Methotrexate as a corticosteroid-sparing agent in leprosy reactions: A French multicenter retrospective study.

INTRODUCTION: Leprosy reactions (LRs) are inflammatory responses observed in 30%-50% of people with leprosy. First-line treatment is glucocorticoids (GCs), often administered at high doses with prolonged courses, resulting in high morbi-mortality. Methotrexate (MTX) is an immunomodulating agent used to treat inflammatory diseases and has an excellent safety profile and worldwide availability. In this study, we describe the efficacy, GCs-sparing effect and safety of MTX in LRs. METHODS: We conducted a retrospective multicentric study in France consisting of leprosy patients receiving MTX for a reversal reaction (RR) and/or erythema nodosum leprosum (ENL) since 2016. The primary endpoint was the rate of good response (GR) defined as the complete disappearance of inflammatory cutaneous or neurological symptoms without recurrence during MTX treatment. The secondary endpoint was the GCs-sparing effect, safety and clinical relapse after MTX discontinuation. RESULTS: Our study included 13 patients with LRs (8 men, 5 women): 6 had ENL and 7 had RR. All patients had had at least one previous course of GCs and 2 previous treatment lines before starting MTX. Overall, 8/13 (61.5%) patients had GR, allowing for GCs-sparing and even GCs withdrawal in 6/11 (54.5%). No severe adverse effects were observed. Relapse after MTX discontinuation was substantial (42%): the median relapse time was 5.5 months (range 3-14) after stopping treatment. CONCLUSION: MTX seems to be an effective alternative treatment in LRs, allowing for GCs-sparing with a good safety profile. Furthermore, early introduction during LRs may lead to a better therapeutic response. However, its efficacy seems to suggest prolonged therapy to prevent recurrence.

Methotrexate monotherapy versus methotrexate and apremilast combination therapy in the treatment of palmoplantar psoriasis: A prospective, randomised, assessor-blinded, comparative study.

BACKGROUND: Palmoplantar psoriasis is a chronic debilitating condition which significantly impairs quality of life. OBJECTIVES: To assess the efficacy and safety of the combination of apremilast and methotrexate compared with methotrexate monotherapy in the treatment of palmoplantar psoriasis. Also, to study the impact on treatment on the Dermatology Life Quality Index and Palmoplantar Quality of Life Index. METHODS: A total of 64 patients were randomised to two groups in a 1:1 ratio - Group A received both methotrexate and apremilast in combination, while Group B received only methotrexate, for 16 weeks. The primary endpoints were the mean score of Modified Palmoplantar Psoriasis Area and Severity Index at week 16, the proportion of patients achieving modified palmoplantar psoriasis area severity index-75 and/or Palmoplantar Psoriasis Physician Global Assessment score 0/1 at week 16. RESULTS: A significantly higher proportion of patients in Group A achieved Modified Palmoplantar Psoriasis Area and Severity Index-75 at week 16 (43% in Group A vs 30% in Group B). The Modified Palmoplantar Psoriasis Area and Severity Index score was significantly lower in the combination group at week 16 (4.03 ± 2.05 in Group A and 5.89 ± 2.31 in Group B, P-value = 0.002). About 80% of patients in the combination group with baseline Palmoplantar Psoriasis Physician Global Assessment ≥3 achieved Palmoplantar Psoriasis Physician Global Assessment 0/1 compared to 60% in Group B. The combination group showed a significantly higher reduction in Dermatology Life Quality Index and Palmoplantar Quality of Life Index scores compared to the methotrexate alone group (P-value = 0.025). No notable adverse events were observed. LIMITATION: The limitations of the study were single blinding, small sample size and a lack of longer follow up to assess the rate of relapse. We did not account for attrition during sample size calculation. Also, due to the paucity of data regarding the use of apremilast in palmoplantar psoriasis, definitive comparisons could not be made with previous studies. CONCLUSION: The combination of apremilast and methotrexate has superior efficacy and a similar safety profile as compared to methotrexate monotherapy for the treatment of moderate to severe palmoplantar psoriasis.

