Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new arava research articles will be listed here shortly after becoming available to us.
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Medical research on arava
Clinical images: Healing of sacroiliitis with leflunomide and sulfasalazine treatment.
Arthritis Rheum. 2008 Apr 25; 58(5): 1520
Li SG
Z Rheumatol. 2008 Apr 18;
Hartmann U, Schmitt S, Reuss-Borst M
Elevated liver enzymes in patients with rheumatoid arthritis may have various causes. These can range from the rheumatic disease itself, the anti-rheumatic medication or be the manifestation of an associated autoimmune disease. We present the case of a 19-year-old female with known seropositive rheumatoid arthritis who developed severe liver damage after 9 months of anti-rheumatic therapy with leflunomide and adalimumab. Both drugs were stopped. In addition to the underlying disease and the specific anti-rheumatic drugs, a temporary therapy with flucloxacillin as well as an association with newly diagnosed celiac disease had to be considered as possible causes of elevated liver enzymes. Following repeated liver biopsy, autoimmune hepatitis was assumed and prednisolone and azathioprine were initiated. Elevated liver enzymes and bilirubin rapidly returned to normal values.
Novel Therapies for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.
Drugs. 2008; 68(6): 747-770
Lee RW, D'Cruz DP
The rapid expansion in the therapeutic modalities available for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (AAV), with clear limitations in existing strategies, prompted us to undertake a review of novel therapies reported in MEDLINE and EMBASE.Tumour necrosis factor (TNF)-alpha antagonism with infliximab is described favourably in retrospective series and open-label trials. However, evidence from the WGET (Wegener's Granulomatosis Etanercept Trial) does not support the clinical use of etanercept, and a significantly higher malignancy rate following TNFalpha inhibition questions the role of this approach. Uncontrolled evidence alone supports remission induction with rituximab-mediated B-lymphocyte depletion and may be less effective in predominantly granulomatous AAV. Remission following T-lymphocyte depletion can be achieved with alemtuzumab and antithymocyte globulin, but it is not yet clear what the clinical role will be for these agents in AAV. In addition, these agents are associated with prolonged lymphopenia and pulmonary complications, respectively. Stem cell transplantation to support immune reconstitution following the use of such agents has been trialled in AAV, but studies included very few patients.Purine and pyrimidine antimetabolites mycophenolate mofetil and leflunomide are likely to play an important role in the treatment of AAV, but results supporting remission maintenance and induction in the former are limited to uncontrolled trials, such that their use remains experimental at this time. Similarly, 15-deoxyspergualin may provide an alternative to cyclophosphamide but awaits randomized controlled trial evidence. The MEPEX (MEthylprednisolone versus Plasma EXchange) trial supports plasma exchange in renal disease but this may be limited by pulmonary complications. Randomized controlled evidence also exists for intravenous immunoglobulin, although improvement may not be sustained. Antimicrobial therapy may be of use in Wegener's granulomatosis patients with predominantly upper respiratory tract involvement.Safety concerns, notably of infection and malignancy, were common and need to be explored in subsequent trials. In addition, concomitant immunosuppressants and non-standardized definitions were major limitations, and future studies of these and newer agents must follow agreed standards of study design and reporting to facilitate clearer interpretation of the circumstances (e.g. disease stage, severity or organ involvement) under which these agents perform optimally. Consequently, use is still limited to centres experienced in such agents and mostly in the context of clinical trials.
Leflunomide-induced subacute cutaneous lupus erythematosus with erythema multiforme-like lesions.
Lupus. 2008; 17(4): 329-31
Marzano A, Ramoni S, Del Papa N, Barbareschi M, Alessi E
Leflunomide is an immunosuppressive agent that acts by inhibiting pyrimidine synthesis in lymphocytes and other rapidly proliferating cells, as well as by suppressing tumor necrosis factor-alpha-induced cellular responses. A number of leflunomide-related adverse events have been reported. Among cutaneous side effects, a few cases of subacute cutaneous lupus erythematosus have been described. We report a previously undocumented reaction to leflunomide, manifesting as subacute cutaneous lupus erythematosus and erythema multiforme-like lesions, in a young woman treated with this drug for ankylosing spondylitis. Withdrawal of leflunomide combined with a short cycle of systemic corticosteroid led to the resolution of the patient's rash, indicating this drug as being responsible for the development of the disease. We conclude that leflunomide might have triggered the occurrence of both subacute cutaneous lupus erythematosus and erythema multiforme in a patient with pre-existing autoimmune diathesis. The suppressive effect of this drug on tumor necrosis factor-alpha-related mechanisms might have played a role in the induction of such a unique reaction to leflunomide.
