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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2006 February 14;12(6):843-852

 

Cutaneous manifestations in celiac disease

 

L Abenavoli, I Proietti, L Leggio, A Ferrulli, L Vonghia, R Capizzi, M Rotoli, PL Amerio, G Gasbarrini, G Addolorato

 

 


 

 

L Abenavoli, L Leggio, A Ferrulli, L Vonghia, G Gasbarrini, G Addolorato, Institute of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy

I Proietti, R Capizzi, M Rotoli, PL Amerio, Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy

Correspondence to: Giovanni Addolorato, MD, Institute of Internal Medicine, Catholic University, L.go Gemelli 8, 00168 Rome, Italy. g.addolorato@rm.unicatt.it

Telephone: +39-06-30154334               Fax: +39-06-35502775

Received: 2005-05-06                     Accepted: 2005-07-28

  

Abstract

Celiac disease (CD) is an autoimmune gluten-dependent enteropathy characterized by atrophy of intestinal villi that improves after gluten-free diet (GFD). CD is often associated with extra-intestinal manifestations; among them, several skin diseases are described in CD patients. The present review reports all CD-associated skin manifestations described in the literature and tries to analyze the possible mechanisms involved in this association. The opportunity to evaluate the possible presence of CD in patients affected by skin disorders is discussed.

 

© 2006 The WJG Press. All rights reserved.

 

Key words: Celiac disease; Dermatological disease; AGA; EmA; TTG

 

Abenavoli L, Proietti I, Leggio L, Ferrulli A, Vonghia L, Capizzi R, Rotoli M, Amerio PL, Gasbarrini G, Addolorato G. Cutaneous manifestations in celiac disease. World J Gastroenterol 2006; 12(6): 843-852 

 http://www.wjgnet.com/1007-9327/12/843.asp 

 

INTRODUCTION

Celiac disease (CD) can be defined as a chronic immune-mediated gluten-dependent enteropathy, resulting from an inappropriate T-cell-mediated immune response, against ingested gluten in genetically predisposed people[1]. Epidemiological studies have shown that CD is very common and affects about 1 in 250 people[2]. CD is a multigenic disorder associated with HLA-DQ2 (DQA1*/DQB1*2) expressed in more than 90% of patients, or HLA-DQ8 (DQA1*0301/DQB1*0302)[3]. The expression of these molecules is necessary, but not sufficient, to develop the disease[4]. The immune response to gluten takes place in two compartments: the lamina propria and the epithelium. While lamina propria CD4 T cells have a recognized role in the pathogenesis of CD, the role of CD8 T cells in the intestinal epithelium is controversial[5].

CD is characterized by intestinal malabsorption and subtotal or total atrophy of intestinal villi which improves after gluten-free diet (GFD)[6]. The classic form of CD presents several symptoms such as diarrhea, abdominal pain, weight loss and nutritional deficiencies, particularly of iron, folate, calcium, and vitamin D[7]. However, there is a large variety of clinical presentations characterized by the presence of extra-intestinal manifestations, including anemia[8], persistent hypertransaminasemia[9], osteopenia[10], neurological[11], psychiatric and affective disorders[12-14], features of hyposplenism (Howell-Jolly bodies and thrombocytosis)[15] and autoimmune diseases[6]. In the last years, growing evidence has documented the involvement of skin diseases among the extra-intestinal manifestations of CD[17]. The aim of this review is to report all CD associated skin manifestations described in the English literature and to analyze the possible mechanisms involved in this association.

 

Dermatitis herpetiformis

Dermatitis herpetiformis (DH) is a well-described entity, presenting as an itchy, chronic, papulovesicular eruption which may leave pigmentation and scarring[18]. Classically, skin lesions are characterized by a symmetrical eruption on the extensor surfaces of the body such as the knees, elbows, buttocks, and back. DH tends to occur more in the adult male (M/F ratio 2:1) who may also present with the involvement of oral and genital membranes. However this pattern is reversed in children who may simply have purpura over the palmar surfaces. The age of onset varies with geographical location and the incidence is highest in Ireland and Sweden and rare in Asia[19]. Histology of lesional skin shows micro abscesses consisting of neutrophils and eosinophils within the dermal papillae. Sub-epidermal vesicles and bullae are produced within the lamina lucida as a result of collagen degradation. Furthermore there is an increased number of activated T cells. Direct immunofluorescence of the normal skin shows the pathogenomic granular IgA deposits in the papillary dermis but the exact target antigen is still unknown[19-21]. These deposits are often associated with C3 to support the suggestion that the complement is activated via the alternative pathway and C5[22,23]. The activated fraction, C5a, is highly chemotactic for neutrophils and may contribute to the inflammatory change at the papillary tip.

HLA studies in patients, who have DH based on clinical and immunological criteria, have shown that 85-90% are HLA B8-positive and that there is an even stronger association with HLA DW3 and DRW3. Interestingly, patients with a GSE without DH show a similar high incidence of these antigens[24]. Specific B cell/macrophage antigens have been noted in patients with DH and the gluten-sensitive enteropathy[25]. Family studies have shown that these B cell antigens segregated independently of HLA antigens[26]. One hypothesis is that both HLA and non-HLA disease genes are necessary for the development of lymphoid cell surface receptors that recognize gluten.

Antigluten, antiendomysium, antigliadin and tissue transglutaminase antibodies have been detected in patients with DH[27-29]. These gluten-specific cells migrate to the gut mucosa where they mediate cytotoxic reactions involving the epithelial cells[30]. There is an immunogenetic association with HLA DR3 DQW2 (HLA class II alleles DQAI 0501 and DQBI 0201), which is very much more common in Caucasians than in Orientals and may be important for the different incidences of DH in different ethnic populations. Gluten must be present in the diet for the development of DH; however, a genetic susceptibility to gluten has been proposed as an etiological mechanism. This observation could explain why DH is very common in some Asian populations, which have a low daily gluten intake (e.g., 7-8 g/d in Korea) compared with Western populations which have higher daily gluten intake (e.g., 15-20 g/d in Scandinavia)[19].

As CD and DH may seem to be vastly different, they both share a unique intestinal sensitivity to gluten, with the rash of DH thought to be an external marker of the underlying intestinal sensitivity that is likely to be the result of molecular mimicry between the auto antigen tissue transglutaminase resident in the gut and the skin derived epidermal transglutaminase.

Although patients with DH are unlikely to have gastrointestinal symptoms or features of malabsorption, they have small intestinal histopathologic changes, with either a classical atrophic appearance with complete villous atrophy, or more commonly a more subtle infiltrative pattern with partial or no villous atrophy. When there is a suspicion of DH with a negative skin biopsy but serologic evidence of CD, a skin biopsy should be repeated given the patchy nature of the lesions, and referral to a gastroenterologist for small bowel biopsy should be pursued. Interestingly, topical skin application of gluten-containing products does not produce the rash of DH in susceptible patients; however, oral or rectal introduction of gluten has been found to result in the classic DH rash[31,32].

The DH rash is often treated with dapsone in conjunction with the gluten withdrawal. In addition to improving the histological changes of the small intestine, the gluten-free diet may also allow a reduction of suppressive medication[32]. Just as patients with CD are at a higher risk of malignancies such as lymphomas, so are those patients with DH not compliant with GFD, which should motivate patients with DH to follow the diet regardless of the absence of other symptoms[31].

