Sick leave and disability pension following delivery in women with systemic lupus erythematosus.

OBJECTIVE: To investigate sickness benefits following delivery in mothers with systemic lupus erythematosus (SLE) and mothers without SLE. METHOD: SLE and non-SLE mothers, matched by age and month of delivery, with a singleton liveborn (2004-2008), were identified from the Swedish Lupus Linkage cohort. Work loss (sum of sick leave and disability pension) was studied from 1 year prenatally to 3 years postpartum. Adjusted logistic regression models of covariates associated with > 30 days of work loss in the first and second years postpartum were estimated in SLE mothers. RESULTS: Among 130 SLE mothers and 440 non-SLE mothers, SLE mothers were more likely to have work loss from the prenatal year (42% vs 16%) to 3 years postpartum (49% vs 15%). In SLE mothers, work loss was on average 61 ± 112 days (mean ± sd) in the prenatal year and 38 ± 83 days in the first year postpartum, which increased to 71 ± 114 days in the third year postpartum. Having > 30 days of sick leave in the year of delivery [odds ratio (OR) 4.4, 95% confidence interval (CI) 1.5-12.9] and ≤ 12 years of education (OR 2.6, 95% CI 1.1-6.0) were associated with work loss in the first year postpartum. No covariates were associated with work loss in the second year postpartum. CONCLUSION: SLE mothers more often had work loss in the prenatal year to 3 years postpartum compared to non-SLE mothers. Lower education and sick leave in the year of delivery were associated with a higher odds of work loss in the first year postpartum in SLE.

Preterm birth phenotypes in women with autoimmune rheumatic diseases: a population-based cohort study.

OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort. DESIGN: Retrospective cohort study. SETTING: California, USA. POPULATION: All live singleton births in California between 2007 and 2011 were analysed. Patients with autoimmune disease at delivery were identified by International Classification of Diseases, Ninth Revision , Clinical Modification (ICD-9-CM), codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA). METHODS: Maternally linked hospital and birth certificate records of 2 481 516 deliveries were assessed (SLE n = 2272, RA n = 1501, SSc n = 88, JIA n = 187, DM/PM n = 38). Multivariable Poisson regression models estimated the risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared with the general obstetric population, adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care. MAIN OUTCOME MEASURES: Preterm birth (PTB) was assessed overall (20-36 weeks of gestation) and by subphenotype: preterm prelabour rupture of membranes (PPROM), spontaneous birth, or medically indicated PTB. The risk of PTB overall and for each phenotype was partitioned by gestational age: early (20-31 weeks of gestation) and late (32-36 weeks of gestation). RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27, 95% CI 3.01-3.56), RA (RR 2.04, 95% CI 1.79-2.33), SSc (RR 3.74, 95% CI 2.51-5.58), JIA (RR 2.23, 95% CI 1.54-3.23), and DM/PM (RR 5.26, 95% CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well. CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counselling and close monitoring during pregnancy is crucial. TWEETABLE ABSTRACT: This study found that women with systemic autoimmune diseases have an elevated risk of preterm birth phenotypes.

Does SLE widen or narrow race/ethnic disparities in the risk of five co-morbid conditions? Evidence from a community-based outpatient care system.

OBJECTIVE: The heterogeneous spectrum of systemic lupus erythematosus (SLE) often presents with secondary complications such as cardiovascular disease (CVD), infections and neoplasms. Our study assessed whether the presence of SLE independently increases or reduces the disparities, accounting for the already higher risk of these outcomes among racial/ethnic minority groups without SLE. METHODS: We defined a cohort using electronic health records data (2005-2016) from a mixed-payer community-based outpatient setting in California serving patients of diverse racial/ethnic backgrounds. The eligible population included adult patients with SLE and matched non-SLE patients (≥18 years old). SLE was the primary exposure. The following outcomes were identified: pneumonia, other infections, CVD and neoplasms. For each racial/ethnic group, we calculated the proportion of incident co-morbidities by SLE exposure, followed by logistic regression for each outcome with SLE as the exposure. We evaluated interaction on the additive and multiplicative scales by calculating the relative excess risk due to interaction and estimating the cross-product term in each model. RESULTS: We identified 1036 SLE cases and 8875 controls. The incidence for all outcomes was higher among the SLE exposed. We found little difference in the odds of the outcomes associated with SLE across racial/ethnic groups, even after multivariable adjustment. This finding was consistent on the multiplicative and additive scales. CONCLUSION: We demonstrated that SLE status does not independently confer substantial interaction or heterogeneity by race/ethnicity toward the risk of pneumonia, other infections, CVD or neoplasms. Further studies in larger datasets are necessary to validate this novel finding.

