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Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interest. Bac...

placed): 0.929(0.712); (undisplaced/displaced): 0.847(0.249); Comorbidities (no/yes): 0.963(0.836); Surgical types (arthroplasty/osteosynthesis): 1.405(0.026); Antiosteoporotic treatment (Ͻ2years/none): 0.512(0.006); (2years/none): 0.529 (0.004). CONCLUSIONS: The risk of second hip fracture in elderly 8 year follow up period was the highest in female, in older age-group, in patient after arthroplasty and in patient without pharmacologic treatment for osteoporosis. The effect of single risk factors on the risk of subsequent hip fractures should be investigated in the future. OBJECTIVES:To perform a systematic review of prospective observational studies in patients with RA to examine the safety of TNF-I in daily practice, with particular focus on malignancy, and serious and opportunistic infections. METHODS: Comprehensive searches of Medline, Embase, the Cochrane Database of Systematic Reviews, and ACR, EULAR and BSR conference abstracts were performed according to a pre-specified protocol that excluded randomised controlled trials. Type and site of malignancies, as well as serious and opportunistic infections, such as tuberculosis, were extracted. Publications that reported incidence rates, standardised incidence ratios or measures of relative risk, such as incidence rate ratios, odds ratios or hazard ratios, were selected for random effects meta-analyses. RESULTS: A total of 2039 papers and 1979 abstracts were identified, of which 48 and 21 respectively met the pre-specified inclusion criteria. The pooled estimate for the relative risk (RR) of overall malignancy from seven studies was 0.94 (95% CI 0.84, 1.05; I2 ϭ 0.0%). In contrast, the meta-analysis of serious infections had much higher heterogeneity, I2 ϭ 40.9%, RR ϭ 1.34 (95% CI 1.06, 1.62). CONCLUSIONS: This review included data from European, US and Japanese studies with Ͼ130,000 patient years of exposure. Data from such a large number of patients, often with extended follow-up, overcomes the weaknesses of clinical trial data, specifically fewer patient numbers and usually shorter exposure times. Observational data has known weaknesses related to non-randomisation such that statistical techniques have to be used to overcome differences between the exposed and reference cohorts. Despite such confounding factors, consideration of the available evidence leads to the conclusion that there is an increased risk of serious and opportunistic infections with TNF-I, although no evidence of increased the risk of malignancy. Meta-analyses of randomised controlled trials have come to different conclusions regarding both the risk of infections and of malignancy.

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