 

Linear IgA bullous dermatosis

Linear IgA bullous dermatosis (LABD) is a rare disease characterized by erythematous papules or groups of small vesicles. The onset may be acute or gradual and the predominant symptom is usually pruritus. Immunoelectron microscopic studies have shown a linear deposition of IgA along the lamina lucida or in the sub-basal lamina area of stratified squamous epithelium[32]. At the moment, it is considered as a distinct entity from DH and Bullous pemphigoid[32,33]. The incidence of gluten sensitivity enteropathy (GSE) in LABD has been described in the literature to range from 0% to 24%[33-36]. The HLA haplotype (A1, B8, DR3) of LABD patients is often that found in classic DH which is in >85% of CD patients[37,38]. Although the prevalence of CD is low in LABD, some authors have suggested a diagnosis of GSE in these patients[34-36,39].

 

Urticaria

Urticaria is an eruption of transient erythematous or edematous swellings of the dermis or sub-cutaneous tissue and is due to a local increase of permeability of capillaries and small venules. Hautekeete et al[40] first described the association between CD and chronic urticaria, although this association is still debated[41]. Adults with CD also often have an increase of atopic or immunologic disorders[42,43]. Scala et al reported that a GFD eliminated both skin and intestinal symptoms in patients with concomitant CD and chronic urticaria[44]. The passage of antigens and immune-complex formation may be facilitated by an increased mucosal permeability. Theoretically, this mechanism might cause urticarial lesions and so, by restoring the integrity of the mucosa, a gluten-free diet might resolve skin symptomatology.

 

Hereditary angioneurotic edema

Hereditary angioneurotic edema (HANE) is characterized by recurrent edematous attacks in the sub-cutis and sub-mucous due to C1-esterase inhibitor (C1-INH) deficiency[45]. Brickman et al[46,47] described HANE in association with inflammatory bowel diseases (IBD). In 2002, Farkas et al[48] first described the simultaneous occurrence of HANE and CD. The classic activation pathway of the complement system plays a potential role in the immune regulation of both disorders: it is deficient in HANE and gluten is a potent activator of the alternative pathway in CD[49]. There might also be a genetically determined etiology of both diseases[50]. Complement testing is justified whenever the GI symptoms of CD persist despite restoration of damaged mucous. Conversely HANE unresponsive to adequate prophylaxis should prompt for complete GI group tests[48].

 

Cutaneous vasculitis

CD may give rise to many skin manifestations but vasculitic skin lesions have rarely been encountered[51,52]. Leucocytoclastic vasculitis is characterized by the involvement of postcapillary venules. The skin is the most common organ involved with the usual clinical appearance of a palpable purpura. In most cases, leucocytoclastic vasculitis is mediated by immunocomplex deposition and the antigen being either exogenous or endogenous[53]. The coexistence of cutaneous vasculitis and CD might be related to increased intestinal permeability[54], and immune complexes, originating from exogenous or endogenous antigens, might circulate because of the impaired phagocytic function of reticular endothelium system and be deposited in the skin[55]. As in inflammatory bowel disease (IBD), exogenous antigens may permeate the damaged CD mucous in larger quantities than normal[54,56]. This is reflected by significant serum milk and gluten fraction antibody titers[57,58]. Alternatively, an autoimmune sensitization may result because of the release of endogenous antigens from damaged small bowel mucosa[59]. Meyers et al[60] described a case of cutaneous vasculitis complicating CD and the remission of skin lesions after the treatment with a strict GFD. Treatment of leucocytoclastic vasculitis has generally been difficult, but corticosteroids and a gluten-free diet may improve the dermatosis in cases associated with CD[52].

 

Erythema nodosum

Erythema nodosum (EN) is a chronic panniculitis characterized by inflammation of the fat septa and its etiology seems to involve an allergic or immune complex-mediated reaction to many antigens. Triggers include infections, sarcoidosis, adverse drug reaction, IBD, and lymphomas[61]. EN generally resolves in 5-8 weeks but if antigenic stimulus persists, the disease may last for a long period[62]. In 1991, Durand et al first observed a causal linkage between CD and EN[63]. CD can be a triggering factor of EN because an altered intestinal permeability to endogenous or exogenous antigens may provoke the immunologic response. EN is also a common finding in sarcoidosis which frequently coincides with CD[62-65]. When EN skin lesions are chronically recurrent or persistent, it is advisable to search for an underlying CD even if it is difficult to estimate the true incidence of the coexistence of both diseases.

 

Erythema elevatum diutinum

Erythema elevatum diutinum (EED) is a rare variation of cutaneous leucocytoclastic vasculitis, originally described in 1894[66]. Its lesions appear as soft erythematous papule-plaques and become hard nodules mainly symmetrically affecting the backs of the hands and other extensor surfaces overlying the joints[67]. Ulceration, arthralgia and pain can be other features of this disease[67,68]. Even if it is presumed to be an immune reaction by bacterial antigens, the etiology of EED is unknown[69]. EED has been described in association with several other immunological diseases, especially paraproteinemias (i.e., monoclonal IgA gammopathy)[70]. Tasanen et al[70] detected dermo-epidermal IgA and complement deposits in lesional skin of a patient affected by CD; the histopathology was suggestive of EED[71]. The EED skin lesions appear to result from an immune complex reaction, as suggested by the association of various infections or autoimmune diseases. Joint pains are often present in patients affected by autoimmune disease such as EED but are also often found in association with CD[72]. Some authors have therefore suggested that it is important to warrant consideration of underlying CD in at least some patients with EED[71-73].

 

Necrolytic migratory erythema

The features of necrolytic migratory erythema (NME) have been reviewed by several authors. Becker et al[74] first described a cutaneous reaction pattern with specific histopathologic features in association with a pancreatic islet cell carcinoma. NME is a term used by Wilkinson[75] to describe the characteristic skin disease related with glucagonoma. Typically lesions start with figurate areas of erythema followed by erosions mainly over the trunk, perineum, lower extremities and perioral area. Eventual shedding is caused by superficial necrosis[76]. Most patients have angular cheilitis, stomatitis, glossitis, diffuse alopecia and brittle nails. Gastrointestinal symptoms such as weight loss and diarrhea are common[77]. Most cases of NME were part of the glucagonoma syndrome[76-77]. NME occasionally occurs with chronic liver disease or malabsorption with villous atrophy[78,79]. Kelly et al[80], Goodenberg et al[79] and Thorisdottir et al[81] described the association between CD and NME. The etiology of NME is uncertain, although deficiencies of zinc, amino acids, or essentially fatty acids could play an important role[77,78,82,83]. It must be stressed that in CD patients with NME, this latter disorder seems to have an excellent response to GFD[79,81].

 

Psoriasis

Psoriasis is a chronic, relapsing dermatosis characterized by scaling, erythema, and less commonly pustulation[84]. It has been demonstrated that psoriasis is an immunological disease with hyperproliferation of T-cell mediated keratocytes[85]. Recent data indicate that HLA-Cw*0602 may play an important pathogenetic role in the majority of psoriasis patients[86]. Immune mechanisms have an important role in the pathogenesis of this disease. In particular, an overexpression of T helper cell type 1 (Th1) cytokines and a relative under-expression of Th 2 cytokines have been shown in psoriatic patients[87]. The treatment is often difficult; all currently available effective remedies are retinoids or immunosuppressant drugs such as steroids or cyclosporin[84], other than topical treatment[88], photochemotherapy (PUVA)[89] and biological treatment such as infliximab or etanercept[90]. Recent studies have showed an association between CD and psoriasis[91,92,93] and an improvement of skin lesions after 3-6 mo of GFD, without other pharmacological approaches, was described[91]. However at present the relationship between CD and psoriasis remains controversial since there are few data on this topic and other authors sustain that this association seems to be coincidental[94].

