Introduction: Leflunomide is a prodrug which is rapidly converted following oral administration and absorption to an active metabolite with anti-proliferative effects (A77 1726/teriflunomide). Leflunomide was developed as an immunomodulatory agent and subsequently developed as a disease-modifying anti-rheumatic drug (DMARD) for the management of rheumatoid arthritis (RA). Areas covered: This review article covers the mechanism of action of the drug, clinical indications, including efficacy data from clinical trials, safety data from clinical trials, post marketing studies and surveillance databases and safety in special populations. Additionally, the review discusses the current place of leflunomide in the management of RA, and its likely future as an anti-rheumatic drug. Expert opinion: Leflunomide is a relatively safe drug, with proven efficacy in RA management. Its clinical use is limited by the historic parallel development of other agents, including methotrexate, which has become the synthetic DMARD of choice and biological DMARDs that have superior efficacy.

To investigate the efficacy of leflunomide in experimental autoimmune uveitis (EAU) in rats.Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to generate EAU. Rats received three dose of leflunomide through intragastric administration (prevention or treatment protocols) after immunization at three separate doses (3 mg/kg/d; 6 mg/kg/d; 12 mg/kg/d). Cyclosporin A was administered as a positive) control. Rats were euthanized during peak disease activity (day 14 or 15). Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d14) and histopathological evaluation of enucleated eyes after experimental termination. The expression levels of inflammatory cytokines in the serum were quantified by ELISA. Eyeball of rats were harvested and mRNA expression of interleukin 17 (IL17) and IFN-γ were quantified through RT-PCR. Intracellular expression of interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. The effects of leflunomide inhibition on immune responses in rats were investigated in isolated lymphocytes.Histopathological and clinical data revealed severe intraocular inflammation in the immunized rat. Inflammation reached its peak on day 14 in this EAU model. Treatment with leflunomide significantly prevented and treated EAU-induced ocular inflammation and decreased clinical and pathological scores compared to vehicle-treated eyes. Gene expression of IL17 and IFN-γwas markedly reduced in leflunomide-treated eyes. Leflunomide significantly decreased the serum levels of IL17 and IFN-γ. The study of IL17+ T cells in peripheral blood and spleen by flow cytometry showed a decreased number of Th17 cell in rats of leflunomide prevented group. Lymphocytes from animals treated with leflunomide had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals.Oral administration of leflunomide effectively suppressed IRBP-induced uveitis in rats. These results suggest that leflunomide may be potentially clinical application in uveitis.

OBJECTIVE:

to analyze the efficacy and safety of non-biologic immunosuppressants in the treatment of non-renal systemic lupus erythematosus (SLE).

METHODS:

Systematic review. We conducted a sensitive literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials up to October 2011. Selection criteria: a) population: adult patients with SLE, b) intervention: treatment with non-biologic immunosuppressant, c) comparator: placebo or active comparator, d) outcome measures assessing efficacy and/or safety. Meta-analyses, systematic reviews, clinical trials and cohort studies were included. The quality of each study was evaluated using the Jadad's scale and Oxford Levels of Evidence.

RESULTS:

one hundred fifty-eight articles were selected for detailed review of the 2,827 initially found. Finally, 65 articles fulfilled the predetermined criteria. Overall, they were low-quality studies with only 11 randomized clinical trials (RCT). Cyclophosphamide demonstrated efficacy for neuropsychiatric SLE preventing relapses with additional steroid-sparing effect although its use was associated with cumulative damage, development of cervical intraepithelial neoplasia and ovarian failure. Other immunosuppressants (azathioprine, methotrexate, leflunomide, mycophenolate mofetil and cyclosporine A) demonstrated efficacy in reducing non-renal activity and flares with a steroid-sparing effect, although on occasions in non placebo-controlled RCTs of small number of patients.

CONCLUSION:

several immunosuppressants have demonstrated their safety and efficacy in non-renal SLE. A specific drug for each particular manifestation cannot be recommended although cyclophosphamide may be kept to be used in more severe cases and methotrexate may be the first option in most cases of moderately active SLE. High-quality RCTs of a larger number of patients are needed. © 2013 by the American College of Rheumatology.

