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We describe a patient with rheumatoid arthritis and Hashimotos thyroiditis who developed chronic diarrhea and subsequently diagnosed with collagenous colitis (CC) 5 years after leflunomide initiation. Cessation of leflunomide resulted in complete resolution of diarrhea within 2 months. Although rare, leflunomide-induced colitis should be considered in patients with otherwise unexplained chronic diarrhea. Diagnosis is challenging as symptom onset can occur many years after leflunomide initiation, but diarrheal symptoms typically resolve within weeks to months of stopping the instigating drug.

Leflunomide can be used in management of psoriatic disease. Leflunomide's active metabolite, teriflunomide, is used in the treatment of multiple sclerosis and has unexpectedly been rarely reported to induce pustular psoriasis. In this report, we present a patient with multiple sclerosis who developed inverse psoriasis after starting teriflunomide.

Leflunomide (LEF) is a well-known disease-modifying anti-rheumatic agent (DMARDs) that was approved in 1998 for rheumatoid arthritis (RA) management. It is enzymatically converted into active metabolite teriflunomide (TER) inside the body. LEF and TER possess several pharmacological effects in a variety of diseases including multiple sclerosis, cancer, viral infections and neurobehavioral brain disorders. Despite the aforementioned pharmacological effects exploring these effects in nanomedicine applications has been focused mainly on RA and cancer treatment. This review summarises the main pharmacological, and pharmacokinetic effects of LEF along with highlighting the applications of nanoencapsulation of LEF and its metabolite in different diseases. [ABSTRACT FROM AUTHOR]

Background/Objectives: Polymyalgia Rheumatica (PMR) is an inflammatory condition that primarily affects individuals aged 50 and older, especially in Western countries. Although glucocorticoids are the cornerstone of PMR treatment, these drugs are associated with side effects, making it advisable to use them for the shortest duration possible. However, tapering or discontinuation of glucocorticoids often leads to disease relapses. In this review, we focus on the traditional management of PMR, as well as the potential for therapies that may reduce glucocorticoid use. Special attention is given to the efficacy of biologic agents in PMR management. Methods: A literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing various glucocorticoids and conventional disease-modifying drugs used for the management of isolated PMR, this review specifically focused on the information reported regarding new therapies, with particular emphasis on biologic agents. Results: Prednisone or prednisolone at a dose ranging between 12.5 and 25 mg/day is the agreed-upon treatment for PMR. Due to the side effects associated with prolonged glucocorticoid use and the high frequency of relapses when glucocorticoids are tapered, glucocorticoid-sparing agents have emerged as tools in the management of PMR. Methotrexate has traditionally been the conventional disease-modifying antirheumatic drug (DMARD) unanimously recommended for use in PMR. Other conventional DMARDs, such as leflunomide, have shown promising results but require further study. The use of biologic agents has marked a significant step forward in the management of PMR. While anti-TNF agents failed to provide beneficial effects in isolated PMR, anti-IL-6 receptor agents, such as tocilizumab and sarilumab, have demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease. Other biologic agents, many of which have been used in giant cell arteritis, as well as Janus kinase (JAK) inhibitors, are currently under investigation. Conclusions: Glucocorticoids are the primary treatment for isolated PMR but are associated with comorbidities, especially in patients with pre-existing conditions or frequent relapses. Glucocorticoid-sparing agents, such as methotrexate and biologics, in particular tocilizumab and sarilumab, offer alternatives, improving symptoms and reducing glucocorticoid use. While biologic agents reduce long-term side effects and help achieve disease remission, their use must consider potential side effects and higher costs compared to traditional therapies. [ABSTRACT FROM AUTHOR]

This work focused on analyzing the properties of N‐(5‐nitrothiazol‐2‐yl)furan‐2‐carboxamide (C8H5N3O4S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good‐quality crystals were obtained and studied by NMR (1H and 13C), DEPT 135, UV–Vis, IR, MS and single‐crystal X‐ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C—N—C(=O)—C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N—H...N, N—H...O and C—H...O hydrogen bonds, and C—H...π and π–π interactions that facilitate self‐assembly and the formation of hydrogen‐bonded dimers, which implies the appearance of R22(8) graph‐set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C—S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N—H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol−1 and a minimum of −36.06 kcal mol−1. The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N—H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide. [ABSTRACT FROM AUTHOR]

Background/Objectives: Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. Methods: Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (p < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. Results: Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. Conclusions: These effects may be related to the observed weight loss induced by leflunomide. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine immune-mediated polyarthritis is a common disease that affects young dogs. This study aims at assessing whether leflunomide as add-on treatment to steroids would reduce the rate of relapse and improve survival in dogs with the disease. However, the results of this study suggest that there was no difference in outcomes between dogs that received or did not receive the drug as an add-on therapy. This could provide another step in understanding the nature of immune-mediated diseases and assist practicing veterinarians in making informed decisions about the most appropriate treatment for these conditions. Immune-mediated polyarthritis (IMPA) has a relatively high relapse rate compared to other immune-mediated diseases. Leflunomide is frequently used to treat dogs with IMPA in conjunction with prednisolone. This retrospective cohort study aimed to evaluate the therapeutic efficacy of leflunomide as an adjunctive therapy to prednisolone in reducing relapse and mortality rates in dogs diagnosed with IMPA in Australia. The medical records of client-owned dogs diagnosed with IMPA at a specialist referral hospital in Southeast Queensland from 2017 to 2024 were reviewed. A total of 93 dogs were included in this study, divided into two groups based on the treatment received: Group PRED, consisting of 53 dogs treated with prednisolone as the sole immunosuppressive agent, and Group L+PRED, consisting of 40 dogs that received leflunomide as adjunctive therapy alongside prednisolone. Data collected included breed, age, weight, sex, serum C-reactive protein concentration, results of synovial fluid analysis and microbial culture, treatment protocol, relapse rates and time to relapse, and mortality rates. There was no difference in relapse or mortality rates, time to relapse, nor time to discontinue prednisolone between the PRED and L+PRED groups. The L+PRED group had higher body weights and lower prednisolone dose rate at discharge compared to those in the PRED group. This study demonstrated that the use of leflunomide as an adjunctive therapy to prednisolone for the treatment of dogs with IMPA had no improved outcomes, reduced relapse rates, or shortening in the duration of prednisolone therapy when compared to dogs receiving prednisolone monotherapy. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) chronic retinal necrosis (CRN) is a rare viral retinal infection that occurs in mildly immunocompromised people. It shares some features with both acute retinal necrosis and CMV retinitis. It is typically treated with combination intravitreal and systemic ganciclovir. We discuss the management of a case of CMV CRN with ganciclovir resistance. Case presentation: An 80-year-old female presented with one month of blurry vision in the left eye. She was being treated with abatacept, methotrexate, and prednisone for rheumatoid arthritis. Examination revealed anterior chamber and vitreous cell along with peripheral retinal whitening. Fluorescein angiogram showed diffuse retinal non-perfusion. Aqueous fluid PCR testing returned positive for CMV. The retinitis was initially controlled with oral and intravitreal ganciclovir, but then recurred and progressed despite these therapies. Ganciclovir resistance was suspected and the patient was switched to intravitreal foscarnet injections, along with oral letermovir and leflunomide, which lead to resolution of the retinitis. The patient has now continued with letermovir and leflunomide for approximately 2.5 years without reactivation of the retinitis or need for further intravitreal anti-viral injections and with adequate control of her rheumatoid arthritis. Conclusion: The incidence of CMV CRN may increase in the future as the use of non-cytotoxic immunosuppressive therapies that result in relatively mild immunosuppression also increases. Treatment with ganciclovir is effective but frequently leads to resistance, as in our case. In this situation, combination therapy with letermovir and leflunomide, particularly in the setting of rheumatoid arthritis where leflunomide can also have an anti-inflammatory effect, can be considered. [ABSTRACT FROM AUTHOR]