Endometriosis and systemic lupus erythematosus: a population-based case-control study.

OBJECTIVE: To investigate the association between endometriosis and systemic lupus erythematosus (SLE) in prospectively collected population-based data. METHODS: We conducted a case-control study using Swedish registers, identifying female SLE cases from the National Patient Register and female controls sampled from the general population matched on birth year, sex and county during 1964-2011. We identified endometriosis diagnoses from the National Patient Register using ICD codes. We estimated odds ratios and 95% confidence intervals using conditional logistic regression models. RESULTS: We identified 2834 cases of SLE and 14,164 controls. Seventy-eight cases were diagnosed with endometriosis prior to their SLE diagnosis and 288 controls were diagnosed prior to the index date. We observed a significant association between endometriosis and subsequent SLE with an odds ratio of 1.39 (95% confidence interval = 1.09-1.78). The association was similar when requiring a laparoscopy/laparotomy within six months of the endometriosis diagnosis (odds ratio = 1.33; 95% confidence interval = 0.84-2.12) while the association was stronger when restricted to endometriosis diagnosed at the same time as hysterectomy (odds ratio = 2.26; 95% confidence interval = 1.47-3.64). CONCLUSIONS: Our findings suggest an association between endometriosis and SLE. Future prospective studies with extended follow-up will be necessary to clarify whether this association is influenced by the timing and severity of endometriosis diagnosis.

What is the impact of chronic systemic inflammation such as rheumatoid arthritis on mortality following cancer?

BACKGROUND: Emerging evidence links inflammation and immune competence to cancer progression and outcome. Few studies addressing cancer survival in the context of rheumatoid arthritis (RA) have reported reduced survival without accounting for the underlying mortality risk in RA. Whether this increased mortality is a cancer-specific phenomenon, an effect of the decreased lifespan in RA or a combination of both remains unknown. METHODS: Using Swedish register data (2001-2009), we performed a cohort study of individuals with RA (N=34 930), matched to general population comparators (N=169 740), incident cancers (N=12 676) and deaths (N=14 291). Using stratified Cox models, we estimated HRs of death associated with RA in the presence and absence of cancer, by stage and time since cancer diagnosis, for all cancers and specific sites. RESULTS: In the absence of cancer, RA was associated with a doubled mortality rate (HR=2.1, 95% CI 2.0 to 2.2). In the presence of cancer, the relative effect of RA on mortality was varied by stage. For cancer (tumour, node, metastases) stages I and II at diagnosis, the relative effect of RA on mortality was the same as in the absence of cancer. For cancers diagnosed at advanced stages with absolute higher mortality, the effect decreased (HR=1.2, 95% CI 1.1 to 1.3). These associations remained across time since cancer diagnosis and were reasonably similar across cancer sites. CONCLUSIONS: Much of the increase in mortality in patients with RA diagnosed with cancer seems to reside with effects of RA independently of the cancer.

Perinatal risk factors for future SLE: a population-based nested case-control study.

OBJECTIVE: To investigate the association between perinatal characteristics and the offspring's risk of lupus using population-based registers in Sweden. METHODS: We conducted a nested case-control study, identifying systemic lupus erythematosus (SLE) cases from the National Patient Register and controls sampled from the general population matched on birth year, sex, and residential county. We obtained data on the mother's health and age during pregnancy and characteristics of labor and delivery from the Medical Birth Register (births from 1973 through 2008) for cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models overall and separately for males and females. RESULTS: We identified 774 cases and 3337 controls. Age at which SLE was first observed ranged from 0 to 36 years old. High birth weight was not a risk factor for SLE and did not differ by sex. Males had a 2.4-fold increased odds of SLE if born preterm (<37 weeks; OR = 2.41; 95% CI 1.09, 5.36). Birth order was significantly associated with SLE, particularly among females (first born vs. not OR = 0.77, 95% CI 0.64, 0.94; continuous birth order OR = 1.12. 95% CI 1.02, 1.24). CONCLUSION: Being born first was associated with reduced odds of SLE and the odds of SLE increased by 12% for every additional birth. Preterm birth was associated with increased odds in males only. Unlike previous work, high birth weight was not a risk factor for SLE.

Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab.

OBJECTIVE: To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy). RESULTS: During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001). CONCLUSIONS: Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.

Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study.

BACKGROUND: Iron-loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first-degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH. OBJECTIVE: To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs. DESIGN: Population-based cohort study. SETTING AND SUBJECTS: A total of 3531 haemochromatosis patients and 11 794 FDRs were identified using nationwide, population-based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997-2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression. RESULTS: Of the 3531 patients, 259 were diagnosed with IHD compared with 3077 of the 37 369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03-1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15-4.81). Of 11 794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6197 among FDRs of controls (HR = 1.05; 95% CI, 0.97-1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72-1.56). CONCLUSIONS: In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD.

Time trends in risk and risk determinants of non-Hodgkin lymphoma in solid organ transplant recipients.

Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after ≥15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.

Sick leave and disability pension before and after initiation of antirheumatic therapies in clinical practice.

OBJECTIVE: To investigate sick leave and disability pension in rheumatoid arthritis (RA) in relation to the initiation of biological and non-biological antirheumatic therapies in clinical practice. METHODS: Patients aged 19-60 years initiating non-biological mono (n=2796) or combination disease-modifying antirheumatic drug (DMARD) therapy (n=973), or biological agents (n=4787) were identified in the Swedish Rheumatology Quality Register between 1999 and 2007. Sick leave and disability pension data (1995-2010) were retrieved from national registers. RESULTS: During the year before the start of mono DMARD, combination DMARD and biological treatment, 10%, 12% and 43% of patients received disability pension benefits, respectively. The corresponding combined annual sick leave and disability pension days were 78 (54+25), 132 (105+27) and 190 (79+111). Irrespective of treatment type, initiators were characterised by a history of increasing sick leave and disability pension. Treatment start was associated with a break in this trajectory: sick leave decreased while disability pension increased, resulting in a net stabilisation of total days. Higher levels of days on sick leave and disability pension at treatment start were observed in patients initiating biologics in 1999 (236 days/year) compared with 2007 (150 days/year; p<0.001), but the trajectory thereafter remained largely similar and contrasted markedly with the level in the general population. CONCLUSION: Sick leave and disability pension increased rapidly before the initiation of antirheumatic therapy, which was associated with a halt but not a reversal of this development. Work ability is a metric of importance for clinical practice, signalling large remaining needs in the RA population, and the need for intervention earlier in the disease process.

Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden.

Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study.

OBJECTIVE: Reports of therapy-related adverse events suggest an elevated rate of malignancy in patients with juvenile idiopathic arthritis (JIA) treated with biologic therapies. However, the scarcity of data on the underlying risk of malignancy in JIA hampers interpretation of these signals. Therefore, the aim of this study was to determine the risk of cancer in patients with JIA as compared with that in the general population. METHODS: Through linkage with a national database, the Swedish Patient Register (comprising inpatient discharges in 1969-2007 and specialist outpatient visits in 2001-2007 in Sweden), a national JIA cohort (n = 9,027) was identified, and each JIA case was matched with 5 general population comparators. Using data from the Swedish Cancer, Census, Death, and Biologics Registers, the occurrence of cancer, vital status, and start of a biologic therapy were identified. The relative risk (RR) of first occurrence of a primary cancer in patients who had not been treated with biologics (biologics-naive patients with JIA) was estimated using Poisson regression, stratified a priori by year of earliest identification of JIA (before 1987 versus 1987 and thereafter). In sensitivity analyses, the data were followed up to 1999, when biologics first became available. RESULTS: In this biologics-naive JIA cohort, 60 malignancies were observed during 131,144 person-years of followup, compared with 266 cancers observed during 661,758 person-years in the general population comparator (0.46 cases/1,000 person-years versus 0.40 cases/1,000 person-years; RR 1.1, 95% confidence interval [95% CI] 0.9-1.5). Patients with JIA identified before 1987 were not at increased risk of cancer, whereas JIA identified in 1987 and thereafter was significantly associated with incident lymphoproliferative malignancies (RR 4.2, 95% CI 1.7-10.7) and cancers overall (RR 2.3, 95% CI 1.2-4.4). Sensitivity analyses did not reveal any ready explanation for this heterogeneity. CONCLUSION: Although absolute risks were low, an elevated risk of malignancy was observed among biologics-naive patients in whom the diagnosis of JIA was made in the past 20 years, which may have implications for the interpretation of cancer signals in patients with JIA treated with newer therapies.