Nihon Kokyuki Gakkai Zasshi. 2008 Mar; 46(3): 195-201
Uruga H, Izumi S, Hojo M, Sugiyama H, Toyota E, Kobayashi N, Kudo K
An 80-year-old woman presented with rapid, progressive and multiple cavitary lesions in both lungs. Rheumatoid arthritis had been diagnosed and been treated with prednisolone (5 mg/day) and bucillamine since 1996. Due to worsening of arthralgia, methotrexate (6 mg/week) and leflunomide (10 mg/day) had been added to the medication since 2003. In April 2005, her chest radiography revealed multiple cavities and nodules predominantly in both upper lung fields, although she complained of no respiratory symptoms. No pathogenic organisms were found, and the cavitary and nodular shadows were increased rapidly within the next 2 months. Therefore, the patient was referred to our hospital in July 2005. Repeat microbiologic findings of sputum were negative for bacteria and fungi, except for Mycobacterium avium (M. avium). She was given a diagnosis of M. avium lung disease, and it seemed to be associated with her compromised status caused by disease modifying anti-rheumatic drugs (DMARDs). She was then successfully treated with combined chemotherapy employed clarithromycin, rifampicin, ethambutol and streptomycin. So far, rapid and progressive deterioration of non-tuberculous mycobacterial lung disease accompanied with an intake of DMARDs had not been reported in Japan. An increase of M. avium complex lung disease in the elderly is now becoming a problem among respiratory physicians. This case highlights the fact that patients who are scheduled to be given DMARDs, particularly elderly case, should be considered to be at an elevated risk of developing non-tuberculous mycobacterial (NTM) lung disease, and the risk of NTM infection should be excluded before prescribing drugs.
Leflunomide as a remission-maintaining therapy in difficult-to-treat dermatomyositis.
Ann Rheum Dis. 2008 May; 67(5): 723
Sangle VS, Sangle SR, D'Cruz DP
Ann Rheum Dis. 2008 Apr 8;
Kis E, Nagy T, Jani M, Molnár E, Jánossy J, Ujhelly O, Német K, Herédi-Szabó K, Krajcsi P
BACKGROUND: Earlier publications have suggested a possible role of the efflux transporter, BCRP (ABCG2, MXR) in acquired resistance to DMARDs, like leflunomide and it's metabolite, A771726 (Teriflunomide). However, direct evidence that BCRP interacts with these drugs was missing. OBJECTIVES: To characterize the interaction between BCRP transporter and leflunomide and its active metabolite, A771726, with emphasis on the nature of interaction (substrate or inhibitor) as well as the kinetic characterization of the interactions. METHODS: Different in vitro membrane based methods (ATPase and Vesicular transport assay) using BCRP-HAM-Sf9 membrane preparations and cellular assays (Hoechst assay and Cytotoxicity assay) on PLB985-BCRP and HEK293-BCRP cell lines overexpressing BCRP were performed. RESULTS: In all assays applied interaction between the investigated drugs and BCRP was detected. In the vesicular transport assay both leflunomide and its metabolite inhibited the BCRP mediated methotrexate transport. Both compounds are likely substrates of BCRP as revealed by the vanadate sensitive ATPase assay. In line with the membrane assays leflunomide and A771726 inhibited BCRP mediated Hoechst efflux from PLB985-BCRP cells. In the cytotoxicity assay overexpression of BCRP confered 20.6 and 7.5-fold resistance to HEK293 cells against leflunomide and A771726, respectively. The resistance could be reversed by Ko134, a specific inhibitor of BCRP. CONCLUSION: Based on the results, we suggest that BCRP via interactions with leflunomide and A771726 could play an important role in the resistance to these drugs. In addition, BCRP may mediate drug-drug interactions when leflunomide is coadministered with other BCRP substrate drugs such as methotrexate.
A single-center experience with BK virus nephropathy.