The therapeutic role of methotrexate in chronic urticaria: A systematic review.

BACKGROUND: Chronic urticaria, in many cases, has an unsatisfactory response to antihistamines. The current recommendations in urticaria do not mention the dose and duration for methotrexate. AIMS: This study aims to systematically review the use/efficacy of methotrexate in chronic urticaria. METHODS: A systematic search in four databases, that is, PubMed/Medline, Cochrane central, Google Scholar and Clinicaltrials.gov was done to identify studies on the use of methotrexate in chronic urticaria using key words "methotrexate [MeSH terms]" and "urticaria" or "urticaria, chronic" or "urticaria, chronic spontaneous." RESULTS: Nine articles (study participants 127), including three randomized control trials, one prospective interventional trial without control, three retrospective reviews and two case reports, were identified and finally included in the systematic review. There was a paucity of literature and the three randomized control trials did not show any benefit of methotrexate over antihistamines alone. However, in studies where steroid-dependent cases were given methotrexate, marked benefit was reported with steroid-sparing effect, particularly on methotrexate dose escalation. LIMITATIONS: Due to a paucity of published literature on methotrexate in urticaria, a meta-analysis could not be done. CONCLUSION: In chronic recalcitrant or steroid-dependent cases, methotrexate may be a therapeutic agent of interest; however, current evidence does not point to any added advantage in efficacy over antihistamines. More evidence based on larger, well-executed randomized control trials is needed in the future to get more definitive answers.

Juvenile dermatomyositis in Thai children: Retrospective review of 30 cases from a tertiary care center.

BACKGROUND: Juvenile dermatomyositis is a rare condition, but it is the most common idiopathic inflammatory myopathy in pediatric patients. AIM: To study the clinical manifestations, investigations, treatment, clinical course, and outcomes of juvenile dermatomyositis in Thai children. METHOD: This retrospective study included juvenile dermatomyositis patients treated at Siriraj Hospital, a 2,300-bed national tertiary referral center in Bangkok, Thailand, from 1994 to 2019. RESULTS: Thirty patients (22 females and 8 males) were included with a female to male ratio of 2.7:1. Median age at diagnosis was 5.1 years (range, 2.6-14.8 years). Median duration of illness before diagnosis was 6.5 months (range, 0.3-84.0 months). Acute and subacute onset occurred in the majority of patients. Presenting symptoms included muscle weakness in 27/30 (90%), skin rash in 26/30 (86.7%), muscle pain in 17/26 (65.4%), and arthralgia in 4/18 (22.2%) of patients. Dermatologic examination revealed Gottron's rash, heliotrope rash, and periungual telangiectasia in 25/30 (83.3%), 21/30 (70.0%), and 15/24 (62.5%) of patients, respectively. Interestingly, scalp dermatitis was found in 8/21 (38.1%) of patients. The most commonly used treatment regimen in this series was a combination of prednisolone and methotrexate. During the median follow-up of 3.1 years (range, 0.0-18.5 years), only one-third of patients were seen to have monocyclic disease. Extraskeletal osteosarcoma at a previous lesion of calcinosis cutis was observed in one patient at 12 years after juvenile dermatomyositis onset. LIMITATIONS: This was a retrospective single-center study, and our results may not be generalizable to other healthcare settings. Prospective multicenter studies are needed to confirm the findings of this study. CONCLUSION: juvenile dermatomyositis usually poses a diagnostic and therapeutic challenge, which can be compounded by the ethnic variations in the clinical presentation, as observed in this study. Asian patients tend to present with acute or subacute onset of disease, and arthralgia and/or arthritis are less common than in Caucasian patients. Scalp dermatitis is not uncommon in pediatric juvenile dermatomyositis patients. An association between juvenile dermatomyositis and malignancy, though rare, can occur.

Methotrexate in erythema nodosum leprosum: Pitfalls to avoid.

