Number Age (years, mean (SD)) Sex (% women) Follow-up (years, mean (SD)) Number of rheumatologist visits in 6 months before index date (mean (SD)) NSAID prescription within last 45 days Extra-articular RA DMARD prescription within past 45 days† Methotrexate Sulfasalazine Leﬂunomide Chloroquine/hydroxychloroquine Azathioprine Cyclophosphamide Anti-TNF therapy Gold Others (ciclosporin, mycophenolate mofetil, d-penicillamine) No of hospital admissions in year preceding index date (mean (SD)) No of GP visits in year preceding index date (mean (SD)) No of hospital specialist visits (excluding rheumatologist) in year preceding index date (mean (SD)) Comorbidity (from ICD-9 or drug codes) Diabetes Chronic respiratory disease (COPD/asthma/ILD) Osteoporosis Chronic renal disease Cancer PPI/H2 blocker prescription within last 45 days 55.2 0.2 33.3 2.4 0.3 29.4 1.9 1.7 0.1 7.1 1.8 9.3 20.3 17.9 20.3 4.3 27.9 Cases 13 634 71.9 (6.0) 68.9 1.2 (1.5) 1.5 (2.7) Controls* 68 170 71.8 (5.9) 68.9 1.2 (1.5) 1.4 (2.5) 0.5 (1.0) 7.8 (9.0) 9.9 (13.1) 0.4 (0.8) 6.1 (7.7) 7.6 (10.8) Extended report Table 1 Baseline characteristics of RA subjects at cohort entry (n=16 207) Table 2 Baseline characteristics of cases and matched controls from a base population of 16 207 RA patients, 1985–2003 Age (years, mean (SD)) Female (number (%)) DMARD use at cohort entry* Methotrexate Sulfasalazine Leﬂunomide Chloroquine/hydroxychloroquine Azathioprine Cyclophosphamide Anti-TNF therapy Gold Others (ciclosporin, mycophenolate mofetil, d-penicillamine) 70.9 (5.9) 68.3 37.9 3.3 0.2 42.9 2.2 2.3 0.01 10.6 2.8 *Patients could receive combination disease-modifying antirheumatic drug (DMARD) therapy and contribute to more than one drug category, allowing total to exceed 100%. RA, rheumatoid arthritis; TNF, tumour necrosis factor. the antimalarials chloroquine and hydroxychloroquine (43%) followed by methotrexate (38%). Less than 1% of patients were treated with anti-TNF drugs, reﬂecting the introduction of biological therapy late in the calendar period of the study. During the study period, there were 13 634 ﬁrst-episode NSI during 28 695 person-years of follow-up, generating an overall incidence rate of 47.5/100 person-years. The commonest site of infection was the respiratory tract. The crude rate of NSI in glu- cocorticoid-exposed and unexposed person time was 52.4 and 38.8/100 person-years, respectively. The 13 634 patients with ﬁrst episodes of NSI comprised the cases for the nested case– control analysis. Cases and controls had similar age and sex proﬁles, despite being matched only on entry date and time in cohort (table 2). The mean age was slightly higher in the cases and controls than it was for the whole cohort. The cases had more extra-articular RA and more general practitioner and hospital specialist visits in the year before the index date. They also had a higher preva- lence of all comorbidities (diabetes, chronic respiratory disease, osteoporosis, chronic renal disease and cancer), and more com- monly used gastric acid suppressants. Approximately 35% of patients had current exposure to glu- cocorticoid therapy. Exposure to current glucocorticoid therapy was associated with an increased risk of NSI (age and sex- adjusted RR (aRR) 1.28, 95% CI 1.23 to 1.33; table 3). Further adjustment for concurrent DMARD therapy made little differ- ence to the estimate, although additional adjustment for the a priori confounders reduced the estimate to 1.20 (1.15 to 1.25). Adjusting the deﬁnition of current glucocorticoid exposure to prescriptions dispensed within 15, 30, 90 or 180 days before the index date resulted in aRR estimates of 1.22 (1.16 to 1.28), 1.21 (1.16 to 1.26), 1.18 (1.13 to 1.23) and 1.16 (1.11 to 1.20), respectively. Using the unexposed cohort event rate of 38.8/100 person- years and the aRR of 1.20, the attributable risk from gluco- corticoid therapy was 7.8/100 person-years. In other words, for every 13 patients treated with glucocorticoid therapy over a 1-year period, there would be one additional NSI compared with patients not treated with glucocorticoids. The most commonly dispensed dose of oral glucocorticoid therapy was between 5 and 9.9 mg PEQ per day. All dose categories of oral glucocorticoid therapy appeared to have an increased RR of infection, with a noticeably higher risk at doses greater than 20 mg PEQ per day. There appeared to be a step- wise increased risk associated with increasing dose through the dose categories, notably at 10 and 20 mg PEQ. Only 2% of 958 55.7 0.1 33.0 3.0 0.3 30.7 1.5 0.7 0.1 6.5 1.7 7.8 12.1 15.6 12.1 2.7 20.0 Numbers are percentages unless otherwise stated. *Each patient within the cohort could contribute more than once to the controls. †Patients could receive combination disease-modifying antirheumatic drug (DMARD) therapy and contribute to more than one drug category. COPD, chronic obstructive pulmonary disease; GP, general practitioner; ICD, International Classiﬁcation of Diseases; ILD, interstitial lung disease; NSAID, non-steroidal anti- inﬂammatory drug; PPI, proton pump inhibitor; RA, rheumatoid arthritis. patients had had a systemic glucocorticoid injection in the 45 days before the index date. The association between injectable glucocorticoid therapy and infection was inconclusive, with possible effect sizes ranging from a slight protective effect to a 22% increased risk. Too few patients (<1%) were dispensed both oral and injectable glucocorticoid therapy to enable robust effect estimates. Current exposure to methotrexate was associated with no increased risk of infection compared with no methotrexate (aRR 1.00, 0.95 to 1.04; table 4). Patients currently prescribed sulfasala- zine or antimalarials had a lower rate of infection than those not prescribed those drugs. Cyclophosphamide was associated with a higher risk of infection (aRR 2.14, 1.51 to 3.03). The results for anti-TNF therapy were inconclusive given the small number of patients exposed to them. Gastric acid-suppressive drug pre- scription (proton pump inhibitors or H2 blockers) in the 45 days before the index date was associated with an increased risk of NSI (aRR 1.36, 1.30 to 1.43). In order to explore the validity of the event deﬁnition, we per- formed a sensitivity analysis by requiring any NSI to have both a billing code and an anti-infective prescription within a week of each other. The aRR of NSI for oral glucocorticoid exposure in the preceding 45 days using the stricter outcome deﬁnition was 1.09 (0.98 to 1.22). Ann Rheum Dis 2011;70:956–960. doi:10.1136/ard.2010.144741