Introduction: Cochlear implantation has become an increasingly common strategy for aural rehabilitation in patients with severe to profound hearing loss who no longer benefit from conventional amplification. In conjunction, immunosuppressive therapies (e.g. disease-modifying anti rheumatic drugs (DMARDs) have become the keystone of management in numerous autoimmune conditions. Given the increasing prevalence of both, a greater proportion of patients will undergo cochlear implantation while on immune-modulating medications. While these medications are usually well tolerated, immunosuppression may put patients a higher risk for device infections. At present, this is not extensively studied within the cochlear implant literature. Methods: We conducted a retrospective chart review and review of the literature. Results: We present the case of an 81-year-old male who experienced wound dehiscence and infection secondary to leflunomide use for treatment of rheumatoid arthritis. Resolution of these issues was noted with a therapeutic drug holiday, and the patient has subsequently undergone re-implantation without issue. Conclusions: The case highlights a potential CI-associated wound complication in the setting of DMARD therapy. Given the increasing prevalence of both CIs and immunosuppressive therapy, future study on the potential for interaction is warranted to identify the best management strategy in the perioperative setting. [ABSTRACT FROM AUTHOR]

Gastrointestinal intolerance is common in rheumatoid arthritis (RA) patients using methotrexate and may lead to treatment discontinuation. To study the prevalence of gastrointestinal symptoms in a sample of RA methotrexate users as well as its possible association with clinical and epidemiological variables. Cross-sectional study of 192 patients with gastrointestinal symptoms using the MISS (methotrexate intolerance severity score). Clinical and epidemiological variables were collected through chart review and direct questioning. Patients' adherence to methotrexate was evaluated through Moriski–Green–Levin questionnaire. The prevalence of gastrointestinal complaints was high with 55.7% of the sample classified as intolerant. Nausea and pain after drug ingestion were the most common reported complaints. This intolerance was associated with afro-descendant background (p = 0.02); presence of associated fibromyalgia (p = 0.04), concomitant use of glucocorticoids (p = 0.03) and Jak inhibitors (0.03). A tendency towards association with leflunomide use was observed (p = 0.06). Logistic regression was used to test drug associations with methotrexate intolerance, and showed that glucocorticoid use was independently associated with methotrexate intolerance OR = 1.85; 95% CI = 1.01–3.44; p = 0.04. Route of administration, presence of previous gastric complaints, age and methotrexate dose did not interfere with MISS. MISS results were associated with moderate adherence to the drug. There is a high rate of methotrexate intolerance that is more common in afro-descendants, those with associated fibromyalgia, glucocorticoid and Jak inhibitors users. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic inflammatory rheumatic disease that can cause extra-articular manifestations, in particular pleuropulmonary involvement, which is the second leading cause of death in this connective tissue disease. We report a rare pulmonary manifestation of RA. This was a 58-year-old patient being followed for RA on leflunomide with 3 excavated pulmonary nodules measuring 13 mm, 10 mm and 6 mm, for which the diagnostic hypotheses of infection, pulmonary metastases and rheumatoid nodules had been put forward. The diagnosis of excavated pulmonary nodules in rheumatoid arthritis was made after aspiration of one of the nodules, which ruled out infectious and cancerous causes. These nodules regressed 6 months after leflunomide was stopped.

Abstract Background Cytomegalovirus (CMV) chronic retinal necrosis (CRN) is a rare viral retinal infection that occurs in mildly immunocompromised people. It shares some features with both acute retinal necrosis and CMV retinitis. It is typically treated with combination intravitreal and systemic ganciclovir. We discuss the management of a case of CMV CRN with ganciclovir resistance. Case presentation An 80-year-old female presented with one month of blurry vision in the left eye. She was being treated with abatacept, methotrexate, and prednisone for rheumatoid arthritis. Examination revealed anterior chamber and vitreous cell along with peripheral retinal whitening. Fluorescein angiogram showed diffuse retinal non-perfusion. Aqueous fluid PCR testing returned positive for CMV. The retinitis was initially controlled with oral and intravitreal ganciclovir, but then recurred and progressed despite these therapies. Ganciclovir resistance was suspected and the patient was switched to intravitreal foscarnet injections, along with oral letermovir and leflunomide, which lead to resolution of the retinitis. The patient has now continued with letermovir and leflunomide for approximately 2.5 years without reactivation of the retinitis or need for further intravitreal anti-viral injections and with adequate control of her rheumatoid arthritis. Conclusion The incidence of CMV CRN may increase in the future as the use of non-cytotoxic immunosuppressive therapies that result in relatively mild immunosuppression also increases. Treatment with ganciclovir is effective but frequently leads to resistance, as in our case. In this situation, combination therapy with letermovir and leflunomide, particularly in the setting of rheumatoid arthritis where leflunomide can also have an anti-inflammatory effect, can be considered.

