To assess the liver stiffness in patients with rheumatoid arthritis treated with methotrexate monotherapy using non-invasive, ultrasound-based elastography (acoustic radiation force impulse (ARFI) imaging) in a longitudinal approach.

In total, 23 MTX-naive patients were longitudinally assessed using acoustic radiation force impulse (ARFI) imaging. Baseline assessments were carried out between July 2018 and April 2019, and the follow-up evaluations took place after an average of 2.6 years. The main outcome variable was the mean shear wave velocity as measured by the ARFI method. It was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (within-group comparisons) were performed using t-tests for dependent samples or suitable nonparametric procedures.

The main finding was that observed ARFI shear wave velocities did not increase during the observation period. In fact, this parameter decreased over time from 1.07 m/s (SD = 0.23) at baseline without MTX exposure to 0.97 m/s (SD = 0.16) at follow-up after a mean of 2.6 years (P = 0.013). Moreover, the magnitude of the change in shear wave velocity could not be predicted by indicators of inflammation or disease activity, BMI, age, sex or NSAR intake (corresponding regression analysis: corrected R2 = 0.344; P = 0.296).

No increased risk of liver fibrosis was found in RA patients treated with MTX monotherapy during observation period.

Prednisone is currently recommended as the first-line treatment for pulmonary sarcoidosis but is associated with many side effects. Methotrexate, which is recommended as a second-line treatment, appears to have fewer side effects than prednisone but a slower onset of action. Data are needed on the efficacy and side-effect profile of methotrexate as compared with prednisone as first-line treatment for pulmonary sarcoidosis.

In this multicenter, open-label, noninferiority trial involving patients with pulmonary sarcoidosis who had not previously received treatment, we randomly assigned patients, in a 1:1 ratio, to receive prednisone or methotrexate according to a prespecified treatment schedule. The primary end point was the mean change from baseline to week 24 in the percentage of the predicted forced vital capacity (FVC), as estimated with the use of mixed models for repeated measures. The noninferiority margin for the primary end point was 5 percentage points.

Of the 138 patients who underwent randomization, 70 were assigned to receive prednisone and 68 to receive methotrexate. The unadjusted mean change from baseline to week 24 in the percentage of the predicted FVC was 6.75 percentage points (95% confidence interval [CI], 4.50 to 8.99) in the prednisone group and 6.11 percentage points (95% CI, 3.72 to 8.50) in the methotrexate group. Methotrexate was noninferior to prednisone with regard to the primary end point, with an adjusted between-group difference of -1.17 percentage points (95% CI, -4.27 to 1.93). Adverse events occurred in a similar percentage of patients in the two trial groups. Weight gain, insomnia, and increased appetite were the most common adverse events with prednisone, and nausea, fatigue, and any abnormal liver-function test were among the most common adverse events with methotrexate.

In patients with pulmonary sarcoidosis, initial treatment with methotrexate was noninferior to that with prednisone with regard to the change from baseline to week 24 in the percentage of the predicted FVC. Differences in the side-effect profile between methotrexate and prednisone may inform shared decision making by providers and patients about the appropriate treatment approach. (Funded by the Dutch Lung Foundation; PREDMETH ClinicalTrials.gov number, NCT04314193.).

Hydroxychloroquine (HCQ) has been demonstrated to be potential to enhance the therapeutic efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) patients. However, the pharmacokinetics (PK) alterations and underlying mechanisms differentiating MTX-HCQ combination therapy from MTX monotherapy remain uncharted.

Thirty-three Sprague-Dawley rats were divided into single-dose and multiple-dose groups, with each group further randomized into an MTX monotherapy group an Hydroxychloroquine monotherapy group (HTG), and an MTX-HCQ combination therapy group Blood samples were collected at various time points before and after dosing to determine drug concentrations in plasma and red blood cells (RBC). The area under the concentration-time curve (AUC) for each compound was calculated, and pharmacokinetics models were established to analyze parameter variations across groups.

In the single-dose group, the CTG exhibited a significant increase in the RBC MTX Cmax compared to the MTG (P = 0.023), whereas the AUC of RBC MTX showed an increasing trend (P = 0.056). In the multiple-dose group, the CTG demonstrated significant increases in plasma MTX Cmax and AUC (P = 0.023, P = 0.028, respectively) as well as RBC MTX Cmax and AUC (P = 0.010, P = 0.003, respectively). The RBC MTX polyglutamates (MTXPG2 and MTXPG3) also showed an increasing trend in Cmax and AUC for the CTG. Additionally, the CTG displayed a significant reduction in clearance rate (CLe) (P = 0.001). No significant differences were observed in the Cmax or AUC of HCQ or desethylhydroxychloroquine (DHCQ) in plasma or RBC across dosing groups.

These findings provide insights into the enhanced efficacy, faster onset, and prolonged effect of MTX-HCQ combination therapy compared to MTX monotherapy. The observed increases in MTX Cmax and AUC suggest the need for careful monitoring of MTX-related adverse effects, particularly in patients with renal insufficiency, during combination treatment with HCQ.

We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin-1 receptor-associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone.

This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C-reactive protein (DAS28-CRP) at week 12. Treatment-emergent adverse events (TEAEs) were monitored.

Overall, 460 patients were randomized. At week 12, zimlovisertib + tofacitinib demonstrated a greater magnitude of mean CFB in DAS28-CRP (-2.65; 90% confidence interval [CI], -2.84 to -2.46) versus tofacitinib (-2.30; 90% CI, -2.49 to -2.11; P = 0.032); mean CFB with zimlovisertib + ritlecitinib (-2.35; 90% CI, -2.54 to -2.15) was similar to tofacitinib. TEAEs were reported in 246 patients (53.5%), with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by 9 patients (2.0%) and 10 patients reported serious AEs. One patient receiving tofacitinib died because of severe COVID-19 infection. Safety profiles were similar across all treatment groups, with no evidence of additive/synergistic issues.