Exposure to maternal smoking and incident SLE in a prospective cohort study.

Current cigarette smoking is a risk factor for SLE, and recent work has demonstrated that early-life smoke exposure was related to the risk of related rheumatic conditions in female children. Therefore, we sought to investigate whether early-life cigarette smoke exposure might be associated with incidence of SLE in adult women. We studied 93,054 Nurses' Health Study (NHS) and 95,554 NHSII participants free of SLE at baseline who provided information on perinatal exposures. By medical record review, 236 incident SLE cases were confirmed (142 NHS and 94 NHSII) among these women using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of smoke exposure with SLE adjusting for race, birth weight, preterm birth and parents' occupation. Combined estimates were computed using random effects meta-analytic techniques. Maternal cigarette smoking did not increase the risk of SLE (relative risk (RR) = 0.9, 95%CI: 0.6 to 1.4) nor did paternal smoking during the participant's childhood (RR = 1.0, 95% CI: 0.8 to 1.3) in combined analyses. Early-life exposure to cigarette smoke due to mothers' or fathers' smoking was not associated with increased risk of adult-onset SLE in women.

Is birthweight associated with risk of rheumatoid arthritis? Data from a large cohort study.

OBJECTIVES: The "fetal origins of adult disease" hypothesis suggests the uterine environment can influence the susceptibility of a fetus to future disease. We examine whether the fetal environment, as reflected by birthweight, could modulate an individual's future risk of rheumatoid arthritis (RA). METHODS: The relationship between birthweight and the risk of incident RA was studied in 87 077 women followed prospectively in the Nurses' Health Study cohort. New cases of RA diagnosed between 1976 and 2002 were confirmed in 619 women. The association between birthweight and the future development of RA was studied in age-adjusted and Cox proportional hazard models adjusting for age and potential confounders, including history of maternal diabetes, childhood socioeconomic status, prematurity, maternal and paternal smoking, as well as additionally adjusting for risk factors for RA including smoking, age at menarche, use of oral contraceptives, use of post-menopausal hormones, total lifetime breastfeeding, and body mass index (BMI) at age 18. RESULTS: In an age-adjusted model, birthweight >4.54 kg vs birthweight 3.2-3.85 kg was associated with a two-fold increased risk of RA (relative risk (RR) = 2.1, 95% CI 1.4 to 3.3). Further adjusting for potential confounders and risk factors did not change this relationship (RR = 2.0, 95% CI 1.3 to 3.0). Findings were similar when we limited cases to those with rheumatoid factor positive RA (RR = 2.1, 95% CI = 1.2 to 3.6). CONCLUSIONS: In this large prospective cohort, birthweight >4.54 kg was associated with a two-fold increased risk of adult onset RA, compared with those of average birthweight. Further study of this observation may provide insight into the pathogenesis of RA.

What can epidemiology tell us about systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is an often-severe autoimmune rheumatic disease most commonly diagnosed in women in their childbearing years. It is thought to develop when genetically predisposed individuals are exposed to one or more environmental triggers. This review outlines the epidemiologic evidence for several putative risk factors including cigarette smoke, hormonal and reproductive factors, environmental silica and infectious exposures, as well as many yet to be identified. We also review the evidence for factors associated with increased disease activity and adverse outcomes in SLE. We review the literature on the epidemiology of SLE, its distribution, potential risk factors for its onset and for adverse outcomes. The information considered in this review was gathered through extensive review of the literature. Online Pubmed literature searches, previous reviews of the epidemiology of SLE and original studies were employed. Epidemiologic studies have helped to identify some of these potential risk factors, including exogenous hormone use, cigarette smoking, infections such as Epstein-Barr virus (EBV) and crystalline silica exposure, but many more have yet to be studied. These exposures may interact with multiple genetic factors in determining susceptibility to SLE. While epidemiologic research has contributed an enormous amount to our understanding of the disease and its pathogenesis, there are many more avenues of epidemiologic research that deserve to be pursued.

Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis.

BACKGROUND: Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents. OBJECTIVE: To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA). METHODS: Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model. RESULTS: 1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment. CONCLUSIONS: In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.