OBJECTIVE: To retrospectively evaluate safety and tolerance of leflunomide for long-term treatment of canine idiopathic immune-mediated polyarthritis (IMPA), ANIMALS: 27 dogs with clinical signs and synovial fluid cytology supportive of IMPA with 26 months' follow-up after starting leflunomide. METHODS: Medical records were reviewed to identify dogs prescribed leflunomide for treatment of IMPA from February 2012 to May 2022. Initial leflunomide doses of 2 to 4 mg/kg once daily were prescribed and were titrated to the lowest effective dose with concurrent anti-inflammatory therapy. Complete blood count, serum chemistry, and clinical signs were monitored throughout the course of treatment. RESULTS: Adverse effects potentially attributable to leflunomide noted in 9 of 27 dogs (33%) included vomiting, diarrhea, lethargy, decreased or absent appetite, polyuria and polydipsia, and secondary antibiotic responsive infection and were self-limiting or resolved with outpatient therapy. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) elevation were documented in all dogs prescribed leflunomide plus prednisone, with persistent liver enzyme elevation in 6 of 9 dogs (67%) and normalization after antibiotic therapy in 3 of 9 dogs (33%). The majority of dogs prescribed leflunomide plus NSAID (11/17 [65%] dogs) did not experience liver enzyme elevation; 2 of 17 (12%) dogs developed transient antibiotic-responsive liver enzyme elevations, and 4 of 17 (23%) dogs had persistent liver enzyme elevation. CLINICAL RELEVANCE: Leflunomide was well tolerated for long-term management of IMPA. A significant difference in liver enzyme elevation was identified between dogs prescribed prednisone versus NSAID in combination with leflunomide. Leflunomide with NSAID therapy resulted in less hepatotoxicity compared with leflunomide with prednisone. [ABSTRACT FROM AUTHOR]

Objective: To identify the prevalence and clinical features of leflunomide‐associated peripheral neuropathy in patients with rheumatic disease over a 42‐month observational period between January 1, 2016 and June 30, 2019. Methods: A retrospective observational study was conducted using regional prescription data identifying all patients treated with leflunomide for rheumatic diseases in the Southern District Health Board of New Zealand. Medical records were used to identify patients who developed peripheral neuropathy while receiving treatment with leflunomide. Demographic characteristics, co‐therapies, and additional risk factors for peripheral neuropathy were also recorded. Results: A total of 482 patients were identified as receiving leflunomide for the treatment of rheumatic during the study period. In total, 23 patients developed leflunomide‐induced peripheral neuropathy within the cohort giving a prevalence of 4.7%. Nerve conduction studies (NCS) performed in 18 (78.2%) of these patients confirmed a distal axonal, sensory, or sensorimotor peripheral neuropathy. The majority of patients (n = 22; 95.6%) either improved, stabilized, or resolved on cessation of the drug, with or without medication washout. Adverse symptoms were reported in association with peripheral neuropathy in 15 of the 23 patients (65.2%): these included pain, poor sleep, compromised skin integrity, poor balance, and a Charcot‐like arthropathy. Additional treatment was required to manage symptoms of peripheral neuropathy including nine patients (39%) who received pain relief. Conclusions: This study supports the previously reported association between leflunomide treatment and the development of a peripheral neuropathy. However, our findings suggest that this is more common than the previous estimates. In patients with psoriatic arthritis and previous tarsitis, there appeared to be an association with a Charcot's‐like arthropathy, a complication not previously noted in the literature. [ABSTRACT FROM AUTHOR]

Aim: This study examines treatment patterns and preferences among patients diagnosed with Axial Spondyloarthritis (AxSpA) across different age groups. Material and Method: Ankara Bilkent City Hospital registry enabled a comprehensive cross-sectional analysis of 2,811 patients stratified into three age groups: 18-40, 41-55, and over 55 years. These groups were compared in terms of their treatments. Results: Our findings indicate an increasing prevalence of female patients and comorbidities with age. Medication usage patterns showed a trend towards increased use of Methotrexate and Colchicine with age, while Sulfasalazine and Leflunomide were more commonly prescribed in older age groups. Notably, the use of biologic Disease-Modifying Anti-Rheumatic Drugs (bDMARDs), including anti-Tumor Necrosis Factor (anti-TNF)", "anti-Interleukin (anti-IL) agents, demonstrated a declining trend with advancing age, though not reaching statistical significance. This trend was also reflected in gender-specific treatment distributions, where no significant difference was found in bDMARDs administration among patients over 55 years, contrasting with a higher usage rate in younger male patients. Conclusion: Our study highlights a shift towards more conservative treatment approaches, such as increased conventional synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) use in older patients, likely due to their safety profile and the specific challenges associated with treating older adults, including higher comorbidity rates and medication side effects. These findings emphasize the need for personalized treatment strategies and suggest potential adjustments in clinical practices to better accommodate the aging population, advocating for ongoing research to optimize treatment efficacy and safety for elderly patients with AxSpA. [ABSTRACT FROM AUTHOR]

Objectives To understand the relative efficacy and safety of bimekizumab, a selective inhibitor of IL-17F in addition to IL-17A, vs other biologic and targeted synthetic DMARDs (b/tsDMARDs) for PsA using network meta-analysis (NMA). Methods A systematic literature review (most recent update conducted on 1 January 2023) identified randomized controlled trials (RCTs) of b/tsDMARDs in PsA. Bayesian NMAs were conducted for efficacy outcomes at Weeks 12–24 for b/tsDMARD-naïve and TNF inhibitor (TNFi)-experienced patients. Safety at Weeks 12–24 was analysed in a mixed population. Odds ratios (ORs) and differences of mean change with the associated 95% credible interval (CrI) were calculated for the best-fitting models, and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine relative rank. Results The NMA included 41 RCTs for 22 b/tsDMARDs. For minimal disease activity (MDA), bimekizumab ranked 1st in b/tsDMARD-naïve patients and 2nd in TNFi-experienced patients. In b/tsDMARD-naïve patients, bimekizumab ranked 6th, 5th and 3rd for ACR response ACR20/50/70, respectively. In TNFi-experienced patients, bimekizumab ranked 1st, 2nd and 1st for ACR20/50/70, respectively. For Psoriasis Area and Severity Index 90/100, bimekizumab ranked 2nd and 1st in b/tsDMARD-naïve patients, respectively, and 1st and 2nd in TNFi-experienced patients, respectively. Bimekizumab was comparable to b/tsDMARDs for serious adverse events. Conclusion Bimekizumab ranked favourably among b/tsDMARDs for efficacy on joint, skin and MDA outcomes, and showed comparable safety, suggesting it may be a beneficial treatment option for patients with PsA. [ABSTRACT FROM AUTHOR]