Zimlovisertib + tofacitinib was more effective than tofacitinib for the primary endpoint, whereas the efficacy of zimlovisertib + ritlecitinib did not achieve statistical significance versus tofacitinib. All treatments were well tolerated.

Despite the beneficial effects of a healthier lifestyle, lack of more robust data hampers standardization of recommendations for patients with systemic lupus erythematosus (SLE). Thus, this study explores the experiences, perceptions, and health effects of a newly developed healthy lifestyle intervention in patients with SLE. This was a qualitative, descriptive study using focus group discussions with SLE patients with high cardiovascular risk who participated in a 6-month behavioral lifestyle intervention versus standard of care randomized controlled trial. The intervention group received the Living Well with Lupus (LWWL) program aimed at changing lifestyle behaviors. Focus groups were composed of 4-6 LWWL participants each. Deductive and inductive qualitative content analysis was performed using the MAXQDA data management software. A thematic analysis was conducted wherein thick descriptions of key themes around SLE patients' perceptions related to the intervention and interventions' effects on routine, health-related outcomes and well-being were developed. 19 patients participated in the focus groups (age: 42 ± 7 years; BMI: 28.3 ± 2.4 kg/m2; mild disease activity and organ damage index). Overall, (a) participants were mostly positive about the intervention components, although views of home-based exercise and food diaries were both positive and negatives; (b) barriers and facilitators to intervention adherence included socioeconomic, environmental and individual factors; (c) new behaviors and knowledge were achieved, which participants intended to maintain after the study; and (d) the intervention positively impacted daily functioning, physical and mental health, and overall wellbeing. LWWL participants reported success in achieving healthy lifestyle behaviors in addition to improvements in perceived physical and mental health and overall wellbeing during the LWWL program. Results of this qualitative assessment, including an overview of barriers and facilitators to program initiation and adherence, should guide future research on the implementation of lifestyle interventions in SLE care.Clinicaltrials.govNCT04431167.

The treatment of pemphigus vulgaris (PV) often requires long-term systemic corticosteroids. Although new biologicals like rituximab are changing the landscape, traditional immunosuppressants still prevail in many underdeveloped areas. One such medication is methotrexate (MTX), which has been widely used in autoimmune and autoinflammatory diseases, but its role in treating pemphigus remains somewhat unclear and controversial. This study aimed to evaluate the effect and safety profile of using low-dose MTX in PV patients receiving glucocorticoids. PV patients who visited the Department of Dermatology, Peking University First Hospital from January 2010 to December 2021 were retrospectively screened. Based on different treatment regimens, patients were automatically divided into a corticosteroid monotherapy group and a corticosteroid combined with low-dose MTX group (MTX was administered at a dose of no more than15 mg per week, with a minimum duration of 8 weeks). All patients were followed up for 1 year. A total of 142 patients with PV were eligible for the study (100 in the corticosteroid monotherapy group and 42 in the corticosteroid combined with low-dose MTX group). The Kaplan-Meier curve indicated that the corticosteroid combined with low-dose MTX group achieved a 50% reduction in glucocorticoid use faster, with a P value of 0.0132, especially among patients who initially received more than 60 mg of steroids per day. The inclusion of MTX reduced the occurrence of hyperpilidemia. There was not sufficient evidence to determine if the addition of MTX was associated with more bacterial infection cases for certain. The inclusion of low-dose MTX in the corticosteroid treatment regimen for patients with PV, particularly those receiving high doses, can facilitate the reduction of glucocorticoid dosages and lower the incidence of hyperlipidemia, without increasing the risk of other adverse effects.

Methotrexate is a commonly utilized agent in pediatric oncology therapy. However, significant interindividual variability in its clearance can lead to delayed clearance and resultant severe toxicity. This underscores the urgent need for efficient and sensitive analytical methods to ensure patient safety. In this study, we aimed to establish a high-performance liquid chromatography-tandem mass spectrometry (HPLC-ESI/triple) method for the quantitative determination of methotrexate concentrations in plasma. This method is intended to facilitate therapeutic drug monitoring in pediatric patients, thereby allowing for a better understanding of the pharmacokinetics of methotrexate in vivo. The results indicate that the established HPLC-ESI/triple method can accurately and sensitively quantify methotrexate using only 10 μL of plasma. The recovery rates for all analytes exceeded 90 %, and matrix effects were minimal. Furthermore, our optimized method revealed that patient age significantly influences methotrexate blood concentration. Specifically, under identical dosage and administration intervals, an increase in patient age correlates with a decrease in measured blood concentration. Additionally, our findings suggest that measuring methotrexate concentrations within 24 h post-administration enhances the effectiveness of monitoring, thereby promoting rational drug use and ensuring optimal therapeutic dosing. In summary, we have conducted a comprehensive study establishing a robust method for determining methotrexate concentrations in patient plasma. The optimized HPLC-ESI/triple method is poised for widespread application in clinical practice to monitor methotrexate therapy in pediatric patients.

Methotrexate (MTX) is the first line therapy for rheumatoid arthritis (RA), and despite its widespread use, there is very little information about MTX intolerance in sub-Saharan Africa. The aim of this study was to assess the prevalence of MTX intolerance and other reasons for stopping MTX in RA in South Africa.

A retrospective chart review of all RA patients seen at Inkosi Albert Luthuli Hospital in Durban from 2009 to 2019 was undertaken. We included patients who received MTX for at least three months. All patients received folic acid supplements. Patients who discontinued MTX were categorized as having either MTX related toxicity or other reasons.

