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Methotrexate is a frequently prescribed drug and is considered to be safe at a low dosage. However, serious complications may occur during treatment. In this article we describe a 78-year-old male who used low-dose methotrexate for psoriatic arthritis. He died of multi-organ failure caused by sepsis and methotrexate intoxication as a result of deteriorating renal function. The second patient was a 56-year-old male who used low-dose methotrexate for rheumatoid arthritis. This patient developed pancytopenia and methotrexate pneumonitis during treatment with methotrexate. We recommend the frequent monitoring of blood count and renal and liver function tests to detect early deterioration. Furthermore, doctors should be aware of conditions and factors predisposing to methotrexate intoxication, such as impaired kidney function and co-medication. If methotrexate intoxication is suspected, intravenous folinic acid should be administered immediately.

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Reactivation of tuberculosis is a severe side effect of anti-TNF treatment. Especially extrapulmonary forms of tuberculosis may occur, which are difficult to diagnose. The diagnosis may be obtained by a thorough search for Mycobacterium tuberculosis. We describe two patients who developed tuberculous peritonitis after infliximab therapy that was prescribed for treatment of rheumatoid arthritis. These cases illustrate that tuberculous peritonitis has a nonspecific clinical manifestation and that Mycobacteria can be difficult to find in ascites fluid. For this reason, tuberculostatic therapy has to be started in case of clinical suspicion. Before starting infliximab therapy, the patient must be thoroughly screened for the presence of (latent) tuberculosis.

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Therapy with disease modifying antirheumatic agents (DMARDs) is often complicated by the occurrence of adverse effects. Although risk factors for several DMARDs have been reported, the prediction of adverse drug reactions is not yet possible. Therefore regular monitoring remains mandatory. Monitoring for adverse effects to DMARDs usually includes one or more of the following: blood count, liver, kidney, urine or ophthalmologic tests. Since most adverse reactions occur during the first few months of treatment, monitoring should be more intense and frequent in this initial phase. Some adverse effects are dose-dependent, and therefore dosage reduction may help alleviate these. Others are idiosyncratic, and often necessitate drug withdrawal. Except for (hydroxy)chloroquine-induced retinopathy and methotrexate-induced liver cirrhosis, most adverse reactions to DMARDs are fortunately reversible.

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Clinical and laboratory factors influencing the discontinuation of second-line antirheumatic drugs were prospectively studied using survival analysis in a consecutive series of 245 patients with recently diagnosed rheumatoid arthritis. A statistically significant influence of age, sex, serum IgA and HLA-DR3 on the discontinuation rate of chrysotherapy because of toxicity was observed. The discontinuation of sulfasalazine was increased by advanced age and high rank order of prescription. With respect to efficacy, high initial disease activity appeared to predispose to treatment termination of hydroxychloroquine, sulfasalazine and penicillamine. Furthermore, an influence of the rank order of prescription on discontinuation of sulfasalazine therapy because of lack of efficacy was found. Of interest is that discontinuation of hydroxychloroquine therapy because of lack of efficacy occurred less frequently in HLA-DR3-positive than in HLA-DR3-negative patients. Although these prognostic factors are of secondary importance in clinical practice, they may be of significance in the interpretation and comparison of clinical trials.

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The disease RA itself is assumed to be a risk factor for the occurrence of adverse drug reactions during sulphasalazine therapy. A meta-analysis comparing treatment termination because of toxicity among RA, inflammatory bowel disease and seronegative spondylarthropathy patients was conducted. It is shown that RA itself does not appear to predispose to treatment discontinuation because of adverse reactions. Differences found in the incidence of side effects among the various disease groups can probably be explained by patient selection, particularly with respect to age, proportion treated for the first time with sulphasalazine, and dosage used. The side effect profiles in the three groups studied are not different. However, a trend towards greater haematological and hepatic toxicity in rheumatic patients is noticed.

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The long-term use of second-line antirheumatic drugs was prospectively studied in a consecutive sample of 245 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment termination due to side-effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of aurothioglucose with treatment termination due to toxicity was significantly less compared with hydroxychloroquine. With regard to lack of efficacy as index cause, the administration time of hydroxychloroquine was significantly less than that of either aurothioglucose or sulphasalazine. Treatment termination due to lack of efficacy or combined insufficient therapeutic response and toxicity proved to be influenced by the initial disease activity and by the rank order of prescription.

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A 56 year old woman with rheumatoid arthritis developed relapsing thrombocytopenia during successive treatments with aurothioglucose, sulphasalazine, and hydroxychloroquine. The presence of IgM or IgG antibodies or immune complexes reactive with autologous platelets could not be shown. Relapsing thrombocytopenia may indicate a genetically determined HLA-DR3 and B8 aberrant immunological response to stimuli such as certain second line drugs.

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