Elizabeth V. Arkema

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.

Being overweight or obese and risk of developing rheumatoid arthritis among women: a prospective cohort study

Objectives To examine the relationship between being overweight or obese and developing rheumatoid arthritis (RA) in two large prospective cohorts, the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII). Methods We followed 109 896 women enrolled in NHS and 108 727 in NHSII who provided lifestyle, environmental exposure and anthropometric information through biennial questionnaires. We assessed the association between time-varying and cumulative Body Mass Index (BMI) in WHO categories of normal, overweight and obese (18.5–<25, 25.0–<30, ≥30.0 kg/m2) and incident RA meeting the 1987 American College of Rheumatology (ACR) criteria. We estimated HRs for overall RA and serologic subtypes with Cox regression models adjusted for potential confounders. We repeated analyses restricted to RA diagnosed at age 55 years or younger. Results During 2 765 195 person-years of follow-up (1976–2008) in NHS and 1 934 518 person-years (1989–2009) in NHSII, we validated 1181 incident cases of RA (826 in NHS, 355 in NHSII). There was a trend toward increased risk of all RA among overweight and obese women (HR (95% CI) 1.37 (0.95 to 1.98) and 1.37 (0.91, 2.09), p for trend=0.068). Among RA cases diagnosed at age 55 years or younger, this association appeared stronger (HR 1.45 (1.03 to 2.03) for overweight and 1.65 (1.34 to 2.05) for obese women (p trend <0.001)). Ten cumulative years of being obese, conferred a 37% increased risk of RA at younger ages (HR 1.37 (1.11 to 1.69)). Conclusions Risks of seropositive and seronegative RA were elevated among overweight and obese women, particularly among women diagnosed with RA at earlier ages.

Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission

Objective The target outcome in early rheumatoid arthritis (ERA) is now remission. This meta-analysis compared the efficacy of initial methotrexate monotherapy versus combination therapy (methotrexate plus biological agent) for clinical remission and radiographic non-progression among ERA patients with minimal or no previous methotrexate exposure. Methods A systematic search was performed for randomised controlled trials of ERA using predefined criteria. A random effects model was used to pool the risk ratio (RR) for clinical and radiographic remission at 52–56 weeks of follow-up. Results Seven trials of combination therapy with infliximab, adalimumab, etanercept or abatacept were included. The majority of studies defined clinical remission as a 28-joint disease activity score (DAS28) of 2.6 or less. Radiographic non-progression was primarily defined as a modified total Sharp score change of less than 0.5 units. All trials demonstrated risk estimates in favour of combination therapy: the pooled RR for achieving clinical remission was 1.74 (95% CI 1.54 to 1.98) and for radiographic non-progression was 1.30 (95% CI 1.01 to 1.68). Significant heterogeneity among studies for the latter outcome was detected (p<0.001). Conclusions The efficacy of combination therapy with a biological agent is superior to methotrexate monotherapy for remission. Combination therapy has a greater initial effect on clinical remission than radiographic non-progression. Uniform definitions of remission are needed and the proportion of subjects who achieve the combined endpoint of clinical and radiographic remission should be considered as a meaningful outcome in future studies of ERA.

A Prospective Study of Periodontal Disease and Risk of Rheumatoid Arthritis

Objective. To test for an association between periodontal disease (PD) and incident rheumatoid arthritis (RA) in a large prospective cohort. Methods. We conducted a prospective analysis of history of periodontal surgery, tooth loss, and risk of RA among 81,132 women in the Nurses’ Health Study prospective cohort. Periodontal surgery and tooth loss were used as proxies for history of PD. There were 292 incident RA cases diagnosed from 1992 to 2004. Information on periodontal surgery and tooth loss in the past 2 years was collected by questionnaire in 1992. Cox proportional hazards models were used to assess relationships between periodontal surgery, tooth loss, and risk of RA adjusting for age, smoking, number of natural teeth, body mass index, parity, breastfeeding, postmenopausal status, postmenopausal hormone use, father’s occupation, and alcohol intake. Results. Compared with those who reported no history of periodontal surgery or tooth loss, women with periodontal surgery or tooth loss did not have a significantly elevated risk of RA in multivariable-adjusted models (RR 1.24, 95% CI 0.83, 1.83; and RR 1.18, 95% CI 0.47, 2.95, respectively). In analyses stratified by ever and never-smokers, ever-smokers with periodontal surgery had an increased risk that was also nonsignificant. Those with severe PD (both history of periodontal surgery and tooth loss) did not have a significant increased risk. Conclusion. In this large cohort of American women, there was no evidence of an increased risk of later-onset RA among those with a history of periodontal surgery and/or tooth loss.

Ten years with biologics: to whom do data on effectiveness and safety apply?

OBJECTIVES During the past decade, the position of biologics in the therapeutic armamentarium, the number of approved indications and the number of available biologics have changed. Available data on (long-term) safety might thus pertain to patient populations not comparable with contemporary patients. The aim of this study was to assess the extent to which contemporary patients who start or switch biologic therapies are comparable with those patients who gave rise to the currently available data on effectiveness and safety. METHODS We identified all adult patients with RA (n=9612), PsA (n=1417) and other SpA (n=1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. RESULTS Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite <50% drug retention at 5 years, most patients remained exposed to some biologic. CONCLUSIONS The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.

Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments

Objective To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies. Methods Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002–2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics. Results Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002–2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007–2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6). Conclusions In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers

Background Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-naïve patients with SpA and to the general population. Methods From the Swedish (Anti-Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS=5448, DANBIO=3255) patients with SpA initiating a first TNFi 2001–2011. From the Swedish National Patient and Population Registers we assembled a TNFi-naïve SpA cohort (n=28,164) and a Swedish age-matched and sex-matched general population comparator cohort (n=131 687). We identified incident cancers by linkage with the nationwide Swedish and Danish Cancer Registers 2001–2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR). Results Based on 1188 cancers among the TNFi-naïve patients with SpA, RR of cancer overall was 1.1 (95% CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-naïve was 0.8 (95% CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6). Conclusions In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study

Objective To examine the association between ultraviolet-B (UV-B) light exposure and rheumatoid arthritis (RA) risk among women in two large prospective cohort studies, the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII). Methods A total of 106 368 women from NHS, aged 30–55 years in 1976, and 115 561 women from NHSII, aged 25–42 in 1989, were included in the analysis. We identified women with incident RA from the start of each cohort until 2008 (NHS) and 2009 (NHSII). Cumulative average UV-B flux, a composite measure of ambient UV exposure based on latitude, altitude and cloud cover, was estimated according to state of residence and categorised as low, medium or high. Estimates of UV-B at birth and age 15 years were also examined. We used multivariable-adjusted Cox proportional hazards models to estimate HR and 95% CI. Results 1314 incident RA cases were identified in total. Among NHS participants, higher cumulative average UV-B exposure was associated with decreased RA risk; those in the highest versus lowest category had a 21% decreased RA risk (HR (95% CI); 0.79 (0.66 to 0.94)). UV-B was not associated with RA risk among younger women in NHSII (1.12 (0.87 to 1.44)). Results were similar for UV-B at birth and at age 15. Conclusions These results suggest that ambient UV-B exposure is associated with a lower RA risk in NHS, but not NHSII. Differences in sun-protective behaviours (eg, greater use of sun block in younger generations) may explain the disparate results.

Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis: a national population-based study

Background Cases of progressive multifocal leukoencephalopathy (PML), a rare but serious disease, have been reported in patients with rheumatoid arthritis (RA) in association with biological therapy, but little is known about the incidence of PML in patients with RA in the absence of treatment exposure. Objective To estimate the incidence rate of PML in patients with RA compared with the general population, with and without exposure to biological agents. Methods Patients with adult onset RA, exposure to biological agents and a diagnosis of PML from 1999 through 2009 were identified from national registries and linked using each Swedish residents unique personal identification number. General population comparators matched on age, sex and county were also identified. Crude and age- and sex-standardised incidence rates (cases per 100 000 person-years) were calculated with 95% CI. Results 66 278 patients with RA and 286 949 general population comparators were included in the study. The incidence rate of PML in the overall RA population was 1.0 (95% CI 0.3 to 2.5) compared with 0.3 (95% CI 0.1 to 0.6) in the general population. The difference in incidence rate was 0.7 (95% CI −0.3 to 17). Among all patients exposed to biological agents, only one patient was diagnosed with PML. Conclusion Data from this national population-based cohort study suggest that patients with RA may have an increased rate of PML compared with the general population.

Patients with ulcerative colitis miss more days of work than the general population, even following colectomy.

BACKGROUND & AIMS It is unclear whether colectomy restores the ability of patients with ulcerative colitis (UC) to work to precolectomy levels. We estimated the burden of sick leave and disability pension in a population-based cohort of patients with UC and the effects of colectomy. METHODS We performed a register-based cohort study using the Swedish National Patient Register and identified working-age patients with UC in 2005 (n = 19,714) and patients who underwent colectomies between 1998 and 2002 (n = 807). Sick leave and disability pension data were retrieved from Statistics Sweden (1995-2005). Data from each patient in the study were compared with those from 5 age-, sex-, education-, and county-matched individuals from the general population. RESULTS In 2005, 15% of patients with prevalent UC received a disability pension, compared with 11% of the general population, and 21% vs 13% had ≥1 sick leave episode (P < .001 for each comparison). The annual median work days lost was 0 in both groups, but patients with UC had higher mean (65 vs 45 days; difference, 20; 95% confidence interval [CI], 18-22 days) and 75th percentile work days lost (37 vs 0 days; difference, 37; 95% CI, 36-38 days). Among patients who underwent colectomies, annual days lost increased from a mean of 40 (median, 0) days 3 years before surgery to 141 (median, 99) days during the year of surgery (P < .001). The number then decreased to a mean of 85 days 3 years after surgery (median, 0). The corresponding 75th percentile days were 17, 207, and 130, respectively. Three years after colectomy, 12% did not work at all compared with 7.2% of the general population (risk difference, 5.2%; 95% CI, 2.7%-7.7%) and compared with 5.9% 3 years before colectomy (P < .001). CONCLUSIONS Patients with UC miss more work days than the general population in Sweden. Although most patients had no registered work loss 3 years after colectomy, work loss was not restored to presurgery or general population levels in the group that underwent colectomy during several years of follow-up.