A total of 695 patients were identified with a female to male ratio of 7:1. The mean age was 57.9 (± 13.3) years, and median duration of MTX use was 67.0 (39.0-106.0) months. Most of the patients were African Blacks (61.2%), and Indians (32.8%). There were 83 (11.9%) patients who stopped MTX, and it was successfully reintroduced in 25 of them. Thus, 58 (8.3%) patients discontinued therapy, 33 (4.7%) due to intolerance and 25 (3.6%) due to factors other than adverse effects. The commonest causes of MTX intolerance were respiratory, gastrointestinal and haematological. The other reasons for discontinuation included co-morbidities and pregnancy related concerns.

The low prevalence of MTX intolerance in a multiethnic population in this single centre study, confirms the value of MTX as anchor therapy, especially in resource constrained settings. Key Points • We report a low and similar prevalence of methotrexate intolerance in a large population of African Blacks and Indians with RA in sub-Saharan Africa. • Even though there was heterogeneity among other studies, our review indicates that MTX was tolerated better in our patients compared to patients in Europe and the United States of America.

To evaluate the efficacy and safety of initial treatment combining corticosteroids and 15 mg/week methotrexate (MTX) for acute Vogt-Koyanagi-Harada disease (VKH).

A retrospective, longitudinal observational case series was conducted. Newly onset VKH patients received corticosteroids combining 15 mg/week MTX, and follow-up period ≥ 6 months were consecutively enrolled. Main outcome measures were the corticosteroid-sparing effect, improvements of visual function, changes of ophthalmic characteristics and recurrences.

In this case series, 39 acute VKH patients (78 eyes) received corticosteroids combining oral MTX as first-line therapy. All the participants achieved corticosteroid-sparing effect and thereafter withdrew corticosteroids. At the last follow-up, 87.2% patients had managed to discontinue MTX. The median period of corticosteroids treatment was 9.2 (8.0-13.3) months, and the mean interval of MTX using was 18.0 ± 6.1 months. Eventually, 83.3% of eyes achieved visual acuity of 0.0 logMAR or better. All the eyes had retinal reattachment and the choroidal thickness significantly decreased. Sun-set glow fundus was identified in 18 eyes (23.1%). The microvascular perfusion was still defect despite the well-controlled inflammation. Recurrence occurred in five patients, with only one progressing to a chronic recurrent stage. No severe adverse event was observed.

Initial treatments with corticosteroids tapered over approximately 9 months and oral methotrexate (15 mg/week) for 18 months in acute VKH patients led to favorable visual outcomes, fairly low recurrence and good safety profile. These findings support the consideration of this combined treatment for acute VKH but should be tempered by recognizing the retrospective and non-control design.

The primary aim of this study was to investigate the real-world occurrence of various adverse drug reactions (ADRs) and assess medication adherence among patients using disease-modifying antirheumatic drugs (DMARDs). Additionally, the study sought to evaluate the degree of methotrexate intolerance among these patients.

This cross-sectional, observational study was conducted at a tertiary care hospital and involved 100 adult patients diagnosed with rheumatoid arthritis (RA) who were currently undergoing treatment with methotrexate. The study systematically recorded all adverse drug reactions reported by the patients as well as those identified through laboratory tests. Medication adherence was measured using the Compliance Questionnaire Rheumatology (CQR5) and both intentional and non-intentional non-adherence questionnaires. The methotrexate intolerance was assessed using the Methotrexate Intolerance Severity Score (MISS).

Out of the total 74 reported ADRs, gastrointestinal were the most common, accounting for 62 (76.53%) of cases, followed by hematological problems at 13 (16.07%), with other types of ADRs comprising the remaining. Despite the prevalence of gastrointestinal ADRs, the study found high levels of medication adherence among the patients. Additionally, the methotrexate intolerance was relatively low, which may be attributed to the use of folic acid supplementation by all participants.

Gastrointestinal adverse drug reactions were the most frequently observed side effects in this study. Despite these reactions, patients demonstrated a high level of adherence to methotrexate therapy. The factors contributing to this adherence- such as patient counseling, disease knowledge, or the duration of the disease- merit further investigation to understand their impact on treatment outcomes.

An association between increased erythrocyte mean corpuscular volume (MCV) and treatment response in patients with inflammatory arthritis receiving methotrexate (MTX) has been reported. We investigated the frequency of red blood cell (RBC) macrocytosis and its clinical implications regarding the initiation of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in patients starting MTX for rheumatoid arthritis (RA).

RBC macrocytosis (MCV >100 fL) and clinical characteristics were retrospectively examined in 1,156 patients starting MTX for RA. Multivariable logistic regression analyses were performed to identify the independent predictors of RBC macrocytosis. The initiation of b/tsDMARDs was assessed using a multivariable Cox proportional hazards regression model.

RBC macrocytosis was observed in 21.6% of RA patients over 35 [8, 89] months following MTX initiation and was persistent in 63.6% of the patients during MTX treatment. Anemia coexisted in only 20.0% of the patients with RBC macrocytosis. The occurrence of RBC macrocytosis was independently associated with age, MTX dose, and concomitant use of sulfasalazine or leflunomide (all p<0.001). A higher dose of MTX and double- or triple-DMARDs therapy were more frequently used in the group with RBC macrocytosis than in the group with normal MCV. Patients experiencing RBC macrocytosis were more likely to use b/tsDMARDs (hazard ratio 1.45 [95% confidence interval 1.13, 1.87], p=0.003).