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid 2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into five groups as control, vehicle, and LFND (2.5, 5, and 10 mg/kg). We investigated cardiac enzymes, histopathology, and the mRNA expression of Nrf2, NF-κB, BAX, and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5- to 0.34-fold decrease in Nrf2 and 2.6- to 4.61-fold increases in NF-κB genes) and increased (1.76- and 2.625-fold) serum creatine kinase (CK) and 1.38- and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear, and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration and highlights, for the first time, dysregulation in Nrf2/NF-κB signaling. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of resolution of corneal findings in a patient with atopic keratoconjunctivitis after treatment with leflunomide. Methods: Case report. Results: A 57-year-old male presented with ocular signs and symptoms consistent with severe atopic keratoconjunctivitis. His case was distinguished by impressive sub-epithelial Salzmann-like nodules in the shape of petaloid plaques in both eyes. These keratinized plaques persisted despite topical steroids, tacrolimus ointment, and routine subconjunctival triamcinolone injections. The patient was started on leflunomide 10 mg daily for seropositive rheumatoid arthritis with rapid subsequent improvement in his symptoms, vision, and keratopathy. The patient has remained stable on oral leflunomide. Conclusion: To the authors' knowledge, this is the first case report to describe rapid resolution of "plaque keratopathy" and improvement of AKC with leflunomide treatment. Further work remains to be done to elucidate the role of disease-modifying drugs in atopic keratoconjunctivitis. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, potentially life-threatening, drug-induced hypersensitivity reaction that involves hematological abnormalities (atypical lymphocytosis, eosinophilia), lymphadenopathy, skin eruption, and internal organ involvement (lung, liver, kidney). The 36-year-old female patient was followed by bloody diarrhea, diffuse skin rashes and hepatitis. She was diagnosed with psoriatic arthritis, and Leflunomide 20 mg was added to the treatment six weeks ago. Upon developing hepatic encephalopathy and deepening the fulminant liver failure during the follow-up, a living donor liver from her son was transplanted on the 4th day of hospitalization. The patient had deceased on the second day after liver transplantation due to multiple organ failures. In the literature, mortality in DRESS syndrome is mostly secondary to hepatic failure. Liver transplantation cannot be effective due to systemic involvement and recurrence in the transplanted liver. [ABSTRACT FROM AUTHOR]

BackgroundVaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.MethodsThe protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.ResultsPreclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.ConclusionsWith ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

Background/Objectives: Adverse drug reactions (ADRs) can result in morbidity, mortality, and higher healthcare costs. Given the limited information available on ADRs associated with antirheumatic medications, this study aims to analyse and compare ADR reporting for these drugs in the pharmacovigilance datasets of Western Australia (WA) and the United States (US). Methods: Therapeutic Goods Administration provided WA pharmacovigilance data of selected antirheumatic drugs to from 1995 to 2015. The proportional reporting ratio (PRR) for WA case reports was compared to corresponding USA pharmacovigilance data by assessing the disproportionality of each ADR. clinically significant or true ADRs were determined using the Evans 2001 criteria (n > 2, chi-square > 4, PRR > 2). Results: A total of 232 reports were found in WA, mostly on sixty-nine women aged 45 to 69. Methotrexate, leflunomide, azathioprine, sulfasalazine, and infliximab had the highest reported ADRs, related to gastrointestinal disorders. Patients who used biological agents in WA had 2.7 times the likelihood of reporting true ADRs compared to conventional antirheumatic drugs. The ADR rates in the two datasets were comparable over the study period. Conclusions: The PRR values of ADRs were consistent between WA and US databases. Methotrexate and infliximab use were commonly associated with ADR reports in WA females, with incidence rates comparable to the US; while patients using biological agents were more likely to report true ADRs than those on conventional antirheumatic drugs in WA. [ABSTRACT FROM AUTHOR]

To assess the incidence and prevalence of rheumatoid arthritis (RA) in Poland for the period 2013–2021, total and dependent on gender, age, region and serological status. Information on reported National Health Fund (NHF) health services and reimbursed prescriptions were used, defining an RA patient as a person who had at least two visits in different quarters with ICD-10 code M05 or M06 and at the same time filled at least one reimbursed prescription for a drug whose active substance is methotrexate, sulfasalazine, leflunomide or was treated with biologic disease-modifying anti-rheumatic drugs (bDMRDs) or targeted synthetic DMARDs (tsDMARDs) as part of a drug program financed by the National Health Fund. The nationwide standardised incidence rate of RA in 2021 was 29 persons per 100,000 population (18 per 100,000 population of seropositive vs. 11 per 100,000 population of seronegative RA). The prevalence of RA in Poland in 2021 was 689.0 people per 100,000 population, a total of 0.7% (1.1% in women and 0.3% in men). The incidence of seronegative RA was approximately 38%. The majority of new RA diagnoses were in the sixth and seventh decades of life, irrespective of patients' gender. The results allow RA to be classified as a disease with a significant social impact. A trend of later onset of RA has been observed, which requires special consideration of the needs of patients over 55 years of age. [ABSTRACT FROM AUTHOR]

Objectives The need for glucocorticoid-sparing drugs (GCSD) remains an important issue and is an unmet need in the treatment of polymyalgia rheumatica (PMR). We therefore aimed to assess the effectiveness and safety of methotrexate (MTX) and of leflunomide (LEF) in daily clinical practice in PMR patients from Argentina. Methods A multicentre and observational study (medical records review) of PMR patients seen between 2007 and 2023, who had at least three months of follow-up after starting a GCSD, either MTX or LEF, was performed. Results are expressed as medians and interquartile ranges [25th–75th (IQR)] for continuous variables and percentages for categorical ones. The two treatment groups were compared using χ2 test for categorical variables, Mann–Whitney U test for continuous variables and the log-rank test for time-to-event data. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression. In all cases, a p -value <0.05 was considered statistically significant. Results One-hundred and eighty-six patients (79% female) with a median age of 72 years (IQR, 65–77 years) were included. One-hundred and forty-three patients (77%) were prescribed MTX (15, IQR 10–15) and 43 (23%) LEF (20 mg, fixed dose). Flare-ups (relapses and recurrences) occurred in 13 patients (7%) and were comparable between both groups. Persistent GCSD intake was observed in 145 patients (78%). Glucocorticoid (GC) withdrawal was achieved in 67 of these 145 patients (46%) and this occurred more frequently in the LEF group (P = 0.001). Furthermore, time until prednisone discontinuation was shorter in the LEF-treated patients (4.7 months, IQR 3–20 on LEF versus 31.8 months, IQR 10–82 on MTX, P = 0.000). Remission was found more frequently in the LEF group (P = 0.003). In the multivariate analysis, the probability of remission was higher with LEF therapy (P  =   0.010) and this finding persisted in the subgroup analysis who were followed up < 40 months (OR 3.12, 95% CI = 1.30–7.47, P  = 0.011). Conclusions This study demonstrated the clinical effectiveness of LEF and even its superiority in achieving remission when compared with MTX as GCSD in PMR patients. Further research is needed to support these findings. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion The COVID‐19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease‐modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID‐19 pandemic.A population‐based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations.An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70–79 year‐olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study.DMARD monitoring rates temporarily deteriorated during the COVID‐19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups. [ABSTRACT FROM AUTHOR]