To study whether the effects of Leflunomide were different in treating patients with rheumatoid arthritis (RA) of different Chinese medical syndrome patterns.Totally 150 RA patients were recruited and assigned to 5 Chinese medical syndrome types, i.e., the heat-dampness blocking collateral type, cold-dampness blocking collateral type, Shen-qi deficiency cold type, Gan-Shen yin deficiency type, and stagnant blood blocking collateral type according to Chinese medical syndrome typing standards. They were treated with Leflunomide, 3 months as one therapeutic course. The parameters including numbers of joint tenderness and swelling, morning stiffness time, scores estimated by Visual Analog Scale (VAS), as well as laboratory indices involving rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), American College of Rheumatology 20% improvement (ACR20), and American College of Rheumatology 50% improvement (ACR50) were observed before and after treatment, and statistically analyzed.After treatment the numbers of joint tenderness, numbers of joint swelling, VAS scores, ESR, CRP, and RF all decreased, showing statistical difference when compared with those before treatment (P < 0.05). The morning stiffness time was shortened in the heat-dampness blocking collateral type, cold-dampness blocking collateral type, and stagnant blood blocking collateral type, showing statistical difference (P < 0.05). Of them, the numbers of joint tenderness, the numbers of joint swelling, the morning stiffness time, RF, VAS scores, and the improvement of the total effective rate were obviously better in the heat-dampness blocking collateral type, cold-dampness blocking collateral type, and stagnant blood blocking collateral type than in the Shen-qi deficiency cold type and Gan-Shen yin deficiency type, showing statistical difference (P < 0.05).Leflunomide showed significant effects in treating RA. Of them, its effects were obviously better in the heat-dampness blocking collateral type, cold-dampness blocking collateral type, and stagnant blood blocking collateral type than in the Shen-qi deficiency cold type and Gan-Shen yin deficiency type.

The objective of this paper is make recommendations for the perioperative management of antirheumatic treatment based on the best available evidence. A systematic review was performed including studies in which patients with rheumatic diseases treated with biological and non-biological disease-modifying antirheumatic drugs (DMARDs) had undergone surgery. A total of 5,285 studies were recorded, of which 27 were finally included. These contained information on 5,268 patients and 7,933 surgeries. The majority were women (mean age 55 years) were diagnosed with rheumatoid arthritis, and the most studied drug was methotrexate (MTX). The final recommendations include: maintaining treatment with MTX or leflunomide in the perioperative period in the absence of other risk factors for postoperative complications (Level of Evidence 1c, Grade D recommendation). Biological DMARDs should be temporarily suspended, or the surgery scheduled as far as possible from the last dose, and, if there were other risk factors a space at least two doses (Level of Evidence 2c; Grade D recommendation).

Date (Phoenix dactylifera L.) fruit soluble phenolics composition and anti-atherogenic properties were examined in nine diverse Israeli grown varieties. Ethanol and acetone extracts of 'Amari', 'Barhi', 'Deglet Noor', 'Deri', 'Hadrawi', 'Hallawi', 'Hayani', 'Medjool', and 'Zahidi' fruit were analyzed for phenolics composition by RP-HPLC and tested for anti-atherogenicity by measuring their effects on LDL susceptibility to copper ion- and free radical-induced oxidation, and on serum-mediated cholesterol efflux from macrophages. The most frequently detected phenolics were hydroxybenzoates, hydroxycinnamates, and flavonols. Significant differences in phenolics composition were established between varieties as well as extraction solvents. All extracts inhibited LDL oxidation, and most extracts also stimulated cholesterol removal from macrophages. Considerable varietal differences were measured in the levels of the bioactivities. Also, acetone extracts exhibited a significantly higher anti-atherogenic potency for most varieties. The presence of soluble ingredients with anti-atherogenic capacities in dates and the possible involvement of phenolics are discussed.