RBC macrocytosis was possibly associated with the use of b/tsDMARD and could be a supplementary marker for assessing MTX resistance.

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts.

Drugs used to treat rheumatic disease are associated with pneumotoxicity (drug-induced lung disease), but little is known about associated risk factors.

To determine expert physician-perceived risk factors for developing pneumotoxicity in patients with rheumatologic conditions.

A modified international 3-tier Delphi exercise was performed. Tier 1 determined patient and drug variables that physicians perceive to be risk factors. Tier 2 determined degree of risk associated with the Tier-1 derived variables. Tier 3 aimed to internally validate and stratify exemplar cases into risk categories.

134 pulmonologists and 49 rheumatologists responded to Tier 1;157 physicians completed all tiers. Perceived risk factors included: drug type; history of previous pneumotoxicity; age; smoking; underlying rheumatic disease type and activity; renal function; pulmonary hypertension; left ventricular failure;presence, nature, severity and progression of pre-existing interstitial lung disease. Tier 2 data stratified these variables into risk profiles e.g. never versus current smoking was perceived as low and high risk respectively. An example of perceived high risk resulting from Tier 3 is a 75-year-old current smoker with high-activity rheumatoid arthritis (RA) with severe, progressive ILD being started on methotrexate. A perceived low risk is a 75-year-old currentsmoker with moderate-activity RA and emphysema with no cardiac or renal disease and no pre-existing ILD being started on rituximab. A risk prediction scoring tool is being developed to be used in validation studies.

This modified Delphi exercise defined and stratified the perceived risk factors for developing pneumotoxicity. Age, current smoking, high underlying rheumatological disease activity, HRCT definite UIP and honeycombing, severity and progression of pre-existing ILD were perceived to be the highest risk-factors.

The therapeutic arsenal for psoriatic arthritis (PsA) is gradually being expanded, but the use of these targeted treatments must be optimal. Our objective was to guide the choice of targeted therapy to use as first-line treatment in a patient with PsA in whom methotrexate (MTX) has failed.

We searched for literature data in PubMed with the appropriate keywords for the six points of our argument: (1) the tolerance of MTX; (2) the efficacy of targeted therapies combined with MTX vs monotherapy; (3) immunogenicity of anti-tumor necrosis alpha (TNFα) monoclonal antibodies (mAbs); (4) immunogenicity of anti-interleukin (IL)-17, anti-IL-12/23, and anti-IL-23 mAbs; (5) the therapeutic maintenance of anti-TNFα mAbs when combined or not with MTX; (6) the therapeutic maintenance of anti-IL-17 vs anti-TNFα mAbs as first-line targeted therapy.

The proposed rational strategy is as follows: in case of initiation of an anti-TNFα agent, maintaining treatment with MTX seems preferable, even in the absence of evidence of the superior efficacy of the combination, to avoid immunization and reduced therapeutic maintenance; in case of initiation of anti-IL-17, anti-IL-12/23, anti-IL-23 agents, or Janus kinase (JAK) inhibitors, again in the absence of evidence of the superior efficacy of the combination, discontinuing MTX therapy may be possible, at least in two steps, after verifying the efficacy of the targeted therapy initiated on the joints and skin.

We have data from the literature to guide the choice of targeted therapy to use as first-line treatment in a patient with PsA in whom MTX has failed.

Methotrexate (MTX) is a folate antagonist used as an immunosuppressant in a number of conditions, including rheumatoid arthritis (RA). Low-dose MTX (MTX-LD) is associated with a risk of haematological, hepatic, gastrointestinal and pulmonary toxicity, which may up until now have limited its use.

In RA, data from retrospective cohorts have reported a possible excess risk of methotrexate toxicity in cases of underlying interstitial lung disease (ILD). However, recent prospective and retrospective multicentre studies have found no such increased risk, and have reassuringly concluded that MTX-LD can be prescribed in cases of RA-associated ILD (RA-ILD).

Current recommendations are not to delay the introduction of MTX in patients with RA at risk of developing ILD or in the presence of RA-ILD with mild to moderate respiratory impairment.

Drug-induced lung disease (DILD) encompasses a broad, highly heterogeneous group of conditions that may occur as a result of exposure to numerous agents, such as antineoplastic drugs, conventional or biological disease-modifying antirheumatic drugs, antiarrhythmics, and antibiotics. Between 3% and 5% of prevalent cases of interstitial lung diseases are reported as DILDs. The pathogenesis of lung injury in DILD is variable, multifactorial, and often unknown. Acute presentation is the most common, can occur from days to months after the start of treatment, and ranges from asymptomatic to acute respiratory failure. The CT patterns are varied and include ground-glass opacities, organizing pneumonia, and diffuse alveolar damage. Notably, there are no clinical manifestations or CT patterns specific to DILD, which makes the diagnosis quite challenging and necessitates a high index of suspicion, as well as the exclusion of alternative causes such as infection, cardiac-related pulmonary edema, exacerbation of a preexisting ILD, and neoplastic lung involvement. Discontinuation of the offending medication constitutes the cornerstone of treatment, and corticosteroid treatment is usually necessary after the onset of clinical manifestations. The prognosis varies widely, with high mortality rates in severe cases. A history of medications related to pulmonary toxicity in patients with new-onset respiratory symptoms should prompt consideration of DILD as a potential underlying cause.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

SLC15A4 is an endolysosome-resident transporter linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptors (TLRs) 7-9 as well as nucleotide-binding oligomerization domain-containing protein (NOD) signaling in several immune cell subsets. Notably, SLC15A4 is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans. Despite its therapeutic potential, the availability of quality chemical probes targeting SLC15A4 functions is limited. In this study, we used an integrated chemical proteomics approach to develop a suite of chemical tools, including first-in-class functional inhibitors, for SLC15A4. We demonstrate that these inhibitors suppress SLC15A4-mediated endolysosomal TLR and NOD functions in a variety of human and mouse immune cells; we provide evidence of their ability to suppress inflammation in vivo and in clinical settings; and we provide insights into their mechanism of action. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune and autoinflammatory conditions.

Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.

The prognosis of rheumatoid arthritis (RA) with interstitial lung disease (ILD) is particularly poor. Although drugs that do not contribute to the progression of ILD should be used in RA treatment, none have been established. This study evaluated the safety of tocilizumab in terms of ILD activity.

This study prospectively enrolled all 55 patients with RA complicated by ILD who were treated with tocilizumab at Dokkyo Medical University Saitama Medical Center from April 2014 to June 2022. The outcome measures were MMP-3 and KL-6 as biomarkers of RA and ILD activity, respectively, and the relationship between them was analyzed.

Both MMP-3 and KL-6 were significantly improved at 6 months of treatment (P < 0.001 and P < 0.05, respectively), and a weak correlation between MMP-3 and KL-6 was observed (R2 = 0.086, P = 0.087). The group with increased MMP-3 due to RA progression had significantly higher KL-6 at 6 months compared with the group with RA improvement (P < 0.05). Also, the group with ILD progression on computed tomography had significantly higher MMP-3 compared with the groups with improvement or no change of ILD (P < 0.05 and P < 0.01, respectively). The mortality rate was 0% at 6 months, 2.0% at 1 year, 16.7% at 2 years, and 32.4% at 3 years, and mortality from acute exacerbation of ILD due to respiratory infection increased over time.

RA activity and ILD activity were found to be related at 6 months of treatment. Tocilizumab does not seem to affect the mechanism of ILD progression, as most patients showed improvement in both MMP-3 and KL-6 with tocilizumab within 6 months, when this drug would be expected to affect the lungs directly. However, respiratory infection exacerbated ILD from 1 year after the start of treatment. As immunosuppressive drugs, including tocilizumab, have a risk of respiratory infection, it is important to identify early signs of infection.

Methotrexate (MTX), a commonly used disease-modifying antirheumatic drug, is generally considered safe at low cumulative doses. However, severe pancytopenia can occur even with doses as low as 10 mg, as illustrated by a fatal case in an older adult with chronic kidney disease (CKI) and vitamin B12 deficiency. Despite the low dose and lack of folate supplementation, the patient developed severe mucositis and pancytopenia leading to fatal complications. This case underscores the challenges in diagnosing and managing MTX-induced pancytopenia, especially in patients with comorbidities such as CKI and vitamin B12 deficiency.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

Immune checkpoint inhibitor (ICI) therapy for advanced malignancies often leads to off-target adverse events. Rheumatic immune-related adverse events can often linger beyond the duration of ICI therapy and sometimes requires the use of immunomodulator therapy. A key question, therefore, is if the commonly used therapies affect cancer outcomes. In this review, the authors summarize the state of the data as it currently stands, taking into consideration the limitations of the various source studies. The most information is known about glucocorticoids, which appear to be harmful especially when used early and at high doses.

There are conflicting findings on the link between liver fibrosis and cumulative methotrexate dosages. We aimed to determine the frequency of liver fibrosis in rheumatoid arthritis patients treated with methotrexate and to identify its associated factors.

We conducted a cross-sectional study over 9 months (April-December 2021), including rheumatoid arthritis patients treated with methotrexate. Demographic and clinical data were collected. Liver stiffness was assessed by FibroScan. Fibrosis and significant liver fibrosis were defined as liver stiffness higher than 6 and 7.2 kPa, respectively. Liver tests, albuminemia, lipid profile, and blood glycemia were measured. Metabolic syndrome was also evaluated. Statistical analyses were performed using SPSS.

We included 21 men and 47 women. The mean age was 51.60 ± 1.82 years. The mean disease duration was 8.29 ± 6.48 years. The mean weekly intake of methotrexate was 13.76 ± 3.91 mg. The mean methotrexate duration was 4.67 ± 4.24 years. The mean cumulative dose was 3508.87 ± 3390.48 mg. Hypoalbuminemia and metabolic syndrome were found in 34% and 25% of cases. We noted increased alkaline phosphatase levels in four cases. The mean liver stiffness was 4.50 ± 1.53 kPa. Nine patients had liver fibrosis, and four had significant fibrosis. Associated factors with liver fibrosis were as follows: age ≥ 60 years (OR:22.703; 95%CI [1.238-416.487]; p = 0.035), cumulated dose of methotrexate ≥ 3 g (OR: 76.501; 95%CI [2.383-2456.070]; p = 0.014), metabolic syndrome (OR: 42.743; 95%CI [1.728-1057.273]; p = 0.022), elevated alkaline phosphatase levels (OR: 28.252; 95%CI [1.306-611.007]; p = 0.033), and hypoalbuminemia (OR: 59.302; 95%CI [2.361-1489.718]; p = 0.013).

Cumulating more than 3 g of methotrexate was associated with liver fibrosis in rheumatoid arthritis patients. Having a metabolic syndrome, higher age, hypoalbuminemia, and elevated alkaline phosphatase levels were also likely to be independently associated with liver fibrosis. Key points • Rheumatoid arthritis patients require monitoring hepatic fibrosis when the cumulated dose of methotrexate is above 3 g. • Metabolic syndrome is a risk factor for liver fibrosis, suggesting that its management is necessary to prevent this complication. • Hypoalbuminemia and elevated alkaline phosphatase levels (twice the upper limit) in rheumatoid arthritis patients treated with methotrexate were associated with liver fibrosis.