Neonatal hypoxia-ischemia (HI) affects 2–3 per 1000 live births in developed countries and up to 26 per 1000 live births in developing countries. It is estimated that of the 750,000 infants experiencing a hypoxic-ischemic event during birth per year, more than 400,000 will be severely affected. As treatment options are limited, rapidly identifying new therapeutic avenues is critical, and repurposing drugs already in clinical use offers a fast-track route to clinic. One emerging avenue for therapeutic intervention in neonatal HI is to target mitochondrial dysfunction, which occurs early in the development of brain injury. Mitochondrial dynamics are particularly affected, with mitochondrial fragmentation occurring at the expense of the pro-fusion protein Optic Atrophy (OPA)1. OPA1, together with mitofusins (MFN)1/2, are required for membrane fusion, and therefore, protecting their function may also safeguard mitochondrial dynamics. Leflunomide, an FDA-approved immunosuppressant, was recently identified as an activator of MFN2 with partial effects on OPA1 expression. We, therefore, treated C17.2 cells with Leflunomide before or after oxygen-glucose deprivation, an in vitro mimic of HI, to determine its efficacy as a neuroprotection and inhibitor of mitochondrial dysfunction. Leflunomide increased baseline OPA1 but not MFN2 expression in C17.2 cells. However, Leflunomide was unable to promote cell survival following OGD. Equally, there was no obvious effect on mitochondrial morphology or bioenergetics. These data align with studies suggesting that the tissue and mitochondrial protein profile of the target cell/tissue are critical for taking advantage of the therapeutic actions of Leflunomide. [ABSTRACT FROM AUTHOR]

Objective: To describe leflunomide as an adjunctive therapy in the treatment of non‐associative immune‐mediated thrombocytopenia. Materials and Methods: A retrospective study of dogs with a diagnosis of non‐associative immune‐mediated thrombocytopenia treated with leflunomide March 2008 to September 2021 was conducted. Data collected included signalment, clinical signs, physical examination findings and diagnostic testing performed. Medications administered, duration of hospital stay, time to platelet concentration >150×109/L and adverse events during leflunomide therapy were recorded. Relapses within a year of diagnosis were reported. Results: A total of 20 client‐owned dogs met inclusion criteria. Nineteen of 20 dogs (95%) achieved a platelet concentration >150×109/L with leflunomide and prednisone combination therapy and four dogs (21.1%) relapsed during treatment or shortly after treatment. Adverse effects included diarrhoea (n=5), mild lymphopenia (n=9) and mild intermittent anaemia (n=1). A single dog developed hepatotoxicity presumed to be secondary to leflunomide therapy that resolved after drug discontinuation. One dog was treated for aspiration pneumonia during treatment. Two dogs were euthanased while receiving leflunomide. Clinical Significance: Length of hospitalisation, time to platelet recovery, treatment response and relapse rate were comparable with alternative treatment protocols. Most adverse effects did not require leflunomide dose adjustment; however, two dogs died while undergoing leflunomide treatment and there is compelling evidence that one of these dogs experienced fatal infection secondary to immune‐suppression. Hepatotoxicity remains a known complication of leflunomide treatment and serial biochemistry testing is recommended. [ABSTRACT FROM AUTHOR]

The development of perovskite photoelectric devices with excellent performance is largely dependent on the defects in the perovskite films. To address this issue, a specific drug, leflunomide (LF, C12H9F3N2O2), was incorporated into the perovskite to reduce defects and improve its photoelectric properties. It is believed that the C=O bond on LF molecule can interact with the uncoordinated Pb2+ of the perovskite, thereby reducing non-radiative recombination. This novel approach of incorporating LF into perovskite films has the potential to revolutionize the development of high-performance perovskite photoelectric devices. The trifluoromethyl functional (-CF3) group on LF can form a protective layer on the surface of the perovskite film, shielding it from water erosion. Moreover, LF can be utilized to alter the nucleation position of perovskite, thus minimizing the number of defects and optimizing the film quality. Consequently, the LF-doped perovskite film displays low trap density and high photoelectric performance. The LF-doped perovskite film showed a trap density of 8.28 × 1011, which is notably lower than the 2.04 × 1012 of the perovskite film without LF. The responsivity and detectivity of the LF-doped perovskite photodetector were 0.771 A/W and 2.81 × 1011 Jones, respectively, which are much higher than the 0.23 A/W and 1.06 × 1010 Jones of the LF-undoped perovskite photodetector. Meanwhile, the LF-doped photodetector maintained an initial photocurrent of 86% after 30 days of storage in air, indicating drastically increased environmental stability. This strongly suggests that LF is an effective additive for perovskites utilized in optoelectronic devices with high performance. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis is a chronic inflammatory autoimmune skin disease. Several treatment options are available including topical and systemic options. Methotrexate was the main systemic medication in treating severe psoriasis, yet adverse events can limit its use. Leflunomide is an isoxazole derivative that inhibits the synthesis of pyrimidines, and subsequently inhibits RNA and DNA synthesis. Objective: As available data directly comparing MTX to leflunomide in psoriasis are lacking, this double blinded study was designed to compare the efficacy of methotrexate versus leflunomide in the treatment of moderate to severe psoriasis. Methods: The study included 40 patients (25 males and 15 females) with chronic plaque psoriasis, s. Patients were randomly assigned to one of two equal groups, group A for subcutaneous methotrexate injections and group B for leflunomide (loading dose 100mg daily for the first 3 days then 20 mg daily for 3 months. Disease severity was determined by psoriasis area and severity index (PASI) score before and at the end of treatment The treatment response was evaluated at the baseline and weeks 4, 8 and 12 PASI score. Results: Both groups were matching at the baseline in aspects of gender, age, disease duration and PASI scores Both medications yielded comparable results with no significant difference between both groups in PASI score neither in side effects.. Conclusion: Leflunomide can be as effective as methotrexate in treatment of moderate to severe psoriasis.

Abstract Background and objective The effectiveness of immunosuppressive and corticosteroid treatments for Immunoglobulin A (IgA) nephropathy (IgAN) remains thoroughly evaluated. We undertook a meta-analysis to investigate the efficacy and safety of low-dose corticosteroids plus leflunomide for progressive IgA nephropathy. Methods Eligible studies were obtained from PubMed, Embase, and Cochrane Library databases. We also searched the references of the included studies. Our protocol followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist. Eligibility criteria were defined using a PICOS framework. Results Our study included three articles presenting 342 patient cases. Findings revealed that low-dose corticosteroids combined with the leflunomide group were effective in relieving urine protein excretion (UPE) [mean difference (MD) = -0.35, 95% confidence interval (CI): -0.41 to -0.30, P 0.05). Regarding safety, low-dose corticosteroids combined with leflunomide significantly reduced the risk of serious adverse events [odds ratio (OR): 0.11, 95% CI: 0.01 to 0.91, P = 0.04]. Besides, no significant differences were observed between the two groups in the incidence of respiratory infection, abnormal liver function, diarrhea, herpes zoster, alopecia, pruritus, insomnia, pneumonia, diabetes, and urinary tract infection (P > 0.05). Conclusions Low-dose corticosteroids combined with leflunomide are a safe and effective treatment for progressive IgA nephropathy. Trial registration The PROSPERO registration number is CRD42022361883.