In one study, 10 out of 32 (31%) subjects affected by different clinical forms of psoriasis had positive antireticulin antibodies with a variability of titers, related to the extent of the disease[95]. Subsequently, in a first screening study conducted by Michaelsson et al[96] 16% of 302 subjects with psoriasis had IgA and/or IgG AGA. Only in 1 of 11 IgA AGA-positive patients from this group screened for antibodies to reticulin/EMA was this positive. An increase of EG2-positive eosinophils in duodenal mucosa associated with elevated serum levels of eosinophil cation protein (ECP) has been documented in psoriatic subjects with AGA, but no tendency to higher ECP values has been detected in those with AGA[97]. The same authors reported that the increase in the number of eosinophils in the gastrointestinal tract is explained as being part of some unknown process that may be related to the development of skin psoriatic lesions. Cardinali and co-workers[92] performed a study to verify whether gluten intolerance is more frequent in Mediterranean subjects with psoriasis than in healthy controls. The sera of 39 psoriatic patients and 39 controls were screened for AGA, EMA, antibodies anti-transglutaminase (TgA), ECP, serum total IgE levels and number of eosinophils. The results showed positivity for IgG AGA in two psoriatic patients, one borderline for TgA, and none was positive for EMA or IgA AGA. In these subjects the authors found high serum levels of ECP and IgE, but a normal number of eosinophils; on the contrary eosinophil count and serum IgE levels were within the normal range in the controls. Michaelsson et al[91] evaluated the effect of GFD in 33 AGA positive patients and six AGA negative patients with psoriasis in an open study. Of the 33 AGA-positive patients, 2 had IgA EMA, and at the duodenal biopsy 15 showed an increased number of lymphocytes in the epithelium, but in some this increase was only slight. GFD was for 3 mo. Thirty out of thirty-three patients strictly complied with GFD, after which they showed a significant decrease of psoriatic lesions. This included a significant decrease in the 16 AGA positive patients with normal routine histology in duodenal biopsy. The AGA negative patients did not improve. There was also a significant decrease in the serum of eosinophil cation protein in patients with elevated AGA. In conclusion, the positive effects of GFD were observed not only in patients with an increased number of lymphocytes in the duodenal epithelium, but also in some patients with seemingly normal epithelium[91,98].

Our group recently reported a case of severe psoriasis in a CD patient, not responding to specific therapies for psoriasis and in whom the regression of skin lesions after GFD was very rapid[99,100]. The association between psoriasis and CD was subsequently confirmed by Ojetti et al[101]. The authors evaluated the prevalence of CD in patients affected by psoriasis, showing a high frequency of CD (4.34%) in psoriatic patients.

At present the mechanisms implicated in the possible association between CD and psoriasis, and the effect of GFD on psoriatic skin lesions are not known. There are some hypotheses:

Hypothesis 1: Abnormal small intestinal permeability, frequently present both in psoriasis[102] and  in CD patients[103], could be a triggering factor between CD and psoriasis.

Hypothesis 2: T cells play an important role in the pathogenesis of both psoriasis and CD. An increased number of T cells in the blood, in the dermis and in the epidermis of psoriatic patients has been documented[87]. In CD patients, gliadin induces a sensitization of T cells[104] and this may play a role in the pathogenesis of psoriatic skin lesions[99].

Hypothesis 3: Psoriatic lesions in CD patients could be related to vitamin D deficiency, which is present both in CD[105] and in psoriasis[106-107].

 

Vitiligo disease

Vitiligo is a specific, common, often heritable acquired disorder characterized by well-circumscribed milky white cutaneous macules devoid of identifiable melanocytes[108]. This disease appears to be more commonly observed in parts of the body exposed to the sun and in darker skin types and may develop at any age. The etiology is complex: there appears to be a certain genetic predisposition and a number of potential precipitating causes (i.e. crisis, illness, physical injury, etc.). Numerous attempts to identify HLA markers have revealed certain ethnic-specific markers: HLA-DR4 (blacks), B13 (Jews) and BW-35 (Yemenites). Theiligore[108] has proposed three prevailing theories to explain vitiligo: the neural hypothesis, the self-destruct hypothesis and the immune hypothesis. It carries a risk for ocular abnormalities, particularly iritis, and a significant risk for thyroid disease, diabetes mellitus, Addison’s disease and pernicious anemia.

The relationship between CD and vitiligo is controversial. Although some authors have described some cases of vitiligo in patients affected by CD[109,110], a serological screening study for CD in patients with vitiligo did not show any correlation between these two immunological disorders[111]. This implies that the sporadic associated cases must be considered as coincidental.

 

Behçet’s disease

A history of oral ulceration has been described in 25% of patients with CD and about 2-4% of patients with recurrent oral ulceration also have CD[112]. Behçet’s disease (BD) is characterized by recurrent ulceration of the mouth and genitalia associated with iritis. Males are affected 5-10 times more frequently than females and the onset is usually between the ages of 10 and 30. The oral ulcers usually show only non-specific inflammatory changes, although there may be infiltration of the grossly thickened walls of thrombosed arterioles. Some authors have suggested that BD may be caused by a virus[113] and antibodies against mucous membrane were demonstrated in 17 of 40 patients[114] but their significance has not yet been evaluated. Triolo and co-workers[115] described 3 cases of coexistence of BD and symptomless CD in 11 patients with BD (defined according to International Study Group-ISG criteria). IgA and IgG class AGA and EMA were found in one patient, another two had IgG AGA alone. There is suggestive but as yet inconclusive evidence of a probable association between CD and autoimmune diseases such as BD. It could be supposed that both diseases are likely the result of molecular mimicry between two undefined auto antigens or virus trigger action. In patients affected by BD, it may therefore be important to search for underlying undiagnosed CD, but future studies are needed to shed light on this point.

 

Oral lichen planus

The associations between CD and recurrent oral ulceration, glossitis, angular cheilitis and burning mouth are common[112]. Three to six percent of patients with these oral manifestations may have underlying undiagnosed CD[112,116]. Fortune et al[117] described the erosive type of oral lichen planus (OLP) in a patient with gluten enteropathy. OLP is not rare and frequently involves the buccal mucosa, gingiva and tongue. In both the diseases, the lesions had a mucosal T-cell infiltrate and the relief from eating a gluten-free diet was surprising. It is not clear whether the oral lesions are a direct manifestation of CD or due to the effect of malabsorption on the rapidly dividing mucosal cells already predisposed to soreness by a pre-existing disease; because palliative medication of chronic ulcerative stomatitis is often ineffective, it is important to detect the underlying nutritional deficiencies for the patient’s general well-being also.

 

Dermatomyositis

Dermatomyositis is a disorder mainly of the skin, muscle and blood vessels in which characteristic erythematous and edematous changes in the skin are associated with muscle weakness and inflammation. An underlying carcinoma is commonly described in adults. Juvenile dermatomyositis (JDM) has a more favorable prognosis for life but functional disability is usually severe. Its pathogenesis is probably due to cell-mediated immunity to muscle antigens, humoral immunity and immune complex deposition[118].

Some authors have described an association with CD[119-122]. Both diseases have a strong association with DQA1 0501 heterodimer because a linkage disequilibrium with HLA-DR3 haplotype or alternatively DR5/DR7 heterozygosity in CD[123,124] DQA1 0501 may lead to the activation of CD4-positive T cells by presentation of a still unidentified peptide that may induce CD or JDM. Evron
et al[125] and Marie et al[121] have also described the association between dermatomyositis (DM) and polymyositis (PM) and CD in adults. For these authors CD may be included within the spectrum of gastrointestinal manifestations of DM/PM and they showed that GFD may resolve clinical and laboratory abnormalities.