Introduction: Prescribing strength training (ST) for people with rheumatoid arthritis (RA) is complicated by factors (barriers and facilitators) that affect participation. It is unclear whether guidelines include recommendations beyond prescription parameters (frequency, intensity, time, type, volume, and progression) and adequately incorporate participation factors tailored to people with RA. Objective: To summarize available recommendations to aid in the tailoring of ST prescriptions for people with RA. Methods: Medline, Embase, and CINAHL databases and gray literature were searched for guidelines, recommendations, and review articles containing ST prescription recommendations for RA. Article screening and data extraction were performed in duplicate by two reviewers. Results: Twenty-seven articles met the inclusion criteria. The recommendations address RA-specific ST participation factors including: knowledge gaps (of equipment, ST benefits, disease), memory problems, the management of joint deformity, comorbidity, the fluctuating nature of the disease and symptoms (pain, stiffness, flares), fear avoidance, motivation, need for referral to other professionals, and provision of RA-specific resources. Conclusion: This review summarizes recommendations for tailoring ST prescriptions for people with RA. Future research is required to understand how pain, symptom assessment, and unaddressed ST participation factors like sleep and medication side effects can be addressed to support ST participation amongst people with RA.

To explore the toxicity of low-dose methotrexate (MTX), an uncommon, but life-threatening event.

We analysed the presentation, course and risk factors of all patients admitted to the rheumatology ward with severe low-dose MTX toxicity. These patients were compared with patients without signs of relevant MTX toxicity.

The 12 patients admitted for MTX toxicity included 7 patients with rheumatoid arthritis, 2 with psoriatic arthritis or psoriasis, 2 patients with giant cell arteritis and 1 with myositis. 1 patient died from infections, while 11 survived under folinic acid administration. All patients suffering from severe MTX toxicity were older than 70 years and were therefore compared with 400 patients who were also older than 70 years, but without MTX toxicity. Of these 400 control patients, the group of patients not on MTX (n=232) had more renal impairment than the group of patients on MTX (n=168). Compared with the 168 MTX-treated patients without toxicity, the 12 patients with life-threatening toxic events had a lower median estimated glomerular filtration rate (eGFR) at the routine visit preceding the acute event (64 (range 32-77) vs 69 (range 8 to >90) mL/min x 1.73, p=0.0251). A multivariate analysis found that patients with toxicity were more frequently treated with diuretics (6/12 vs 24/168), proton pump inhibitors (PPIs; 10/12 vs 70/168) and levetiracetam (2/12 vs 1/168).

Patients older than 70 years with lower eGFR and being on diuretics, but also on PPIs and levetiracetam, have a significantly higher risk for MTX toxicity.

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with the functional impairment of multiple joints and the destruction of bone and cartilage. Methotrexate (MTX) is a first-line drug commonly used to treat RA; however, even low doses of MTX can potentially cause rare but severe adverse reactions, such as neutropenic enterocolitis (NE), a life-threatening disease characterized by intestinal mucosal damage and immunodeficiency.

Here, we report on an 82-year-old RA patient who developed life-threatening NE after ten years of low-dose MTX treatment. The condition of the patient rapidly worsened, requiring emergency electrical cardioversion and intravenous treatment with immunoglobulin (IVIG). Immunophenotypic responses were analyzed before and after treatment to evaluate therapeutic efficacy.

This case highlights the importance of monitoring elderly patients with RA receiving low-dose MTX treatment for the potential accumulation of MTX toxicity. Our findings also illustrate the importance of providing timely IVIG therapy for MTX-induced NE.

Toxicity associated with low doses of methotrexate (MTX) is low, but it may be fatal. Bone marrow suppression and mucositis are among the common side effects of low dose MTX toxicity. Different risk factors have been reported for toxicities associated with low doses of MTX, including accidental use of higher doses, renal dysfunction, hypoalbuminemia, and polypharmacy. In this paper, we present a female patient who had mistakenly used 7.5 mg of MTX daily instead of the same dose of MTX on Thursday and Friday. She was presented with mucositis and diarrhea to the emergency department. Moreover, we searched the databases Scopus and PubMed for available studies and case reports on toxicities associated with MTX dosing errors. The most frequently observed toxicities included gastrointestinal lesions, nausea, vomiting, skin lesions, and bone marrow suppression. Leucovorin, hydration, and urine alkalinization were among the most frequently used treatments. Finally, we summarize the data on the toxicities of low doses of MTX in different diseases.

This study aimed to assess the prevalence and identify predictors of hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis (JIA) during methotrexate treatment.

This cross-sectional study included JIA patients who had received methotrexate for > 1 year. Laboratory data including liver chemistry and lipid profiles were collected. Liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) were determined by transient elastography. Significant hepatic fibrosis was defined as LSM > 7 kilopascal (kPa), and hepatic steatosis was defined as CAP > 225 decibel/meter (dB/m). Logistic regression analysis was performed to identify predictors associated with hepatic steatosis and fibrosis.

Of 60 patients, 66.7% were female, and the median age (IQR) was 12.8 (10.6-15.0) years. The median duration of methotrexate usage (IQR) was 45 (22-85) months, and the median cumulative dose of methotrexate (IQR) was 3768 (1806-6466) mg. The median LSM (IQR) and CAP (IQR) were 4.1 (3.4-4.6) kPa and 191.0 (170.3-223.8) dB/m, respectively. No patients had transient elastography-defined hepatic fibrosis, whereas 21.7% had hepatic steatosis. A body mass index Z-score > 1 (OR 5.71 [95%CI 1.31-24.98], p = 0.021) and higher cumulative dose of methotrexate (OR 1.02 [95%CI 1.00-1.04], p = 0.041) were associated with hepatic steatosis, whereas the cumulative dose of steroids was not (OR 1.00 [95%CI 1.00-1.01], p = 0.097).