We read with interest the short report by Rani et al. entitled "An uncommon variant of erythema nodosum leprosum responding well to methotrexate: Report of two cases." The article describes two cases of erythema nodosum leprosum (ENL) with 'atypical features' and good response to low dose methotrexate. The authors address a few concerns regarding methotrexate in ENL, emphasizing the rational usage of this agent.

Management practice, quality of life and associated factors in psoriasis patients attending a dermatological center in Ethiopia.

BACKGROUND: Psoriasis is a chronic inflammatory disease characterized by keratinocyte hyperproliferation and aberrant differentiation with great negative impact on patients' quality of life (QoL). This study aimed at assessing factors influencing management practice, and QoL and its associated factors among ambulatory psoriatic patients visiting All Africa Leprosy, Tuberculosis and Rehabilitation Training (ALERT) Center in Addis Ababa, Ethiopia. MATERIALS AND METHODS: A cross sectional study was conducted in 207 patients with psoriasis attending the dermatology clinic of ALERT Center in Addis Ababa, Ethiopia. Data were collected using structured questionnaire and patients' chart review. Dermatology Life Quality Index (DLQI) was used to measure patients' QoL. Patients' characteristics were summarized using descriptive statistics and predictors of QoL were identified by binary logistic regression. RESULTS: Among 207 study participants, 122 (58.9%) were females. The mean age of the study population was 37.92 (SD = 14.86) years (ranging from 16 to 68 years). The mean age at which diagnosis of psoriasis made was 32 (SD = 13.7) years ranging from 10 to 62 years. The duration of the disease in 112 (54.1%) patients were more than or equal to 5 years. Majority of study participants 145 (70.0%) had plaque psoriasis followed by sebopsoriasis, 24 (11.6%). The majority of plaque psoriasis (80%) cases were managed by topical corticosteroids with or without salicylic acid or coal tar and only 21 (14.5%) treated by methotrexate alone. The mean DLQI was 6.25 corresponding to a moderate effect. Symptoms and feelings were the most affected domains of QoL. Factors associated with poor QoL were female [AOR = 0.17 (95%CI: 0.06, 0.48)], low, above average and high family income ([AOR = 0.12 (95% CI: 0.02, 0.56)], [AOR = 0.06 (95% CI:0.01, 0.32)], and [AOR = 0.03 (95% CI: 0.01, 0.22)]), respectively, and primary education level [AOR = 0.14 (95% CI: 0.03, 0.64)] while being on systemic therapy [AOR = 4.26 (CI: 1.18, 15.35)] was predictor of better QoL. Poor QoL was predominant in females [AOR = 0.17 (95%CI: 0.06, 0.48)], low income [AOR = 0.12 (95% CI: 0.02, 0.56] patients, and patients with primary education level [AOR = 0.14 (95% CI: 0.03, 0.64)]. Patients on systemic therapy [AOR = 4.26 (CI: 1.18, 15.35)] had good QoL. CONCLUSION: Our study identified that topical corticosteroids were the mainstay of psoriasis treatment in the dermatology clinic of ALERT Center in Addis Ababa, Ethiopia. Moderate effect QoL was achieved by study participants based on DLQL score.

An uncommon variant of erythema nodosum leprosum responding well to methotrexate: Report of two cases.

Reactions in leprosy are acute inflammatory episodes that can be classified as type I or type II. Recognition and timely management of these patients is critical to avoid permanent disability. We present two cases of erythema nodosum leprosum, presenting with recurrent atypical features, responding well to a low dose of methotrexate.

Azathioprine weekly pulse versus methotrexate for the treatment of chronic plaque psoriasis: A randomized controlled trial.