 

Porphyria

Mustajoki et al[126] and subsequently Twaddle et al[127] reported the coincidental diagnosis of CD in porphyrics. Patients with CD and porphyria present particular problems in terms of management[128]. The porphyrias are a group of rare diseases affecting the enzymes of the heme biosynthetic pathway with subsequent accumulation of porphyrins in the tissues. These substances are photosensitizers and their accumulation in the skin can cause bullae, erosions, increased fragility, scarring, hirsutism and pigmentation on photo-exposed areas. CD is often associated with DH which has some features in common with skin lesions of porphyrias. In one type of porphyria, variegate porphyria (VP), accumulation of porphobilinogen and 5-aminolevulinic acid is associated with gastrointestinal symptoms and an acute neuropsychiatric syndrome. Some drugs such as dapsone are precipitants of these acute attacks[128]. It is essential that patients with bullous skin lesions are adequately investigated to distinguish VP from DH because the administration of dapsone could have a potentially fatal outcome. Furthermore, symptomatic control of CD (e.g., malabsorption, anorexia, calorie restriction) can prevent precipitation of acute attacks of VP and because gluten sensitivity itself may be associated with neurological and psychiatric disorders[12,15], neuropsychiatric porphyria could be one of the differential diagnoses[129].

 

Alopecia areata

Alopecia areata (AA) is a chronic autoimmune disease characterized by non-scarring alopecia. Histologically it is possible to find perifollicular lymphocyte infiltration, pointing to an immunologic etiology such as CD. In both the diseases there is the presence of organ-specific autoa‑ntibodies[110,130-132], T-lymphocyte infiltration at the site of lesion[133,134], association with HLA genes[135,136] and possible etiologic importance of viral co-factors[137,138]

In the general population the prevalence of CD is 1 in 305[139] and of AA is 1 in 819[140]. Corazza and co-workers[141] found that the prevalence of CD in patients with AA was 1 in 85. Although remission and recurrence may be observed during the clinical course of AA[142], many patients on gluten-free diet showed complete regrowth of scalp and other body hair and no further recurrence of AA at follow-up[141,143]. The positive effects of gluten-free diet on the pattern of autoimmune conditions, such as AA, associated with CD have been attributed to a normalization of the immune response. This study suggests that AA patients constitute a novel risk group of CD. Because AA may be the only clinical manifestation of CD, some authors suggest GSE serological screening tests in alopecia universalis[141].

 

Acquired hypertrichosis lanuginosa

Acquired hypertrichosis lanuginosa (AHL) is a rare disease and there are less than 40 cases in the literature[144,145]. This type of hypertrichosis is characterized in its extreme by the rapid growth of fine, down-like hair all over the body, occasionally associated with glossites and loss of taste. A lesser degree of hypertrichosis in which lanugo hair occurs only on the face is more common. It is three times more common in females than in males and most commonly associated with malignancy[146]. Lymphomas, carcinoid tumors, and the Zollinger-Ellison syndrome have also been associated with this pathology[146,147].

In 1988, Corazza et al[148] described the only case reported in the literature of acquired hypertrichosis lanuginosa associated with CD. This case report confirms the paraneoplastic features of AHL. CD is often reported as being associated with tumors and can precede clinical presentation of the tumors[149].

 

Pyoderma gangrenosum

The pyoderma gangrenosum (PG) is a neutrophilic dermatosis, with destructive, necrotizing and non infectious ulcera, involving face and inferior limbs. The association between PG and CD has been described in some case reports and the importance of GFD in the resolution of PG has been suggested[150].

 

Ichthyosiform dermatoses

The ichthyosiform dermatoses consist of a heterogeneous group of hereditary disorders, all of which are characterized by the accumulation of large amounts of scale on the cutaneous surface. The earliest reports of ichthyosis have been traced to the Indian and Chinese literatures several hundred years B.C. and a dermatology text by Willian first discussed the problem. Kinetic studies of the epidermis in the major forms of ichthyosis have shown increased germinative cell hyperplasia and increased transit rate through the epidermis in lamellar ichthyosis[151]. Menni et al[152] first reported a case of ichthyosis revealing CD but the reason for this association is still unknown.

 

Pellagra

Pellagra is a disease characterized by lesions of the skin usually proceeded by prodromal symptoms, especially of digestive and nervous systems. The dermatosis begins as erythema and edema on the back of the hands, with pruritus and burnings, determined especially by exposure to the sun and by localized pressure. In some patients, several days after the onset of erythema, blisters appear; these run together to form bullae and then break. In the second stage, the dermatosis becomes hard and brittle. The skin may look like a goose. The usual sites are the face, neck, dorsal surfaces of the hands, arms, and feet. The cause of pellagra is still not entirely clear. It may arise from a diet deficient in niacin or tryptophan, or more commonly both, and aminoacid imbalance may also play a part[153]. In 1999, Schattner[153] described a case of a man with a pellagra-like syndrome due to CD.

 

Generalized acquired cutis laxa

Cutis laxa (CL) is a heterogeneous group of inherited and acquired (generalized or localized) diseases characterized by looseness of the skin with the development of inelastic folds that gives the affected person a prematurely senile appearance[154-156]. CL presents a destructive phenomenon of previously apparently normal elastic fibers, with cephalocaudal progression[157]. It occurs mainly in adults and the etiology is unknown. Immunological abnormality has been postulated to explain the destruction of elastic tissue[158]. Generalized acquired cutis laxa (GACL) has been reported in association with infectious disorders, drugs and autoimmune diseases[154,158,160-164]. Many authors have described a dermal deposit of immunoglobulins (IgA) in various diseases, suggesting that destruction of elastic tissue may be immunologically mediated[160]. Cases of association between GACL and CD have been reported[160,165]. Bodvarsson et al[166] proposed that dietary intake of glutenin may induce the production of antibodies to elastin and mediate adherence of neutrophils[167,168]. A cross-reaction is possible between gluten and some components of elastic fibers, since glutenin presents a 22.3% amino acid sequence similar to elastin[166,169]. Garcia-Patos and co-workers[165] described a case of GACL associated with CD, evidence of IgA deposits on the dermal elastic fibers and moderate improvement of eruption after treatment with GFD.

 

Atypical mole syndrome and congenital giant naevus

Montalto et al[170] first described the association between CD, atypical mole syndrome and congenital giant naevus. They reported a case of a patient affected by a rare multiple disorder of the cutaneous pigmentary system, which increased the risk of melanoma, and by CD which is frequently associated with some neoplasms[171-174]. Some authors have therefore suggested a more careful objective examination in all the patients with CD[170].

 

CONCLUSION

CD is an enteropathy associated with various extra-intestinal manifestations, including several skin diseases. Several hypotheses have been proposed regarding the possible mechanisms involved in this association. In particular, an abnormal small intestinal permeability appears to be implicated, which may allow the crossing of endogenous or exogenous antigens and may provoke the immunological response, common immune mechanisms, vascular alterations and, lastly, vitamin and aminoacid deficiency secondary to malabsorption in patients with CD. However at present the data are not homogeneous and most of the evidence for the association between CD and skin disorders is based on “case-reports”, making it difficult to draw definitive conclusions on this topic; future controlled studies are consequently needed to verify the real involvement of the cutaneous district in CD (Table 1). Nevertheless, despite these limitations, the opportunity to investigate the possible presence of CD in some dermatological patients seems at present justified.

 

Table 1 Skin disorders in celiac disease

 

ACKNOWLEDGMENTS

We express our gratitude to Dr Cristina D’Angelo, Dr Antonio Mirijello, Dr Silvia Cardone, Dr Veruscka Leso (Università Cattolica del Sacro Cuore, Rome, Italy) for their cooperation in this paper. The study was partially supported by grants from the “Associazione Ricerca in Medicina”, Bologna-Rome, Italy.

