Predictors for the 5-year risk of serious infections in patients with rheumatoid arthritis treated with anti-tumour necrosis factor therapy: a cohort study in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.

OBJECTIVE: The use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy. METHODS: Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses. Data were censored at stopping TNF inhibitors or end of observation time up to 5 years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable. RESULTS: During a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model. CONCLUSION: Age, corticosteroid use, VAS pain, HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients.

Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity.

OBJECTIVE: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxicity. METHODS: We included consecutive rheumatoid arthritis patients starting treatment with leflunomide in the region of Friesland (The Netherlands) between January 2000 and January 2002. During follow-up patient characteristics, disease characteristics, and clinical and laboratory data on liver functions were registered. Severity of hepatotoxicity was categorised using the National Cancer Institute Common Toxicity Criteria, as moderate (grade 2), severe (grade 3) or life threatening (grade 4). RESULTS: One hundred and one patients were followed for a median period of 10 months (range 0.5-12). Grade 2 or 3 elevations in any liver function blood test were recorded in a total of nine patients (8.9%). No grade 4 elevations were recorded. Four patients (4%) showed grade 2-3 aminotransferase elevations. Due to grade 2 hepatotoxicity one patient (1%) was withdrawn from leflunomide treatment, and one patient continued leflunomide at a reduced dose. In eight of nine patients with grade 2-3 liver function blood tests, these elevated liver function tests occurred within 6 months after starting leflunomide. None of the patients with grade 2 or 3 toxicity had a history of hepatic disease, eight patients concomitantly used potential hepatotoxic co-medication. Eight (8%) patients used leflunomide in combination with methotrexate, and one of these patients developed hepatotoxicity. No clinical signs of serious hepatotoxicity were recorded during follow-up. DISCUSSION: In 8.9% of the patients, grade 2 or 3 hepatotoxicity was recorded within the first year after the start of leflunomide therapy based on liver enzyme determinations. In the majority of the patients liver enzyme elevations occurred within the first 6 months of therapy and resolved during continued follow-up. None of the patients showed clinical signs of hepatotoxicity. CONCLUSION: Under continued monitoring of liver functions hepatotoxicity during leflunomide use does not seem to be a major problem in our population.

An evidence-based assessment of the clinical significance of drug-drug interactions between disease-modifying antirheumatic drugs and non-antirheumatic drugs according to rheumatologists and pharmacists.

BACKGROUND: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a need for better assessment of their clinical relevance. OBJECTIVE: This study evaluates the interdisciplinary agreement between rheumatologists and clinical (hospital) pharmacists in assessing the clinical relevance of DDIs with disease-modifying antirheumatic drugs (DMARDs) and non-DMARD medications. METHODS: Potential DDIs were identified from the medical literature using MEDLINE and EMBASE for the years 1968-2009. The following search terms were used for the key word, title, and abstract sections of the publications: interaction(s), DMARD, disease-modifying antirheumatic drug(s), antirheumatic, rheumatology, rheumatoid arthritis, and the names of the individual DMARDs of interest (abatacept, adalimumab, anakinra, auranofin, aurothioglucose, aurothiomalate, d-penicillamine, etanercept, gold, [hydroxy]-chloroquine, interleukin-1 receptor antagonist, IL1-RA, infliximab, leflunomide, methotrexate, rituximab, and sulfasalazine/sulphasalazine). Reference lists of the retrieved publications were searched for further information on potential DDIs. All pharmacodynamic or pharmacokinetic DDIs between a DMARD and a non-DMARD identified were included in the study, with the exception of evidence regarding DMARD doses higher than used in the treatment of rheumatoid arthritis and interactions with phytotherapeutic or homeopathic preparations. Using a standard information set for each DDI (eg, from product labeling, textbooks, and the medical literature), a group of rheumatologists and a group of clinical pharmacists independently assessed whether the individual drug-DMARD combinations interacted and whether they required immediate intervention. Both groups consisted of 3 members (2 men and 1 woman), aged 40 to 60 years, who had >5 years of clinical experience and were currently involved in clinical practice in large, nonacademic teaching hospitals in the Netherlands. RESULTS: Forty potential DDIs with DMARDs were retrieved and assessed by the 2 groups. For 30 (75%) of these, rheumatologists and clinical pharmacists agreed about the requirement for immediate intervention. Specifically, 17 drug combinations (43%) were judged to interact and to require immediate intervention, and 13 combinations (33%) were judged either not to interact or to interact but not to require immediate intervention. For 10 combinations (25%), rheumatologists and clinical pharmacists were not in agreement. Overall, agreement between the groups was good (kappa = 0.80) for judging whether the drug combinations were interactions, and agreement was fair (kappa = 0.39) for judging whether immediate intervention was required. Prospective analysis of the data showed that rheumatologists tended to recommend immediate intervention more often when the adverse reaction to the DDI involved an increased risk of toxicity of the DMARD. In contrast, clinical pharmacists more often advocated immediate intervention when the adverse reaction involved decreased effectiveness of the DMARD. CONCLUSION: For a subset of DMARD-drug combinations, rheumatologists and clinical pharmacists differed in their assessments of clinical relevance.