Background/Objectives: Leflunomide, an isoxazole immunosuppressant, is widely used in the treatment of diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as lupus nephritis (LN). In recent years, clinical data have shown that some patients have obvious weight loss, liver injury, and other serious adverse reactions after taking leflunomide. However, the causes and mechanisms by which leflunomide reduces weight are unclear. Methods: Therefore, we used a mouse animal model to administer leflunomide, and we observed that the weight of mice in the leflunomide experimental group was significantly reduced (p < 0.01). In this animal experiment, a metabolomic method was used to analyze the livers of the mice in the experimental group and found that the main difference in terms of metabolic pathways was in the metabolism of aromatic amino acids, and it was confirmed that leflunomide can inhibit the limitations of phenylalanine, tyrosine, and tryptophan biosynthesis. Results: Our study revealed that leflunomide inhibited the activity of DAHPS in the gut microbiota, disrupting the metabolism of phenylalanine, tyrosine, and tryptophan, as well as the metabolism of carbohydrates and lipids. Leflunomide also increased endoplasmic reticulum stress by activating the PERK pathway, thereby promoting CHOP expression and increasing apoptosis-induced liver damage. Conclusions: These effects may be related to the observed weight loss induced by leflunomide.

Immune-mediated polyarthritis (IMPA) has a relatively high relapse rate compared to other immune-mediated diseases. Leflunomide is frequently used to treat dogs with IMPA in conjunction with prednisolone. This retrospective cohort study aimed to evaluate the therapeutic efficacy of leflunomide as an adjunctive therapy to prednisolone in reducing relapse and mortality rates in dogs diagnosed with IMPA in Australia. The medical records of client-owned dogs diagnosed with IMPA at a specialist referral hospital in Southeast Queensland from 2017 to 2024 were reviewed. A total of 93 dogs were included in this study, divided into two groups based on the treatment received: Group PRED, consisting of 53 dogs treated with prednisolone as the sole immunosuppressive agent, and Group L+PRED, consisting of 40 dogs that received leflunomide as adjunctive therapy alongside prednisolone. Data collected included breed, age, weight, sex, serum C-reactive protein concentration, results of synovial fluid analysis and microbial culture, treatment protocol, relapse rates and time to relapse, and mortality rates. There was no difference in relapse or mortality rates, time to relapse, nor time to discontinue prednisolone between the PRED and L+PRED groups. The L+PRED group had higher body weights and lower prednisolone dose rate at discharge compared to those in the PRED group. This study demonstrated that the use of leflunomide as an adjunctive therapy to prednisolone for the treatment of dogs with IMPA had no improved outcomes, reduced relapse rates, or shortening in the duration of prednisolone therapy when compared to dogs receiving prednisolone monotherapy.

Introduction: Chronic diseases are responsible for about 38 million deaths annually and represent about 70% of all deaths worldwide. Among these, rheumatoid arthritis is the most common inflammatory rheumatic dis-ease, representing about 10% of all such disorders. Its incidence is approximately 1% of the general popula-tion. Material and method: our study aims to create an experimental model of chronic arthritis on Wistar rats, fe-male sex, to follow the dynamics of joint inflammatory phenomena, the effects of Leflunomide in their evolu-tion and the side effects at cardiac, hepatic and renal level. Discussions: The group of young experimental animals developed more extensive inflammatory phenomena compared to the group of adult animals. Leflunomide did not significantly improve the evolution and resolu-tion of inflammatory phenomena in either group. Conclusions: We showed for the first time in the world the effects of Leflunomide on the heart, with the occur-rence of myocardial necrosis (myocardial infarction) as its main adverse effect. [ABSTRACT FROM AUTHOR]

Background Pigmented contact dermatitis (PCD) is a noneczematous form of allergic contact dermatitis characterized by dermal hyperpigmentation. Allergen avoidance is the cornerstone of therapy, but it is difficult to achieve. The use of immunosuppressives seems rational, but data are lacking. Objectives To compare outcomes with azathioprine (AZA), leflunomide and allergen avoidance (AA) in patients with PCD. Methods A comparative study was conducted on 28 patients with patch test-positive PCD who were randomly allocated to one of three treatment groups: AZA 2 mg kg–1 daily for 24 weeks + AA (n = 10); leflunomide (LEF) 20 mg daily for 24 weeks + -AA (n = 8); AA alone (n = 10). Patients were followed up for an additional 24 weeks. The Dermal Pigmentation Area and Severity Index (DPASI) score and Hindi Melasma Quality of Life scale (MELASQOL) were used to assess hyperpigmentation and quality of life (QoL). respectively. Results Hair colorants (n = 12) and paraphenylenediamine (n = 8) were the most common allergens. Mean (SD) DPASI score decreased from 30.97 (3.69), 32.35 (3.90) and 31.86 (3.47) to 13.78 (4.25), 21.67 (2.99) and 20.64 (3.82) at 48 weeks in the three groups, respectively (P < 0.001); the maximum percentage decline was seen with AZA (56%). Mean (SD) MELASQOL score was reduced in the three treatment groups from 48.0 (6.46), 46.75 (3.69) and 46.6 (4.65) to 19.6 (6.98), 24.5 (5.80) and 24.0 (5.49), respectively, at 48 weeks (P < 0.001). Reductions in DPASI and Hindi MELASQOL scores were significantly correlated. The most frequent adverse event was transaminitis in both the AZA and LEF groups. Conclusions Patients on AZA achieved a statistically significantly greater reduction in DPASI and MELASQOL score; therefore, AZA may fulfil an unmet need in PCD treatment. An objective reduction in hyperpigmentation was paralleled by an improvement in QoL score, reiterating the need for active management of this disease. [ABSTRACT FROM AUTHOR]

The incidence and development of cancer are highly dependent on pathological disturbances in calcium homeostasis of the cell. One of the major pathways for calcium entry is store-operated calcium entry (SOCE), which functions in virtually all cell types. Changes in the expression level of the main proteins organizing SOCE are observed during the development of various cancer types, particularly breast cancer (BC). This leads to unique SOCE with characteristics individual for each type of BC and requires particular therapeutic approaches. In this study, we tested the sensitivity of SOCE in various BC cells to selective ORAI channel inhibitors and the less selective compounds Leflunomide and Teriflunomide, approved by the FDA for clinical use. We also analyzed the vulnerability of SOCE to the influence of factors typical of the tumor microenvironment: hypoxia and acidification. We have observed that the SOCE inhibitors Leflunomide and Teriflunomide suppress SOCE in the triple-negative BC cell line MDA-MB-231, but not in the luminal A BC cell line MCF-7. MDA-MB-231 cells also demonstrate higher pH dependence of SOCE compared to MCF-7 cells. In addition, the oxygen scavenger sodium dithionide also affects SOCE, stimulating it in MDA-MB-231 cells but inhibiting in MCF-7 cells. Overall, our data highlight the importance of considering the different sensitivities of various BC cell types to inhibitors and to microenvironmental factors such as hypoxia and acidification when developing targeted drugs. [ABSTRACT FROM AUTHOR]