 

REFERENCES

1    Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119: 234-242

2    Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001; 120: 636-651

3    Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383-391

4    Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, Paparo F, Gasperi V, Limongelli MG, Cotichini R, D'Agate C, Tinto N, Sacchetti L, Tosi R, Stazi MA. The first large population based twin study of coeliac disease. Gut 2002; 50: 624-628

5    Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2: 647-655

6    Corazza GR, Gasbarrini G. Coeliac disease in adults. Baillieres Clin Gastroenterol 1995; 9: 329-350

7    Capristo E, Addolorato G, Mingrone G, De Gaetano A, Greco AV, Tataranni PA, Gasbarrini G. Changes in body composition, substrate oxidation, and resting metabolic rate in adult celiac disease patients after a 1-y gluten-free diet treatment. Am J Clin Nutr 2000; 72: 76-81

8    Howard MR, Turnbull AJ, Morley P, Hollier P, Webb R, Clarke A. A prospective study of the prevalence of undiagnosed coeliac disease in laboratory defined iron and folate deficiency. J Clin Pathol 2002; 55: 754-757

9    Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M, Bianchi FB. Coeliac disease hidden by cryptogenic hypertransaminasaemia. Lancet 1998; 352: 26-29

10   Corazza GR, Di Sario A, Cecchetti L, Jorizzo RA, Di Stefano M, Minguzzi L, Brusco G, Bernardi M, Gasbarrini G. Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult coeliac disease. Bone 1996; 18: 525-530

11   Addolorato G, Di Giuda D, De Rossi G, Valenza V, Domenicali M, Caputo F, Gasbarrini A, Capristo E, Gasbarrini G. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004; 116: 312-317

12   De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997; 242: 421-423

13   Addolorato G, Capristo E, Ghittoni G, Valeri C, Masciana R, Ancona C, Gasbarrini G. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001; 36: 502-506

14   Addolorato G, De Lorenzi G, Abenavoli L, Leggio L, Capristo E, Gasbarrini G. Psychological support counselling improves gluten-free diet compliance in coeliac patients with affective disorders. Aliment Pharmacol Ther 2004; 20: 777-782

15   Corazza GR, Frisoni M, Vaira D, Gasbarrini G. Effect of gluten-free diet on splenic hypofunction of adult coeliac disease. Gut 1983; 24: 228-230

16   Cardenas A, Kelly CP. Celiac sprue. Semin Gastrointest Dis 2002; 13: 232-244

17   Zone JJ, Skin manifestations of celiac disease. Gastroenterol 2005; 128: S87-S91

18   Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002; 346: 180-188

19     Katsambas AD, Lotti TM. European Handbook of dermatological treatments 2nd ed. 123

20   Seah PP, Fry L, Holborow EJ, Rossiter MA, Doe WF, Magalhaes AF, Hoffbrand AV. Antireticulin antibody: incidence and diagnostic significance. Gut 1973; 14: 311-315

21   van der Meer JB. Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofluorescent study. Br J Dermatol 1969; 81: 493-503

22   Katz SI, Hertz KC, Crawford PS, Gazze LA, Frank MM, Lawley TJ. Effect of sulfones on complement deposition in dermatitis herpetiformis and on complement-mediated guinea-pig reactions. J Invest Dermatol 1976; 67: 688-690

23   Mustakallio KK, Blomqvist K, Laiho K. Papillary deposition of fibrin, a characteristic of initial lesions of dermatitis herpetiformis. Ann Clin Res 1970; 2: 13-18

24     Dahl MV. In Year Book of Dermatology Eds. Dobson RI and Thiers BU. Chicago, 1980 Year Book Medical Pub.Inc.

25   Mann DL, Katz SI, Nelson DL, Abelson LD. Specific B-cell antigens associated with gluten-sensitive enteropathy and dermatitis herpetiformis. Lancet 1976; 1: 110-111

26   Eterman KP, Feltkamp TE. Antibodies to gluten and reticulin in gastrointestinal diseases. Clin Exp Immunol 1978; 31: 92-99

27   Seah PP, Fry L, Hoffbrand AV, Holborow EJ. Tissue antibodies in dermatitis herpetiformis and adult coeliac disease. Lancet 1971; 1: 834-846

28   Porter WM, Unsworth DJ, Lock RJ, Hardman CM, Baker BS, Fry L. Tissue transglutaminase antibodies in dermatitis herpetiformis. Gastroenterology 1999; 117: 749-750

29     29   Katz SI, Hall RP 3rd, Lawley TJ, Strober W. Dermatitis herpetiformis: the skin and the gut. Ann Intern Med 1980; 93: 857-874

30   Marks J, Shuster S, Watson AJ. Small-bowel changes in dermatitis herpetiformis. Lancet 1966; 2: 1280-1282

31   Zone JJ, Taylor TB, Kadunce DP, Meyer LJ. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990; 85: 812-820

32   Oxentenko AS, Murray JA. Celiac disease and dermatitis herpetiformis: the spectrum of gluten-sensitive enteropathy. Int J Dermatol 2003; 42: 585-587

33   Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol 1988; 19: 792-805

34   Lawley TJ, Strober W, Yaoita H, Katz SI. Small intestinal biopsies and HLA types in dermatitis herpetiformis patients with granular and linear IgA skin deposits. J Invest Dermatol 1980; 74: 9-12

35   Chorzelski TP, Jablonska S. Diagnostic significance of the immunofluorescent pattern in dermatitis herpetiformis. Int J Dermatol 1975; 14: 429-436

36   Leonard JN, Griffiths CE, Powles AV, Haffenden GP, Fry L. Experience with a gluten free diet in the treatment of linear IgA disease. Acta Derm Venereol 1987; 67: 145-148

37   Sachs JA, Awad J, McCloskey D, Navarrete C, Festenstein H, Elliot E, Walker-Smith JA, Griffiths CE, Leonard JN, Fry L. Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis. Gut 1986; 27: 515-520

38   Hall RP, Sanders ME, Duquesnoy RJ, Katz SI, Shaw S. Alterations in HLA-DP and HLA-DQ antigen frequency in patients with dermatitis herpetiformis. J Invest Dermatol 1989; 93: 501-505

39   Egan CA, Smith EP, Taylor TB, Meyer LJ, Samowitz WS, Zone JJ. Linear IgA bullous dermatosis responsive to a gluten-free diet. Am J Gastroenterol 2001; 96: 1927-1929

40   Hautekeete ML, DeClerck LS, Stevens WJ. Chronic urticaria associated with coeliac disease. Lancet 1987; 1: 157

41   Gabrielli M, Candelli M, Cremonini F, Ojetti V, Santarelli L, Nista EC, Nucera E, Schiavino D, Patriarca G, Gasbarrini G, Pola P, Gasbarrini A. Idiopathic chronic urticaria and celiac disease. Dig Dis Sci 2005; 50: 1702-1704

42   Hodgson HJ, Davies RJ, Gent AE, Hodson ME. Atopic disorders and adult coeliac disease presenting with symptoms of worsening astma. Lancet 1986; 2: 1157-1158

43   Cooper BT, Holmes GK, Cooke WT. Coeliac disease and immunological disorders. Br Med J 1978; 1: 537-539

44   Scala E, Giani M, Pirrotta L, Guerra EC, De Pita O, Puddu P. Urticaria and adult celiac disease. Allergy 1999; 54: 1008-1009

45   Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine 1992; 71: 206-215

46   Brickman CM, Tsokos GC, Chused TM, Balow JE, Lawley TJ, Santaella M, Hammer CH, Linton GF, Frank MM. Immunoregulatory disorders associated with hereditary angioedema. II. Serologic and cellular abnormalities. J Allergy Clin Immunol 1986; 77: 758-767

47   Farkas H, Gyeney L, Nemesanszky E, Kaldi G, Kukan F, Masszi I, Soos J, Bely M, Farkas E, Fust G, Varga L. Coincidence of hereditary angioedema (HAE) with Crohn's disease. Immunol Invest 1999; 28: 43-53