BACKGROUND: Methotrexate is the most commonly used drug in the treatment of psoriasis with good efficacy and safety. Recently, weekly azathioprine pulse has been shown to be effective in this disease. AIM: The aim of this study is to compare the effectiveness and safety of weekly pulse doses of azathioprine and methotrexate for the treatment of chronic plaque psoriasis. METHODS: In this randomized controlled trial, 80 patients with chronic plaque psoriasis were recruited. After detailed clinical and laboratory evaluation, patients were randomized to 2 groups to receive either weekly 300 mg azathioprine (n = 40) or 15 mg methotrexate every week (n = 40) for 20 weeks, following which the response to treatment and adverse effects were assessed. The patients were then followed up every 4 weeks for 3 months to determine any relapse. RESULTS: Overall, 48 (60%) patients achieved PASI 75, while 36 (45%) and 59 (73.8%) patients achieved PASI 100 and 50, respectively. On intention to treat analysis, PASI ≥ 75 was achieved in 47.5% (19/40) patients in group 1 compared to 85% (34/40) patients in group 2 (p < 0.001). However, on per protocol analysis, PASI ≥ 75 was achieved in 86% (19/22) patients in group 1 and 92% (34/37) patients in group 2 (p = 0.497). Minor clinical and biochemical adverse effects were noted in both the groups, which were comparable. One (7.7%) patient in group 1 and 4 (17.4%) in group 2 relapsed during follow-up. LIMITATIONS: Limitations of study include small sample size and short follow-up. CONCLUSION: Weekly azathioprine pulse appears to be beneficial in the management of chronic plaque psoriasis. However, it is less effective than weekly methotrexate. It can thus be of use as a therapeutic option in patients with contraindication to methotrexate or other similar agents in this disease.

Methotrexate and prednisolone study in erythema nodosum leprosum (MaPs in ENL) protocol: a double-blind randomised clinical trial.

INTRODUCTION: Erythema nodosum leprosum (ENL) is an immunological complication of leprosy. ENL results in morbidity and disability and if it is not treated can lead to death. The current treatment consists of thalidomide or high doses of oral corticosteroids for prolonged periods. Thalidomide is not available in many leprosy endemic countries. The use of corticosteroids is associated with morbidity and mortality. Identifying treatment regimens that reduce the use of corticosteroids in ENL is essential. Methotrexate (MTX) is used to treat many inflammatory diseases and has been used successfully to treat patients with ENL not controlled by other drugs, including prednisolone and thalidomide. We present the protocol of the 'MTX and prednisolone study in ENL' (MaPs in ENL) a randomised controlled trial (RCT) designed to test the efficacy of MTX in the management of ENL. METHODS AND ANALYSIS: MaPs in ENL is an international multicentre RCT, which will be conducted in leprosy referral centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal. Patients diagnosed with ENL who consent to participate will be randomly allocated to receive 48 weeks of weekly oral MTX plus 20 weeks of prednisolone or 48 weeks of placebo plus 20 weeks of prednisolone. Participants will be stratified by type of ENL into those with acute ENL and those with chronic and recurrent ENL. The primary objective is to determine whether MTX reduces the requirement for additional prednisolone. Patients' reported outcome measures will be used to assess the efficacy of MTX. Participants will be closely monitored for adverse events. ETHICS AND DISSEMINATION: Results will be submitted for publication in peer-reviewed journals. Ethical approval was obtained from the Observational/Interventions Research Ethics Committee of the London School of Hygiene & Tropical Medicine (15762); The Leprosy Mission International Bangladesh Institutional Research Board (in process); AHRI-ALERT Ethical Review Committee, Ethiopia; Ethics Committee of the Managing Committee of the Bombay Leprosy Project; and The Leprosy Mission Trust India Ethics Committee; the Nepal Health and Research Council and Health Research Ethics Committee Dr. Soetomo, Indonesia. This study is registered at www.clinicaltrials.gov. This is the first RCT of MTX for ENL and will contribute to the evidence for the management of ENL.Trial registration numberNCT 03775460.

Metabolic syndrome and female gender, but not methotrexate, are the important associations of significant liver fibrosis in patients with moderate-to-severe psoriasis as detected by transient elastography.