Hepatic steatosis is common among JIA patients receiving methotrexate, but none had transient elastography-defined hepatic fibrosis. Overweight/obese JIA adolescents and patients with a high cumulative dose of methotrexate are at risk for hepatic steatosis. Key Points •Long-term low-dose methotrexate usage and the concomitant use of other DMARDs did not increase the risk of hepatic fibrosis in JIA patients. •The prevalence of hepatic steatosis in JIA patients receiving methotrexate was higher than in a healthy pediatric population. •Overweight/obesity and a higher cumulative dose of methotrexate were predictors of hepatic steatosis.

Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer.

The therapeutic effects of Huangqin Qingre Chubi (HQC) in rheumatoid arthritis (RA) have been documented. However, there is a lack of real-world clinical evidence supporting its efficacy.

Patients diagnosed with RA were recruited from the First Affiliated Hospital of the Anhui University of Chinese Medicine. Patient information was obtained from the hospital's database. Propensity score matching (PSM), Kaplan-Meier curve, and Cox proportional hazards model were used to control confounding factors and analyze the factors influencing readmission. Association rule analysis and random walk evaluation models were used to evaluate the correlations among HQC treatment, inflammation indicators, and self-perception of patients (SPP) scale.

After PSM, 3423 patients were enrolled, with 1142 in the HQC group and 2281 in the non-HQC group. The readmission risk of the HQC group was significantly lower than that of the non-HQC group. Combined univariate and multivariate analysis results revealed that risk factors for readmission were age >60 years, female sex, hypertension, chronic gastritis, and elevated levels of laboratory indices, including anticyclic citrullinated peptide and complement component 3 (C3) and C4. HQC, disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoid therapy were protective factors for readmission. HQC treatment was closely associated with improvements in many factors, including erythrocyte sedimentation rate, C-reactive protein, C3, rheumatoid factor levels, visual analog scale, depression self-assessment scale, and patient-reported activity index scores with RA.

HQC treatment can reduce the risk of readmission and significantly improve immune inflammatory indicators and SPP in patients with RA, with no risk of hepatorenal toxicity.

To study the prevalence of liver fibrosis (LF) measured by FibroScan and APRI index in patients with rheumatoid arthritis (AR) undergoing treatment with methotrexate (MTX).

We included 59 patients with RA on MTX. Medical records, FibroScan measures and serological markers of liver damage were compared on the basis of cumulative methotrexate dose.

Mean treatment duration was 82.4±65.1 months and mean cumulative dose was 5214.5±4031.9mg. Five patients met LF criteria by fibroscan, while only one patient had a suggestive APRI score. No statistically significant differences were found in terms of LF measured by both APRI and fibroScan between patients with cumulative doses above and below 4000mg. There was also no relationship between LF and treatment duration.

The occurrence of LF in patients with RA on MTX is a multifactorial process that does not seem directly related to its cumulative dose. FibroScan may be a useful technique in clinical practice to screen for this complication.

Methotrexate (MTX) is an antifolate that is inescapable and widely used to treat autoimmune diseases and is the gold standard medicine for the arthritic condition. Despite its importance, it is more prone to gastrointestinal toxicity, which is most common in arthritis patients during MTX treatment. Combination therapies are required to ensure MTX's antiarthritic activity while providing gastrointestinal protection. Zinc (Zn) and L-carnitine (Lc) are well-known potent antioxidants and anti-inflammatory supplements with promising results in pre-clinical studies. Arthritis was induced in Wistar rat's ankles with Freund's adjuvant and treated with either MTX (2.5 mg/kg b.w per week for two weeks) or Zn (18 mg/kg b.w. per day) Lc (200 mg/kg b.w. per day) individually or in combination (MTX + Zn Lc). The antiarthritic effects were evaluated by body weight, paw volume, ankle tissue, and joint histopathology. At the same time, anti-toxicity/gastrointestinal protective activity was examined by tissue oxidative stress markers, antioxidants, mitochondrial function, inflammatory mediators, and antioxidant signaling proteins and their binding mechanism. Repercussions of MTX intoxication induced upregulation of oxidative stress markers, antioxidant depletion, ATP depletion, decreased expression of Nrf2/Sirt1/Foxo3, and the overexpression of inflammatory mediators attenuated by co-treatment with Zn Lc. Zn Lc markedly mitigated MTX-instigated intestinal injury by activating antioxidant signaling mechanisms Nrf2/Sirt1/Foxo3 signaling and tissue architectural anomalies and exhibited an enhanced antiarthritic effect. In conclusion, we report that Zn Lc and MTX combination could presumably protect the intestine from low-dose MTX which managed arthritis but induced severe intestinal damage with increased inflammation and downregulated Nrf2/Sirt1/Foxo3 pathway.

The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD.

In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared.

Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively).