48   Farkas H, Visy B, Fekete B, Karadi I, Kovacs JB, Kovacs IB, Kalmar L, Tordai A, Varga L. Association of celiac disease and hereditary angioneurotic edema. Am J Gastroenterol 2002; 97: 2682-2683

49   Unsworth DJ, Wurzner R, Brown DL, Lachmann PJ. Extracts of wheat gluten activate complement via the alternative pathway. Clin Exp Immunol 1993; 94: 539-543

50   Dawkins R, Leelayuwat C, Gaudieri S, Tay G, Hui J, Cattley S, Martinez P, Kulski J. Genomics of the major histocompatibility complex: haplotypes, duplication, reteroviruses and disease. Immunol Rev 1999; 167: 275-304

51   Jones FA. The skin: a mirror of the gut. Geriatrics 1973; 28: 75-81

52   Holdstock DJ, Oleesky S. Vasculitis in coeliac diseases. Br Med J 1970; 4: 369

53   Alarcon-Segovia D. The necrotizing vasculitides. A new pathogenetic classification. Med Clin North Am 1977; 61: 241-260

54   Menzies IS, Laker MF, Pounder R, Bull J, Heyer S, Wheeler PG, Creamer B. Abnormal intestinal permeability to sugars in villous atrophy. Lancet 1979; 2: 1107-1109

55   Marsh GW, Stewart JS. Splenic function in adult celiac disease. Br J Haematol 1970; 19: 445-447

56   Wands JR, LaMont JT, Mann E, Isselbacher KJ. Arthritis associated with intestinal-bypass procedure for morbid obesity. Complement activation and characterization of circulating cryoproteins. N Engl J Med 1976; 294: 121-124

57   Taylor KB, Truelove SC, Thomson DL, Wright R. An immunological study of coeliac disease and idiopathic steatorrhoea. Serological reactions to gluten and milk proteins. Br Med J 1961; 5269: 1727-1731

58   Falchuk ZM, Strober W. Gluten-sensitive enteropathy: synthesis of antigliadin antibody in vitro. Gut 1974; 15: 947-952

59   Scott BB, Losowsky MS. Coeliac disease: a cause of various associated diseases? Lancet 1975; 2: 956-957

60   Meyers S, Dikman S, Spiera H, Schultz N, Janowitz HD. Cutaneous vasculitis complicating coeliac disease. Gut 1981; 22: 61-64

61   Cribier B, Caille A, Heid E, Grosshans E. Erythema nodosum and associated diseases. A study of 129 cases. Int J Dermatol 1998; 37: 667-672

62   Bohn S, Buchner S, Itin P. Erythema nodosum: 112 cases. Epidemiology, clinical aspects and histopathology. Schweiz Med Wochenschr 1997; 127: 1168-1176

63   Durand JM, Lefevre P, Weiller C. Erythema nodosum and coeliac disease. Br J Dermatol 1991; 125: 291-292

64   Bartyik K, Varkonyi A, Kirschner A, Endreffy E, Turi S, Karg E. Erythema nodosum in association with celiac disease. Pediatr Dermatol 2004; 21: 227-230

65   Douglas JG, Gillon J, Logan RF, Grant IW, Crompton GK. Sarcoidosis and coeliac disease: an association? Lancet 1984; 2: 13-15

66   Barriere H, Bureau B, LeRoux P. Erythema elevatum diutinum. Ann Dermatol Venereol 1977; 104: 75-76

67   Haber H. Erythema elevatum diutinum. Br J Dermatol 1955; 67: 121-145

68   Fort SL, Rodman OG. Erythema elevatum diutinum. Response to dapsone. Arch Dermatol 1977; 113: 819-822

69   Wolff HH, Scherer R, Maciejewski W, Braun-Falco O. Erythema elevatum diutinum: immunoelectron microscopical study of leucocytoclastic vasculitis within the intracutaneous test reaction induced by streptococcal antigen. Arch Dermatol Res 1978; 26: 17-26

70   Archimandritis AJ, Fertakis A, Alegakis G, Bartsokas S, Melissinos K. Erythema elevatum diutinum and IgA myeloma: an interesting association. Br Med J 1977; 2: 613-614

71   Tasanen K, Raudasoja R, Kallioinen M, Ranki A. Erythema elevatum diutinum in association with coeliac disease. Br J Dermatol 1997; 136: 624-627

72   Collin P, Korpela M, Hallstrom O, Viander M, Keyrilainen O, Maki M. Rheumatic complaints as a presenting symptom in patients with coeliac disease. Scand J Rheumatol 1992; 21: 20-23

73   Rodriguez-Serna M, Fortea JM, Perez A, Febrer I, Ribes C, Aliaga A. Erythema elevatum diutinum associated with celiac disease: response to a gluten-free diet. Pediatr Dermatol 1993; 10: 125-128

74     Becker SW, Kahn D, Rothman S. Cutaneous manifestation of internal malignant tumors. Arch Dermatol Syph 1942; 45: 1069-1080

75   Wilkinson DS. Necrolytic migratory erythema with carcinoma of the pancreas. Trans St Johns Hosp Dermatol Soc 1973; 59: 244-250

76   Vandersteen PR, Scheithauer BW. Glucagonoma syndrome. A clinicopathologic, immunocytochemical, and ultrastructural study. J Am Acad Dermatol 1985; 12: 1032-1039

77   Mallinson CN, Bloom SR, Warin AP, Salmon PR, Cox B. A glucagonoma syndrome. Lancet 1974; 2: 1-5

78   Blackford S, Wright S, Roberts DL. Necrolytic migratory erythema without glucagonoma: the role of dietary essential fatty acids. Br J Dermatol 1991; 125: 460-462

79   Goodenberger DM, Lawley TJ, Strober W, Wyatt L, Sangree MH Jr, Sherwin R, Rosenbaum H, Braverman I, Katz SI. Necrolytic Migratory Erythema without glucagonoma: report of two cases. Arch Dermatol 1979; 115: 1429-1432

80   Kelly CP, Johnston CF, Nolan N, Keeling PW, Weir DG. Necrolytic migratory erythema with elevated plasma enteroglucagon in celiac disease. Gastroenterology 1989; 96: 1350-1353

81   Thorisdottir K, Camisa C, Tomecki KJ, Bergfeld WF. Necrolytic migratory erythema: a report of three cases. J Am Acad Dermatol 1994; 30: 324-329

82   Parker CM, Hanke CW, Madura JA, Liss EC. Glucagonoma syndrome: case report and literature review. J Dermatol Surg Oncol 1984; 10: 884-889

83   Masri-Friding GD, Turner MLC. Necrolytic Migratory Erythema without glucagonoma (letter). J Am Acad Dermatol 1992; 27: 486

84   Kirby B, Griffiths CE. Novel immune-based therapies for psoriasis. Br J Dermatol 2002; 146: 546-551

85   Baker BS, Swain AF, Griffiths CE, Leonard JN, Fry L, Valdimarsson H. Epidermal T lymphocytes and dendritic cells in chronic plaque psoriasis: the effects of PUVA treatment. Clin Exp Immunol 1985; 61: 526-534

86   Veal CD, Capon F, Allen MH, Heath EK, Evans JC, Jones A, Patel S, Burden D, Tillman D, Barker JN, Trembath RC. Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus. Am J Hum Genet 2002; 71: 554-564

87   Mailliard RB, Egawa S, Cai Q, Kalinska A, Bykovskaya SN, Lotze MT, Kapsenberg ML, Storkus WJ, Kalinski P. Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses. J Exp Med 2002; 195: 473-483

88   van de Kerkhof PC, Vissers WH. The topical treatment of psoriasis. Skin Pharmacol Appl Skin Physiol 2003; 16: 69-83

89   Tzaneva S, Honigsmann H, Tanew A, Seeber A. A comparison of psoralen plus ultraviolet A (PUVA) monotherapy, tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis. Br J Dermatol 2002; 147: 748-753