Objective Atrial fibrillation (AF) is a potentially lethal complication that leads to increased hospitalization, disability and mortality. Furthermore, the risk of cardiovascular disease is increased in RA. We evaluated whether DMARD treatment is associated with incident AF in patients with seropositive RA (SPRA). Methods The South Korean Health Insurance Review and Assessment Service database was used to identify patients newly diagnosed with SPRA between 2010 and 2020. A nested case-control analysis was performed to match AF-affected patients to unaffected controls for age, sex, follow-up duration, and index year of SPRA diagnosis at a 1:4 ratio. Adjusted conditional logistic regression was used to identify the predictive factors for AF. Results Of the 108 085 patients with SPRA, 2,629 (2.4%) developed new-onset AF, and the proportion of females was ∼67%. In the matched population, pre-existing comorbidities of hypertension, chronic kidney disease, and heart failure were associated with increased risk of AF. Meanwhile, the use of methotrexate (MTX) decreased the risk of incident AF [adjusted odds ratio (aOR), 0.89], whereas the use of leflunomide (LEF) increased AF (aOR, 1.21). In a subgroup of patients aged ≥50 years, LEF and adalimumab increased the occurrence of AF, while MTX decreased AF in males and LEF increased this risk in females. Conclusion Although the number of subjects developing new-onset AF was small, MTX decreased and LEF increased incident AF in patients with RA. Especially, a distinct pattern of AF risk with DMARDs usage was observed according to age and sex. [ABSTRACT FROM AUTHOR]

Background: BK viremia after kidney transplantation (KT) poses significant risk for BK virus‐associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti‐viral therapy with immunosuppressive properties such as leflunomide is an attractive option. Methods: We performed a multi‐center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus‐associated nephropathy in pediatric KT recipients. Results: Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti‐proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni‐ and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). Conclusion: Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction where patients present with fever, morbilliform rash and multiorgan manifestations, which may include acute renal failure, acute respiratory distress syndrome and eosinophilic myocarditis. We present a case of a 60‐year‐old woman with acute heart failure, DRESS syndrome features and human herpesvirus 6 reactivation in the absence of a drug trigger. She was diagnosed with eosinophilic myocarditis and successfully treated with corticosteroid therapy. [ABSTRACT FROM AUTHOR]

To investigate anti-arthritic activity of Quercetin and Curcumin in Freund's complete adjuvant (FCA)-induced arthritis in rats. AA was induced by injecting with Freund's complete adjuvant (FCA). Rats were randomly divided into six groups with 10 mice in each group: (1) Normal group (saline), (2) Vehicle control, (3) Leflunomide (LF, 10 mg/kg), (4) Curcumin (80), (5) Quercetin (40), (6) Curcumin (80) + Quercetin (40). Male SD rats were subjected to treatment with Lut at 10 mg/kg from days 18 to 24 after immunization. Arthritic scores, tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1), paw histopathology and the proteins of P2X4 pathway were assessed at the end of the experiment. Lut reduced the severity of arthritic scores during the experimental period as compared with positive control (RA). Lut significantly suppressed TNF-a and IL-1 as compared with RA group. Histopathological examination indicated that Lut alleviated infiltration of inflammatory cells and synovial hyperplasia as well as protected joint destruction. Lut significantly suppressed inflammatory cells, and Caspase-1p10. Quercetin and Curcumin may be a potential preventive or therapeutic candidate for the treatment of inflammation and arthritis. [ABSTRACT FROM AUTHOR]

Background/Objectives: 25-hydroxy vitamin D (25-OH-D) is a fat-soluble compound that plays many essential functions, including bone formation, neuromuscular functions, and prevention of osteoporosis and inflammation. Recent data indicate that its metabolites are associated with rheumatoid arthritis (RA) progression and neuropathic pain in RA patients. We aimed to assess the effect of RA pharmacotherapy and seasonal variation on serum levels of 25-OH-D in RA patients who received treatment with methotrexate (MTX) or leflunomide (LEF) for at least one year. Methods: This study is a retrospective analysis of data collected from 101 patients with RA who received treatment for at least one year. All of them have supplemented 25-OH-D (2000 IU daily) for at least one year. Results: We observed a significant seasonal variation in 25-OH-D concentration (p = 0.004). Moreover, there were significant differences (p = 0.03) between LEF (50.63 ± 17.73 ng/mL) and MTX (34.73 ± 14.04 ng/mL) treatment groups, but only for the summer population. A correlation was observed between 25-OH-D and RA duration—once again, in the summer population (the whole group—r = −0.64; treatment subgroups—r = −0.82 for LEF and −0.61 for MTX). Deficiency of 25-OH-D (below 20 ng/mL) was confirmed in 28.7% of patients, while 18.8% had suboptimal 25-OH-D levels (20–30 ng/mL). Conclusions: Our results showed that both RA pharmacotherapy and seasonal variation affect the serum levels of 25-OH-D in patients with active RA. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical characteristics, DMARD treatment pattern, remission rate, and factors associated with disease remission of rheumatoid arthritis (RA) patients in Indonesia. Method: A multicenter survey was conducted in 2019–2020 involving 16 hospitals in Indonesia. Inclusion criteria were RA patients who fulfilled the 2010 ACR/EULAR classification criteria, were aged ≥18 years, and have been treated with 1 DMARD or more for at least 6 months, with exclusion criteria being the co‐existence of other autoimmune diseases or pain syndromes. Disease activities and remission rate were defined using DAS28‐ESR. Results: A total of 870 patients were completed for analysis. Remission was achieved in 24.5% of patients, while low disease activity in 18.5%, moderate disease activity in 44.6%, and high disease activity in 12.4%. The distribution of conventional DMARDs from subjects was methotrexate 69.9%, leflunomide 15.9%, sulfasalazine 12.0%, chloroquine/hydroxychloroquine 8.9%, and cyclosporine 4.8%. Patients treated with biologic DMARDs were only 0.3%. The mean methotrexate dose was 11.2 ± 4.0 mg/week, and the mean methotrexate duration was 45.1 ± 36.6 months. The majority of patients received glucocorticoids (65.5%). 71.1% received DMARD monotherapy, while 28.9% had combined DMARDs. According to the multivariate analysis, delayed time to diagnosis and treatment (>6 months), DMARD monotherapy, and glucocorticoid use were negatively associated with disease remission. Conclusion: The remission rate of Indonesian RA patients is 24.5%, and low disease activity is 18.5%. Methotrexate and leflunomide are the most frequent conventional DMARDs used. Delayed diagnosis, delayed treatment, and DMARD monotherapy contributed to the current low remission rate in Indonesia. [ABSTRACT FROM AUTHOR]