Clin Nephrol. 2008 Apr; 69(4): 244-50
Ott U, Steiner T, Busch M, Gerth J, Wolf G
Background: BK virus nephropathy has an increasing role in renal transplant dysfunction, since new, highly potent immunosuppressive drugs have been introduced into therapy following renal transplantation. Diagnosis of acute impairment of renal transplant function is complicated by difficulty in differentiating BK virus nephropathy from acute rejection. Patients and methods: We retrospectively described the findings and therapeutic approaches of 6 consecutive patients with BK virus nephropathy in our transplantation center (75 â 80 transplantations/ year). BK virus nephropathy was classified according to Drachenberg et al. [2004]. Results: We observed an incidence rate of < 1% for BK nephropathy in our center. Four patients had a pattern B whereas 2 patients revealed a pattern C of BK virus nephropathy. Focal C4d-positive staining of peritubular capillaries were found in 2 of the 6 cases. For earlier detection of BK nephropathy, a diagnostic algorithm for each patient after renal transplantation was established. Urine was continuously monitored by cytology for decoy cells and PCR for BK virus DNA. If PCR was also positive for the BK virus in plasma, biopsy of the renal allograft was performed. Thereby diagnosis could be confirmed sooner. For treatment of BK nephropathy in our center, we reduced immunosuppressive agents and initiated a virustatic treatment with cidofovir in the first 3 cases. However, results were not satisfactory and two allografts were lost. We then reconsidered our therapeutic approach and switched the immunosuppressive treatment to leflunomide with consistent lowdose steroids. We use therapeutic drug monitoring for leflunomide and aim at a target level of 40 â 100 mg/ml. We lost no allograft with BK nephropathy since using this therapeutic approach. Conclusion: In our center, leflunomide therapy, but not cidofovir, was effective in patients with BK virus nephropathy of the renal allograft.
Pathol Oncol Res. 2008 Apr 8;
Horvath IF, Szanto A, Csiki Z, Szodoray P, Zeher M
Rheumatoid nodules are well established manifestations of rheumatoid arthritis but in the lungs they are very rare according to the literature. In our study we present the case of a 34-year-old woman with rheumatoid arthritis and secondary Sjögren's syndrome who developed multiplex rheumatoid nodules in the lungs 3 years after initiating leflunomide therapy. During leflunomide therapy we did not detect inflammation in the joints. Surprisingly, in November 2005 she started to cough, had low grade fever and low back pain. On the chest X-ray there were multiplex necrobiotic nodules in the lungs. All bacteriological, viral and fungal investigations including tuberculosis, serological tests and cytology were negative. The X-ray, video-associated thoracoscopy and repeated biopsy of the lung followed by histology of the samples proved intrapulmonary rheumatoid nodules, caused by leflunomide.
Vnitr Lek. 2008 Jan; 54(1): 84-99
Becvár R, Vencovský J, Nĕmec P, Suchý D, Procházková L, Pavelka K
Rheumatoid arthritis (RA) is an autoimmune disease of unknown aetiology characterized by presence of chronic symmetric synovitis, which leads to the formation of joint erosions. Generally recommended method for activity assessment of RA is so called Disease Activity Score (DAS). In early RA when low disease activity is present with oligo- or monoarthritis antimalarials are drugs of choice, while sulfasalazine (SAS) is recommended in cases with medium activity without erosions. Initial treatment with methotrexate (MTX) or leflunomide (LEF) should be applied in a very active polyarthritis with a rapid development of erosions. MTX is often combined with other disease modifying drugs (DMARD) and the blockers of tumour necrosis factor alpha (TNF-alpha). LEF is to be administered to the patients in whom the other DMARD are contraindicated or not tolerated. In established RA with oligo- or monoarthritis with permanent low activity SAS is DMARD of choice. In cases with insufficient response and medium activity MTX is used and if it is inefficient LEF or combination of DMARD should be considered. In a very active disease with a rapid evolution of erosions high doses of MTX or LEF are recommended. When extraarticular symptoms of RA are present azathioprine is to be applied and in case of involvement of vital organs cyclophosphamide should be used. When DMARD are failing or contraindicated TNF-alpha blockers are to be applied. When one TNF-alpha blocker is inefficient it should by replaced by another one from the same group or another biological should be used. For indication of biologicals the activity limit is DAS28 5.1 and the decrease of DAS28 more than 1.2 is an efficacy criterion. Nonsteroidal antirheumatic drugs are an important part in the management of RA, and also corticosteroids are often of used in oral or parenteral form. To the complex therapy of RA nonpharmacological means are usually implemented--different physical procedures and various surgeries.