safety.Dermatology. 1996;193:1-5.
Man M, Wang F. Treatment of psoriasis with aminophylline.Int J Dermatol. 1992;31:370-371.
Golchai J, Kishavars D. Treatment of psoriasis with topical aminophylline.Int J Dermatol. 1994;33:885.
Mease PJ. Apremilast: A phosphodiesterase 4 inhibitor for the treatment of psoriatic arthritis.Rheumatol Ther. 2014;1:1-20.
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, Hu C, Stevens RM, Day RM, Gordon KB. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1).J Am Acad Dermatol. 2015;73:37-49.
Marcusson JA, Talme T, Wetterberg L, Johansson O. Peptide T a new treatment for psoriasis? A study of nine patients.Acta Derm Venereol. 1991;71:479-483.
Overbeck TR, Griesinger F. Two cases of psoriasis responding to erlotinib: time to revisiting inhibition of epidermal growth factor receptor in psoriasis therapy?Dermatology. 2012;225:179-182.
Baroni A, Paoletti I, Greco R, Satriano RA, Ruocco E, Tufano MA, Perez JJ. Immunomodulatory effects of a set of amygdalin analogues on human keratinocyte cells.Exp Dermatol. 2005;14:854-859.
Keshtgarpour M, Dudek AZ. SU-011248, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, controls chronic psoriasis.Transl Res. 2007;149:103-106.
Norman P. BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857.Expert Opin Ther Pat. 2009;19:1165-1168.
Skvara H, Dawid M, Kleyn E, Wolff B, Meingassner JG, Knight H, Dumortier T, Kopp T, Fallahi N, Stary G. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis.J Clin Invest. 2008;118:3151-3159.
Raychaudhuri SP, Sanyal M, Weltman H, Kundu-Raychaudhuri S. K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: an in vivo study using the severe combined immunodeficient mouse-human skin model.J Invest Dermatol. 2004;122:812-819.
Smith N, Weymann A, Tausk FA, Gelfand JM. Complementary and alternative medicine for psoriasis: a qualitative review of the clinical trial literature.J Am Acad Dermatol. 2009;61:841-856.
Balagon MV, Walsh DS, Tan PL, Cellona RV, Abalos RM, Tan EV, Fajardo TT, Watson JD, Walsh GP. Improvement in psoriasis after intradermal administration of heat-killed Mycobacterium vaccae.Int J Dermatol. 2000;39:51-58.
Rath N, Kar HK. Efficacy of intradermal heat-killed Mycobacterium w in psoriasis: a pilot study.Int J Dermatol. 2003;42:756-757.
Cather JC, Cather JC, Abramovits W. Investigational therapies for psoriasis.J Am Acad Dermatol. 2003;49:S133-S138.
Cuevas P, Sanchez I, Lozano RM, Gimenez-Gallego G. Dobesilate is an angiogenesis inhibitor.Eur J Med Res. 2005;10:369-372.
Cuevas P, Arrazola JM. Dobesilate in the treatment of plaque psoriasis.Eur J Med Res. 2005;10:373-376.
Puri N, Puri A. A study on topical calcium dobesilate for the treatment of limited plaque psoriasis.Our Dermatol Online. 2013;4:290-293.
Sauder DN, Dekoven J, Champagne P, Croteau D, Dupont E. Neovastat (AE-941), an inhibitor of angiogenesis: Randomized phase I/II clinical trial results in patients with plaque psoriasis.J Am Acad Dermatol. 2002;47:535-541.