We describe a patient with rheumatoid arthritis and Hashimoto's thyroiditis who developed chronic diarrhea and subsequently diagnosed with collagenous colitis (CC) 5 years after leflunomide initiation. Cessation of leflunomide resulted in complete resolution of diarrhea within 2 months. Although rare, leflunomide-induced colitis should be considered in patients with otherwise unexplained chronic diarrhea. Diagnosis is challenging as symptom onset can occur many years after leflunomide initiation, but diarrheal symptoms typically resolve within weeks to months of stopping the instigating drug. [ABSTRACT FROM AUTHOR]

Introduction: Kidney allograft survival has increased significantly in the past few decades. However, the more potent immunosuppression has also resulted in a higher incidence of infections including BK virus nephropathy (BKVN). The profile of kidney transplant (KT) recipients including age, basic kidney disease, comorbidities, dialysis vintage, and type of kidney donor in India is different from that of high-income countries. There are very few studies on the incidence and outcomes of BKVN from India. We studied the incidence, clinical features, and the impact of a screening strategy on patients with BKVN at our center. Materials and Methods: This was a single-center retrospective record-based study. We screened the medical records of all KT recipients at our center from March 2012 to December 2020 for patients who were diagnosed with BKVN. We compared the incidence of BKVN before and after the implementation of a proactive screening strategy in 2017. Results: From March 2012 to December 2020, a total of 212 KTs were performed at our center. Twenty-eight patients were diagnosed to have BKVN at this time. The incidence of BKVN in our study was 13.2%. The incidence of BKVN before routine screening was initiated at our center was 11.3% whereas it was 13.6% after routine screening was initiated. Graft loss from BKVN was 7.14%. Conclusion: The incidence of BKVN at our center is higher than previously reported in India; however, the rate of graft loss is low. A proactive screening strategy using nucleic acid test may allow early detection of BKVN and may have a beneficial impact on graft outcomes. [ABSTRACT FROM AUTHOR]

A 5 yr old castrated male bichon frise presented with chronic bilateral uveitis that had previously been controlled with systemic steroid administration for 6 mo, resulting in weight gain, polyuria, and polydipsia. To control the uveitis without systemic side effects, oral cyclosporine was started after discontinuing oral steroid, but discontinued one month later because of severe vomiting. Leflunomide (2 mg/kg q 12 hr) was initiated, and the uveitis symptoms resolved after 2 mo. The dose was tapered according to the remission of clinical signs, with no relapse during the following 13 mo. Leflunomide therapy was then discontinued due to vomiting caused by severe gastroenteritis and pancreatitis, and topical prednisolone monotherapy was continued. At 8 mo after discontinuation of leflunomide, bilateral uveitis recurred, and leflunomide therapy was resumed. However, the patient lost vision due to the progression of clinical signs at 33 mo after commencing leflunomide, and evisceration of the glaucomatous right eye was performed at 43 mo. Histopathologic examination revealed lymphocyte and plasma cell infiltration and melanin-laden macrophages in the uveal tissue, and the patient was diagnosed with immune-mediated uveitis. This case indicated that oral leflunomide may be a viable treatment option for canine idiopathic immune-mediated uveitis. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a complex autoimmune disease that affects millions of people worldwide, with a systemic impact. This review explores the role of non-biological conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in its management. We discuss the effectiveness and safety of key csDMARDs such as Nonsteroidal anti-inflammatory drugs, corticosteroids, Hydroxychloroquine, Sulfasalazine, Methotrexate, and Leflunomide in relieving symptoms and slowing the progression of the disease. We also highlight the importance of combination therapy using csDMARDs, supported by clinical studies demonstrating the benefits of various csDMARD combinations. Early intervention with these drugs is emphasized to prevent joint damage, improve clinical symptoms, and enhance patient outcomes. Overall, csDMARDs have proven pivotal in managing RA, providing cost-effective and versatile treatment options. We acknowledge the advantages of biologics but highlight the associated challenges, making the choice between non-biological and biological drugs a personalized decision. This comprehensive overview aims to provide a deeper understanding of RA treatment strategies, contributing to improving the quality of life for patients with this chronic condition. [ABSTRACT FROM AUTHOR]

Abstract Background Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. Results The overall survival time was 769 days (range 14–2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126–2163 days), mycophenolate mofetil 865 days (range 39–2191 days), cyclosporin 441 days (range 11–2176 days), cytosine arabinoside 754 days (range 6–1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23–1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. Conclusions The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.

Objective: This study was to assess the safety and effectiveness of immunosuppressive agents, specifically Voclosporin, when used in conjunction with mycophenolate mofetil (MMF) induction therapy for the management of lupus nephritis (LN). Methods: A systematic review and network meta-analysis (NMA) was conducted on randomized controlled trials investigating the efficacy of immunosuppressant-induced therapy for LN. The random effects model was used in the analysis. I² was used to evaluate the heterogeneity of the model. Odds ratios (OR) and 95% credible intervals (CrI) were computed to assess and compare the relative effectiveness and safety of various treatment protocols. Results: The study included a total of 16 randomized controlled trials (RCTs) involving 2444 patients with LN. The analysis results indicated that there was no significant difference in terms of partial remission (PR) between the drugs. However, when considering complete remission (CR), the combination of Voclosporin with MMF showed the highest remission rate, followed by Tacrolimus (TAC). Unfortunately, Voclosporin in combination with MMF had the highest risk of infection and serious infection, indicating a lower safety profile. Conclusions: Voclosporin in combination with MMF demonstrated the highest efficacy as an induction therapy for LN. However, it should be noted that the risk of infection and serious infection was found to be high with this regimen. On the other hand, TAC not only showed efficacy but also had a lower risk of infection and serious infection, making it a favorable option in terms of safety. This study did' not include results on other adverse events. [ABSTRACT FROM AUTHOR]

Background: Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. Results: The overall survival time was 769 days (range 14–2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126–2163 days), mycophenolate mofetil 865 days (range 39–2191 days), cyclosporin 441 days (range 11–2176 days), cytosine arabinoside 754 days (range 6–1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23–1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. Conclusions: The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed. [ABSTRACT FROM AUTHOR]

Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti‐obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3‐L1 adipocytes by activating TGF‐β‐activated kinase 1 (TAK1), AMP‐activated kinase (AMPK), and Unc‐51 like autophagy‐activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3‐L1 adipocytes, which was blocked by bafilomycin or by beclin‐1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1−/− embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K−/− mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide‐mediated anti‐obesity activity. [ABSTRACT FROM AUTHOR]