90   Rich SJ, Bello-Quintero CE. Advancements in the treatment of psoriasis: role of biologic agents. J Manag Care Pharm 2004; 10: 318-325

91   Michaelsson G, Gerden B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W, Hjelmquist G, Loof L. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Br J Dermatol 2000; 142: 44-51

92   Cardinali C, Degl'innocenti D, Caproni M, Fabbri P. Is the search for serum antibodies to gliadin, endomysium and tissue transglutaminase meaningful in psoriatic patients? Relationship between the pathogenesis of psoriasis and coeliac disease. Br J Dermatol 2002; 147: 187-188

93   Woo WK, McMillan SA, Watson RG, McCluggage WG, Sloan JM, McMillan JC. Coeliac disease-associated antibodies correlate with psoriasis activity. Br J Dermatol 2004; 151: 891-894

94   Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol 2003; 4: 13-20

95   Siri A, Lozano W, Vignale RA. Antireticulin antibodies in psoriasis. Acta Derm Venereol 1980; 60: 348-351

96   Michaelsson G, Gerden B, Ottosson M, Parra A, Sjoberg O, Hjelmquist G, Loof L. Patients with psoriasis often have increased serum levels of IgA antibodies to gliadin. Br J Dermatol 1993; 129: 667-673

97   Michaelsson G, Kraaz W, Gerden B, Hagforsen E, Lundin IP, Loof L, Sj-oberg O, Scheynius A. Patients with psoriasis have elevated levels of serum eosinophil cationic protein and increased numbers of EG2 positive eosinophils in the duodenal stroma. Br J Dermatol 1996; 135: 371-378

98   Kakar S, Nehra V, Murray JA, Dayharsh GA, Burgart LJ. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol 2003; 98: 2027-2033

99   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, Gasbarrini G. 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

100 Abenavoli L, Leggio L, Ferrulli A, Vonghia L, Gasbarrini G, Addolorato G. Association between psoriasis and coeliac disease. Br J Dermatol 2005; 152: 1393-1394

101 Ojetti V, Aguilar Sanchez J, Guerriero C, Fossati B, Capizzi R, De Simone C, Migneco A, Amerio P, Gasbarrini G, Gasbarrini A. High prevalence of celiac disease in psoriasis. Am J Gastroenterol 2003; 98: 2574-2575

102 Humbert P, Bidet A, Treffel P, Drobacheff C, Agache P. Intestinal permeability in patients with psoriasis. J Dermatol Sci 1991; 2: 324-326

103 Montalto M, Cuoco L, Ricci R, Maggiano N, Vecchio FM, Gasbarrini G. Immunohistochemical analysis of ZO-1 in the duodenal mucosa of patients with untreated and treated celiac disease. Digestion 2002; 65: 227-233

104 Molberg O, Mcadam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4: 713-717

105 Cellier C, Flobert C, Cormier C, Roux C, Schmitz J. Severe osteopenia in symptom-free adults with a childhood diagnosis of coeliac disease. Lancet 2000; 355: 806

106 Hein G, Abendroth K, Muller A, Wessel G. Studies on psoriatic osteopathy. Clin Rheumatol 1991; 10: 13-17

107 Holick MF. Vitamin D: A millenium perspective. J Cell Biochem 2003; 88: 296-307

108 Grimes PE. New insights and new therapies in vitiligo. JAMA 2005; 293: 730-735

109 Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologist. Am J Clin Dermatol 2003; 4: 13-20

110 Reunala T, Collin P. Diseases associated with dermatitis herpetiformis. Br J Dermatol 1997; 136: 315-318

111 Volta U, Bardazzi F, Zauli D, DeFranceschi L, Tosti A, Molinaro N, Ghetti S, Tetta C, Grassi A, Bianchi FB. Serological screening for coeliac disease in vitiligo and alopecia areata. Br J Dermatol 1997; 136: 801-802

112  Jones HJ, Mason DH. Oral manifestation of systemic disease. 2nd ed. London: Baillier Tindall, 1990.

113 Evans AD, Pallis CA, Spillane JD. Involvement of the nervous system in Behcet’s syndrome; report of three cases and isolation of virus. Lancet 1957; 273: 349-353

114 Shimizu T, Katsuta Y, Oshima Y. Immunological studies on Behcet’s syndrome. Ann Rheum Dis 1965; 24: 494-500

115 Triolo G, Triolo G, Accardo-Palumbo A, Carbone MC, Giardina E, La Rocca G. Behcet's disease and coeliac disease. Lancet 1995; 346: 1495

116 Ferguson R, Basu MK, Asquith P, Cooke WT. Jejunal mucosal abnormalities in patients with recurrent aphthous ulceration. Br Med J 1976; 1: 11-13

117 Fortune F, Buchanan JA. Oral lichen planus and coeliac disease. Lancet 1993; 341: 1154-1155

118 Volta U, De Franceschi L, Molinaro N, Tetta C, Bianchi FB. Organ-specific autoantibodies in coeliac disease: do they represent an epiphenomenon or the expression of associated autoimmune disorders? Ital J Gastroenterol Hepatol 1997; 29: 18-21

119 Buderus S, Wagner N, Lentze MJ. Concurrence of celiac disease and juvenile dermatomyositis: result of a specific immunogenetic susceptibility? J Pediatr Gastroenterol Nutr 1997; 25: 101-103

120 Falcini F, Porfirio B, Lionetti P. Juvenile dermatomyositis and celiac disease. J Rheumatol 1999; 26: 1419-1420

121 Marie I, Lecomte F, Hachulla E, Antonietti M, Francois A, Levesque H, Courtois H. An uncommon association: celiac disease and dermatomyositis in adults. Clin Exp Rheumatol 2001; 19: 201-203

122 Iannone F, Lapadula G. Dermatomyositis and celiac disease association: a further case. Clin Exp Rheumatol 2001; 19: 757-758

123 Reed AM, Pachman L, Ober C. Molecular genetic studies of major histocompatibility complex genes in children with juvenile dermatomyositis: increased risk associated with HLA-DQA1 *0501. Hum Immunol 1991; 32: 235-240

124 Lundin KE, Sollid LM, Qvigstad E, Markussen G, Gjertsen HA, Ek J, Thorsby E. T lymphocyte recognition of a celiac disease-associated cis- or trans-encoded HLA-DQ alpha/beta-heterodimer. J Immunol 1990; 145: 136-139

125 Evron E, Abarbanel JM, Branski D, Sthoeger ZM. Polymyositis, arthritis, and proteinuria in a patient with adult celiac disease. J Rheumatol 1996; 23: 782-783

126 Mustajoki P, Vuoristo M, Reunala T. Celiac disease or dermatitis herpetiformis in three patients with porphyria. Dig Dis Sci 1981; 26: 618-621

127 Twaddle S, Wassif WS, Deacon AC, Peters TJ. Celiac disease in patients with variegate porphyria. Dig Dis Sci 2001; 46: 1506-1508

128  Moore MR, Disler PB. Drug sensitive diseases-I-acute porphyrias. Adverse Drug React Bull 1988; 129: 484-487

129 Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369-371

130 Karpati S, Burgin-Wolff A, Krieg T, Meurer M, Stolz W, Braun-Falco O. Binding to human jejunum of serum IgA antibody from children with coeliac disease. Lancet 1990; 336: 1335-1338

131 Nunzi E, Hamerlinck F, Cormane RH. Immunopathological studies on alopecia areata. Arch Dermatol Res 1980; 269: 1-11

132 Volta U, Lenzi M, Lazzari R, Cassani F, Collina A, Bianchi FB, Pisi E. Antibodies to gliadin detected by immunofluorescence and a micro-ELISA method: markers of active childhood and adult coeliac disease. Gut 1985; 26: 667-671