BACKGROUND: Many international guidelines on psoriasis management have emphasized upon the need to identify risk factors for liver fibrosis and that the risk may be increased after a certain total cumulative dose of methotrexate. METHODS: Consecutive patients with moderate-to-severe psoriasis were assessed for liver fibrosis using transient elastography and noninvasive scores. Based on the presence of significant liver fibrosis, the Odds ratio associated with various factors was calculated using logistic regression analysis. Receiver operating characteristic curves were calculated to find maximal cutoff values of noninvasive tests to detect fibrosis. RESULTS: In this cross-sectional study, 134 patients completed the study. Significant fibrosis (liver stiffness measurement ≥7, corresponding to F2 fibrosis or higher) was seen in 33 (24.6%) patients. Neither methotrexate exposure nor total cumulative dose of ≥1.5 was associated with significant fibrosis. Female sex (P = 0.024) and the presence of metabolic syndrome (P = 0.034) were the two variables associated with significant liver fibrosis. On logistic regression analysis, the odds ratio for the female gender and metabolic syndrome was estimated to be 2.51 (95% confidence interval - 1.09-5.81) and 2.33 (95% confidence interval - 1.03-5.27), respectively. Aspartate transaminase to platelet ratio index, nonalcoholic fatty liver disease score and the fibrosis-4 index had low sensitivity in comparison to transient elastography. LIMITATIONS: These included small sample size, small number of patients with a total cumulative methotrexate dose of >3-4.5 g, and lack of control group consisting of healthy persons. Another is the absence of liver biopsies considered as the gold standard in the diagnosis of liver fibrosis. CONCLUSIONS: Metabolic syndrome and female sex are associated with the development of significant liver fibrosis in patients with psoriasis. Methotrexate exposure does not seem to be significantly associated with significant liver fibrosis.

Ultrasound liver elastography for the detection of liver fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy: A cross-sectional study.

BACKGROUND: Long-term low-dose methotrexate therapy is associated with liver fibrosis. Although liver biopsy is the gold standard for detecting fibrosis, it is an invasive procedure associated with morbidity and mortality risks. Hence noninvasive imaging techniques such as transient elastography (TE) and shear wave elastography (SWE) have been studied to measure liver stiffness. AIMS: To assess the utility of TE and SWE in detecting fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. METHODS: A cross-sectional prospective study was undertaken on 54 patients with psoriasis and reactive arthritis who had received ≥1.5 g of methotrexate. Various clinical and biochemical [fibrosis 4 index (FIB4), aspartate-transaminase-to-platelet ratio index (APRI)] parameters were calculated and liver stiffness measurement (LSM) was done with TE and SWE. The degree of steatosis was measured using controlled attenuation parameter (CAP). Liver biopsy was done when indicated and was interpreted by a pathologist blinded to clinical and imaging results. RESULTS: Fifty four patients with a mean age of 40.3 years and a male-to-female ratio of 5:1 were included. The mean cumulative methotrexate dose was 3.04 g. The median FIB4, APRI, and gamma-glutamyl transpeptidase-to-platelet ratio values were 0.75, 0.23, and 0.15, respectively. The median LSM for TE and SWE was 5.3 and 7.32 kPa, respectively. SWE and TE showed a weak positive correlation (r = 0.26, P = 0.053). The mean CAP was 217 dB/m (area under the receiver operating characteristic = 0.70). In the 19 of 26 cases whose liver biopsies could be assessed, only 4 (21%) showed F1 fibrosis (Ishak staging). The median LSM on SWE was significantly higher in patients with a cumulative methotrexate dose ≥ 4 g when compared with those with a dose <4 g (9.85 vs 7.1, P = 0.02). Other parameters did not correlate with TE and SWE. LIMITATIONS: The small sample size and the low number of cases with significant fibrosis on histopathology were the major limitations of this study. CONCLUSION: Histologically detectable LF is uncommon in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. Both TE and SWE are good at detecting the absence of fibrosis in these patients. In our study, SWE and TE values did not correlate with clinical, biochemical, or histopathological parameters.

Use of methotrexate for leprosy reactions. Experience of a referral center and systematic review of the literature.