The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Chikungunya fever is a global vector-borne viral disease. Patients with acute chikungunya are usually treated symptomatically. The arthritic phase may be self-limiting. However, many patients develop extremely disabling arthritis that does not improve after months. The aim of this study was to describe the treatment of chikungunya arthritis (CHIKA) patients. A medical records review was conducted in 133 CHIKA patients seen at a rheumatology practice. Patients were diagnosed by clinical criteria and confirmed by the presence of anti-chikungunya IgM. Patients were treated with methotrexate (20 mg/week) and/or leflunomide (20 mg/day) and dexamethasone (0-4 mg/day) for 4 weeks. At baseline visit and 4 weeks after treatment, Disease Activity Score 28 (DAS28) and pain (using a visual analog scale) were ascertained. Five months after the end of treatment, patients were contacted to assess pain, tender joint count, and swollen joint count. The mean age of patients was 58.6 ± 13.7 years, and 119 (85%) were female. After 4 weeks of treatment, mean (SD) DAS28-erythrocyte sedimentation rate (6.0 [1.2] versus 2.7 [1.0], P < 0.001) and pain (81.8 [19.2] to 13.3 [22.9], P < 0.001) scores significantly decreased. A total of 123 patients were contacted 5 months after the end of treatment. Pain score, tender joint count, and swollen joint count significantly declined after 4 weeks of treatment, and the response was sustained for 5 months. In this group of patients with CHIKA, 4-week treatment induced a rapid clinical improvement that was maintained 5 months after the end of therapy; however, the contribution of treatment to these outcomes is uncertain.

Amirdha Gandhi Kukkil Vallathy (AGKV) is a herbo mineral Siddha formulation which has Sulphur, Kukkil, Seendhil and Serankottai as major ingredients and it is indicated for 80 types of Vatham diseases. Uthiravatha suronitham is one among the vatham diseases and it's clinical symptoms are correlated with Rheumatoid arthritis (RA). Since AGKV is a promising drug for RA, the safety of this drug has been validated by performing the acute and 28 days repeated oral dose toxicity study following the OECD guidelines 423 and 407.

The acute toxicity study has been performed by administering orally with a single dose of 300 and 2000 mg/kg body weight in rat models and the animals were observed for 14 consecutive days. Gross pathology was observed and animals were sacrificed at the end of the study. In 28 days repeated oral toxicity study, limit test has been carried out with a dose of 1,000 mg/kg body weight.

No significant abnormality has been observed in the body weight, organ weight, biochemical parameters and histopathology studies. It has been revealed that this drug is safe upto 2000 mg/kg body weight in single dose study and 1,000 mg is a safer dose in the 28 days repeated oral toxicity study.

The results of acute and 28 days repeated oral toxicity studies revealed no adverse effects in animals and hence this drug AGKV is safe and can be administered in human.

This randomized, controlled, open-label, phase 2 clinical trial aimed to assess the efficacy and safety of low-dose methotrexate as maintenance therapy for recurrent postoperative chronic rhinosinusitis with nasal polyps (CRSwNPs).

Forty-one patients with CRSwNPs who experienced postoperative polyp recurrence(s) were randomly divided into three groups to receive one of the following treatments for 8 weeks: daily intranasal mometasone furoate monohydrate 200 mcg (control [intranasal corticosteroids (INCS)] arm, n = 13]); daily per oral methylprednisolone 8 mg (oral corticosteroids [OCS] arm, n = 14); and once weekly per oral 10 mg methotrexate (MTX arm, n = 14). All patients were assessed at three clinical visits according to the Lund-Kennedy endoscopic grading system (LKES), visual analog scale (VAS), Turkish version of the Sinonasal Outcome Test-22 (SNOT-22), peak nasal inspiratory flow (PNIF), butanol olfactory threshold test (BuOT), serum total IgE level, presence of peripheral eosinophilia, serum biochemical assays, and adverse events.

All efficacy outcome measures significantly improved in all three groups, except for the nonrecovery of peripheral eosinophilia in the INCS group. There was no significant difference among the groups in terms of LKES scores. Scores for the Turkish version of the SNOT-22, PNIF, BuOT, and serum IgE levels were also similar among the groups. However, total VAS scores recovered significantly better in the INCS group than in the MTX group. Serum biochemical assays remained normal in all groups. Adverse events were minor and observed only in the OCS group.

Low-dose MTX was a safe and effective maintenance therapy for patients with recurrent postoperative CRSwNPs.

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD).

The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure.

Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression.

None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with synovial proliferation and bone erosion, which leads to the structural and functional impairment of the joints. Immune cells, together with synoviocytes, induce a pro-inflammatory environment and novel treatment agents target inflammatory cytokines. Psoriasis is a chronic immune-mediated skin disease, and several cytokines are considered as typical mediators in the progression of the disease, including IL-23, IL-22, and IL-17, among others.

In this review, we try to evaluate whether cyclin-dependent kinases (CDK), enzymes that regulate cell cycle and transcription of various genes, could become novel therapeutic targets in RA and psoriasis. We present the main results of in vitro and in vivo studies, as well as scarce clinical reports.

CDK inhibitors seem promising for treating RA and psoriasis because of their multidirectional effects. CDK inhibitors may affect not only the process of osteoclastogenesis, thereby reducing joint destruction in RA, but also the process of apoptosis of neutrophils and macrophages responsible for the development of inflammation in both RA and psoriasis. However, assessing the efficacy of these drugs in clinical practice requires multi-center, long-term clinical trials evaluating the effectiveness and safety of CDK-blocking therapy in RA and psoriasis.

It is well known that rheumatoid arthritis (RA) patients are at an increased risk of developing non-infectious pulmonary complications, especially interstitial lung disease (ILD); however, the clinician must keep in mind that lung disease could not only be a manifestation of the underlying condition, but also a consequence of using disease-modifying therapies. New-onset ILD or ILD worsening has also been reported as a possible consequence of both conventional disease-modifying antirheumatic drugs (DMARDs) and biologic agents. This study is a narrative review of the current literature regarding the potential risk of developing interstitial lung disease along with the administration of specific drugs used in controlling rheumatoid arthritis. Its purpose is to fill knowledge gaps related to this challenging patient cohort by addressing various aspects of the disease, including prevalence, disease features, treatment strategies, and patient outcomes.