133 Brandtzaeg P, Halstensen TS, Kett K, Krajci P, Kvale D, Rognum TO, Scott H, Sollid LM. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989; 97: 1562-1584

134 Perret C, Brocker EB, Wiesner-Menzel L, Happle R. In situ demonstration of T cells in alopecia areata. Arch Dermatol Res 1982; 273: 155-158

135 Corazza GR, Tabacchi P, Frisoni M, Prati C, Gasbarrini G. DR and non-DR Ia allotypes are associated with susceptibility to coeliac disease. Gut 1985; 26: 1210-1213

136 Zhang L, Weetman AP, Friedmann PS, Oliveira DB. HLA associations with alopecia areata. Tissue Antigens 1991; 38: 89-91

137 Kagnoff MF, Austin RK, Hubert JJ, Bernardin JE, Kasarda DD. Possible role for a human adenovirus in the pathogenesis of celiac disease. J Exp Med 1984; 160: 1544-1557

138 Stankler L. Synchronous alopecia areata in two siblings: a possible viral aetiology. Lancet 1979; 1: 1303-1304

139 Catassi C, Ratsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F, Coppa GV, Giorgi PL. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 200-203

140 Safavi K. Prevalence of alopecia areata in the First National Health and Nutrition Examination Survey. Arch Dermatol 1992; 128: 702

141 Corazza GR, Andreani ML, Venturo N, Bernardi M, Tosti A, Gasbarrini G. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995; 109: 1333-1337

142 Mitchell AJ, Krull EA. Alopecia areata: pathogenesis and treatment. J Am Acad Dermatol 1984; 11: 763-775

143 Naveh Y, Rosenthal E, Ben-Arieh Y, Etzioni A. Celiac disease-associated alopecia in childhood. J Pediatr 1999; 134: 362-364

144 Hovenden AL. Acquired hypertrichosis lanuginosa associated with malignancy. Arch Intern Med 1987; 147: 2013-2018

145 Jemec GB. Hypertrichosis lanuginosa acquisita. Report of a case and review of the literature. Arch Dermatol 1986; 122: 805-808

146 Ikeya T, Izumi A, Suzuki M. Acquired hypertrichosis lanuginosa. Dermatologica 1978; 156: 274-282

147 Fretzin DF. Malignant down. Arch Dermatol 1967; 95: 294-297

148 Corazza GR, Masina M, Passarini B, Neri I, Varotti C. Ipetricosi lanuginosa acquisita associata a sindrome celiaca. G Ital Dermatol Venereol 1988; 123: 611-612

149  Lowosky MS. Malasorption. In: Wetherall DJ, Lendicham JGG, Warrel DA. Oxford text book of medicine. ed. Oxford 1983; 1: 1290

150  Gasbarrini G, Corazza GR. L’eterogenicità clinica della malattia celiaca. In: Il malassorbimento intestinale e sindromi cliniche ad esso correlate. ed. Luigi Pozzi, 1992; 220-244.

151 Shwayder T. Disorders of keratinization: diagnosis and management. Am J Clin Dermatol 2004; 5: 17-29

152 Menni S, Boccardi D, Brusasco A. Ichthyosis revealing coeliac disease. Eur J Dermatol 2000; 10: 398-399

153 Schattner A. A 70-year-old man with isolated weight loss and a pellagra-like syndrome due to celiac disease. Yale J Biol Med 1999; 72: 15-18

154 Koch SE, Williams ML. Acquired cutis laxa: case report and review of disorders of elastolysis. Pediatr Dermatol 1985; 2: 282-288

155 Schreiber MM, Tilley JC. Cutis laxa. Arch Dermatol 1961; 84: 266-272

156 Goltz RW, Hult AM, Goldfarb M, Gorlin RJ. Cutis laxa. A manifestation of generalized elastolysis. Arch Dermatol 1965; 92: 373-387

157 Fisher BK, Page E, Hanna W. Acral localized acquired cutis laxa. J Am Acad Dermatol 1989; 21: 33-40

158  158 Nanko H, Jepsen LV, Zachariae H, Sogaard H. Acquired cutis laxa (generalized elastolysis): light and electron microscopic studies. Acta Derm Venereol 1979; 59: 315-324

159 Tsuji T, Imajo Y, Sawabe M, Kuniyuki S, Ishii M, Hamada T, Ishimura E, Hamada N, Nishisawa Y, Morii H. Acquired cutis laxa concomitant with nephrotic syndrome. Arch Dermatol 1987; 123: 1211-1216

160 Lewis FM, Lewis-Jones S, Gipson M. Acquired cutis laxa with dermatitis herpetiformis and sarcoidosis. J Am Acad Dermatol 1993; 29: 846-848

161 Randle HW, Muller S. Generalized elastolysis associated with systemic lupus erythematosus. J Am Acad Dermatol 1983; 8: 869-873

162  Mascarò JM Jr, Torras H, Lecha V. Lupus Eritematoso Cutàneo Chalazodérmico Asossociado ag Nefropatia IgA Mesangial, Enfermedad de Berger, Case no.28. XII° International Meeting of Clinical Dermatology, Barcelona, 1993.

163 Linares A, Zarranz JJ, Rodriguez-Alarcon J, Diaz-Perez JL. Reversible cutis laxa due to maternal D-penicillamine treatment. Lancet 1979; 2: 43

164 Harpey JP, Jaudon MC, Clavel JP, Galli A, Darbois Y. Cutis laxa and low serum zinc after antenatal exposure to penicillamine. Lancet 1983; 2: 858

165 Bodvarsson S, Jonsdottir I, Freysdottir J, Leonard JN, Fry L, Valdimarsson H. Dermatitis herpetiformis--an autoimmune disease due to cross-reaction between dietary glutenin and dermal elastin? Scand J Immunol 1993; 38: 546-550

166 Bodvarsson S, Jonsdottir I, Freysdottir J, Leonard JN, Fry L, Valdimarsson H. Dermatitis herpetiformis. An autoimmune disease due to cross-reaction between dietary glutenin and dermal elastin? Scand J Immunol 1993; 38: 546-550

167 Hendrix JD, Mangum KL, Zone JJ, Gammon WR. Cutaneous IgA deposits in bullous diseases function as ligands to mediate adherence of activated neutrophils. J Invest Dermatol 1990; 94: 667-672

168 Tatham AS, Shewry PR. Elastomeric proteins: biological roles, structures and mechanisms. Trends Biochem Sci 2000; 25: 567-571

169 McFadden JP, Leonard JN, Powles AV, Rutman AJ, Fry L. Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid. Br J Dermatol 1989; 121: 759-762

170 Montalto M, Diociaiuti A, Alvaro G, Manna R, Amerio PL, Gasbarrini G. Atypical mole syndrome and congenital giant naevus in a patient with celiac disease. Panminerva Med 2003; 45: 219-221

171 Wright DH. The major complications of coeliac disease. Baillieres Clin Gastroenterol 1995; 9: 351-369

172 Marghoob AA, Schoenbach SP, Kopf AW, Orlow SJ, Nossa R, Bart RS. Large congenital melanocytic nevi and the risk for the development of malignant melanoma. A prospective study. Arch Dermatol 1996; 132: 170-175

 173 Marghoob AA, Kopf AW, Rigel DS, Bart RS, Friedman RJ, Yadav S, Abadir M, Sanfilippo L, Silverman MK, Vossaert KA. Risk of cutaneous malignant melanoma in patients with ‘classic’ atypical-mole syndrome. A case-control study. Arch Dermatol 1994; 130: 993-998

174 Ackerman AB, Sood R, Koenig M. Primary acquired melanosis of the conjunctiva is melanoma in situ. Mod Pathol 1991; 4: 253-263

 

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