Angioinvasive pulmonary infection from filamentous fungi is not an uncommon occurrence in immunocompromised patients like acute lymphoblastic leukemia (ALL). Rarely, these lesions can spread via the hematogenous route and involve multiple visceral organs. We report a case of a 14-year-old boy with ALL who developed angioinvasive pulmonary aspergillosis early in the course of induction therapy, which was followed by hematogenous dissemination and formation of multiple brain abscesses. The patient was treated with intravenous amphotericin B. There was no response to the therapy and the patient succumbed to disseminated infection. Postmortem lung biopsy confirmed angioinvasive pulmonary aspergillosis. Poor penetration of amphotericin B across the blood-brain barrier could be one of the contributory factors for poor response to antifungal therapy. We discuss the various antifungal agents with respect to their penetration in brain.

BACKGROUND:

Reduction in immunosuppression is considered the therapy of proven benefit for BKV infection in renal transplantation, but the use of leflunomide has also been reported. It was observed at this center that the patterns of viral load response while on leflunomide appear to fall into two distinct types.

METHODS:

Medical records of 22 kidney and kidney-pancreas recipients at a single center who received leflunomide therapy for BKV DNAemia were reviewed. Information was collected on demographics, BKV viral loads, other antiviral therapy, immunosuppressive drug levels and doses, adverse effects, and graft and patient outcomes.

RESULTS:

Eighteen of 22 cleared BKV viremia, and 12 of 22 had preserved allograft function; only two graft losses occurred in the screening era among leflunomide-treated patients. Two patterns of viral load reduction were observed, termed the "smooth" and the "zigzag" pattern, which differed in mean time to clear of BKV DNA (2.9 vs. 19.5 months, p = 0.0073). Graft preservation was correlated with lower serum creatinine (SCr) at the start of leflunomide therapy.

CONCLUSIONS:

Long courses and "zigzag" fluctuations in viral load can occur in patients who eventually clear BKV on leflunomide with preserved allograft function. Intermittent increases in viral load do not necessarily portend therapeutic failure. Although the utility of leflunomide is still debated in the transplant community, this information may be useful to clinicians who choose to use it in selected patients.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease with unknown causes and unknown cures in Western medicine. This double-blinded study aimed to investigate the efficacy and safety of a widely used traditional Chinese medicine (Paeoniflorin (PAE) plus cervus and cucumis polypeptide injection (CCPI) using disease-modifying antirheumatic drugs (DMARD) as a control (methotrexate (MTX) plus leflunomide (LEF)). Patients were randomly assigned to one of the three groups: PAE + CCPI, MTX + LEF, and MTX + LEF + CCPI. The primary end point was the American College of Rheumatology 20% improvement response criteria (ACR20). The secondary end point was that of adverse effect frequencies and the speed of onset action. Our results showed that more patients in the CCPI-containing groups responded to the ACR20 during early treatment. After six months, ACR20 showed no significant difference among the three treatments. The maximum improvement in the two DMARD groups was significantly higher than that in the PAE + CCPI group (p < 0.01). CCPI made the onset action of the DMARD therapy 4.6 times faster. PAE + CCPI had significantly lower adverse event incidences than the two DMARD groups. These results indicate that PAE + CCPI appear to be a more acceptable alternative to DMARDs when patients cannot use DMARDs. CCPI appears to be a beneficial add-on to DMARDs that makes the onset of action faster, especially when patients need to relieve RA symptoms as soon as possible. Although not as effective as DMARDs, PAE appears to be a safer option to substitute DMARDs for long-term RA treatment when DMARD toxicity is an issue.

Rheumatic diseases may be active during pregnancy necessitating drug treatment in order to control maternal disease activity and ensure a successful pregnancy outcome. The present literature survey of the last 2 years does not profoundly change the recommendations given in recent reviews: the teratogenic drugs cyclophosphamide, methotrexate, mycophenolate mofetil, and biologics without or with few pregnancy data must be withdrawn before a planned pregnancy. Leflunomide has up to date not shown to be a human teratogen. Drugs that can be used throughout pregnancy include corticosteroids, sulfasalazine, antimalarials, cyclosporine, tacrolimus and azathioprine. Among biological drugs extended pregnancy experience exists only for TNF-inhibitors. The effect of immunosuppressive drugs and biologics on male reproductive function is only partly known.