BACKGROUND: Patients with leprosy can present with systemic inflammatory complications called leprosy reactions (LR), which can be severe and cause a loss of nerve function. The treatment of choice is prolonged corticosteroid therapy, frequently associated with severe side effects. We have used methotrexate as a corticosteroid-sparing regimen with good results. METHODS: To evaluate the role of methotrexate in managing LR, we performed a systematic review of the literature including our cases. We evaluated studies, prospective and retrospective, in both adults and children, which included any dose/regimen of methotrexate for the treatment of LR type 1 or 2. RESULTS: The systematic search revealed 261 records that yield 21 patients including our 3 cases (19 adults/two children), who were treated with methotrexate for LR type 1 and 2. There were 14 males. Median age was 35 years (P25-P75 28 to 52). Patients showed lepromatous (7), borderline lepromatous (9) or borderline tuberculoid (3) leprosy, among the 19 cases in which the type of leprosy was specified. As for the type of LR, 15 patients showed erythema nodosum leprosum (ENL), five showed LR type 1 and one showed polyarthritis and previous ENL. Methotrexate at weekly doses ranging from 7.5 mg to 20 mg (median 15 mg per week), typically administered with low-dose corticosteroids, was effective and safe as a corticosteroid-sparing agent. CONCLUSIONS: Methotrexate could be a suitable ancillary treatment or alternative to corticosteroids, especially in populations who are more prone to its adverse events. However, this evidence is based only on case reports and short clinical series.

Hansen's Disease and Rheumatoid Arthritis Crossover of Clinical Symptoms: A Case Series of 18 Patients in the United States.

Hansen's Disease (HD) is a rare, chronic granulomatous infection of the skin and peripheral nerves caused by the noncultivable organism Mycobacterium leprae. Arthritis is the third most common symptom of HD. Subjects with both confirmed HD on skin biopsy and chronic arthritis were identified at the National Hansen's Disease Program (NHDP). We conducted a series of medical chart reviews and extracted and logged personally deidentified data into a database and carried out descriptive analyses. Eighteen of 261 subjects presented to the NDHP with both HD and chronic arthritis between 2001 and 2015. Among these, 16 were male, 16 were white, and 15 were residents of Louisiana. The median age at diagnosis of HD was 67 years. Ten of these subjects were diagnosed with borderline lepromatous leprosy, seven were diagnosed with lepromatous, and one was diagnosed with borderline tuberculoid leprosy. Patients were symptomatic with arthritis for a median of 5.3 years before HD diagnosis. Sixty-two percent of patients (11) were diagnosed with rheumatoid arthritis (RA) before HD diagnosis, and 10 of which were seronegative RA. Hands, feet, wrists, and elbows were most commonly reported as affected joints. Over half of the patients (61%) had completed HD multidrug therapy at the time of review, and 73% of these subjects had persistent joint pain requiring steroids or methotrexate for symptomatic control. Chronic arthritis in HD patients is present in a series of US-acquired cases of HD. Arthritis did not resolve with successful treatment of HD in most cases.

Management of chronic neuritis with a combination regimen of lower doses prednisolone and methotrexate: a brief report.

INTRODUCTION: Recommended fixed duration prednisolone regimen was not found effective in the treatment of chronic neuritis. Alternate effective treatment was being sought to reduce the deformity in the field of leprosy. OBJECTIVE: We wished to see whether a prolonged course of prednisolone and methotrexate could be of any help for them. METHODOLOGY: In 2012-2014, an open pilot clinical study was undertaken where three chronic neuritic patients were treated with lower doses prednisolone and methotrexate for 12 months and a follow up period was delivered for 12 months. The study was undertaken in one of the outdoor clinics of the university. RESULTS: Complete and permanent remission of neuritis was achieved with appreciable functional recovery. Few mild self-limiting side-effects from prednisolone were observed and there was no side-effects from methotrexate. CONCLUSION: Prolonged course of prednisolone and methotrexate was found safe and effective in treating chronic neuritis.