Audrey Low

Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid arthritis compared with the UK general population

Objectives. To quantify the risk of cancer and compare it with that for the general population in a modern cohort of UK patients with RA and to identify risk factors for cancer among this cohort. Methods. The study population comprised biologic-naïve RA subjects receiving non-biologic disease-modifying therapy recruited to the British Society for Rheumatology Biologics Register from 2002 to 2009. Standardized incidence ratios (SIRs) for cancers were calculated using age- and gender-specific cancer rates in the English population. Poisson regression models adjusted for age and gender using England general population data were used to determine the association of other predictors with incident malignancy. Results. The cohort comprised 3771 individuals with RA contributing 13 315 person-years of follow-up. One hundred and eighty-two cancers were reported: 156 solid and 26 myelo- or lymphoproliferative cancers. The overall SIR was 1.28 (95% CI 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and non-Hodgkin lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were higher compared with the general population and risks of prostate cancer (SIR 0.35, 95% CI 0.11, 0.82) and cancers of the female genital organs (SIR 0.35, 95% CI 0.10, 0.90) were reduced. Within the cohort, cancer risk was more than 2-fold higher in current or ex-smokers than in non-smokers. Conclusion. The overall incidence of cancer was increased in this national cohort of subjects with RA. The association of RA with certain cancers needs to be considered when studying the effects of biologic therapy, such as anti-TNF, on cancer risk.

Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis

Objectives Patients with rheumatoid arthritis (RA) are at increased risk of myocardial infarction (MI) compared with subjects without RA, with the increased risk driven potentially by inflammation. Tumour necrosis factor inhibitors (TNFi) may modulate the risk and severity of MI. We compared the risk and severity of MI in patients treated with TNFi with that in those receiving synthetic disease-modifying antirheumatic drugs (sDMARDs). Methods This analysis included patients with RA recruited from 2001 to 2009 to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis starting TNFi (etanercept/infliximab/adalimumab) and a biologic-naïve comparator cohort receiving sDMARD. All patients were followed via physician and patient questionnaires and national death register linkage. Additionally, all patients were linked to the Myocardial Ischaemia National Audit Project, a national registry of hospitalisations for MI. Patients were censored at first verified MI, death, 90 days following TNFi discontinuation, last physician follow-up or 20 April 2010, whichever came first. The risk of first MI was compared between cohorts using COX regression, adjusted with propensity score deciles (PD). MI phenotype and severity were compared using descriptive statistics. 6-month mortality post MI was compared using logistic regression. Results 252 verified first MIs were analysed: 58 in 3058 patients receiving sDMARD and 194 in 11 200 patients receiving TNFi (median follow-up per person 3.5 years and 5.3 years, respectively). The PD-adjusted HR of MI in TNFi referent to sDMARD was 0.61 (95% CI 0.41 to 0.89). No statistically significant differences in MI severity or mortality were observed between treatment groups. Conclusions Patients with RA receiving TNFi had a decreased risk of MI compared with patients with RA receiving sDMARD therapy over the medium term. This might be attributed to a direct action of TNFi on the atherosclerotic process or better overall disease control.

Anti-TNF therapy in women with rheumatoid arthritis with a history of carcinoma in situ of the cervix

While many studies have investigated the risk of cancer following exposure to tumour necrosis factor (TNF) inhibitors,1–3 data are scarce with respect to people with cancer prior to treatment.2 ,4 To our knowledge, no studies have looked at cancer risk following exposure to anti-TNF in patients with a history of premalignant conditions, such as cervical dysplasia and Barretts oesophagus. Guidelines from the British Society for Rheumatology (BSR) advise caution when using anti-TNF in subjects with premalignant conditions.5 Given the uncertainties regarding the use of anti-TNF in people with premalignant conditions, we investigated the outcome of women with rheumatoid arthritis (RA) with a previous history of carcinoma in situ (CIS) of the cervix registered with the BSR Biologics Register.6 The BSR Biologics Register, established in 2001, is following two cohorts of patients: one cohort of patients with RA …

The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA

Objectives To evaluate the risk of gastrointestinal perforation (GIP) in subjects with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF) therapy compared with non-biological disease-modifying antirheumatic drugs (nbDMARDs). Methods Using data from the British Society for Rheumatology Biologics Register, we compared the incidence of GIPs between 11 881 anti-TNF-treated and 3393 nbDMARD-treated RA patients using Cox regression modelling. Hazard ratios (HRs) with confidence intervals (CI) were calculated. Adjustment was made for potential confounders including current steroid use. The study covered the time period between 2001 and 2011. Results There were 42 (upper 20, lower 22) GI perforations: five in the nbDMARD cohort and 37 in the anti-TNF cohort. After adjustment, treatment with TNF antagonists was associated with an HR of 1.6 (95% CI 0.4 to 6.0) for all GIPs, 2.7 (95% CI 0.4 to 18.1) for lower GIPs and 0.9 (95% CI 0.1 to 5.8) for upper GIPs. Current use of steroids was the single most important predictor of GI perforation with an adjusted HR of 2.9 (95% CI 1.5 to 5.4), but this risk was confined to lower GIPs (HR 8.0, 95% CI 2.6 to 24.1). Conclusions We have not found a statistically significant association between anti-TNF treatment and the risk of GIP.

Serious infection risk after 1 year between patients with rheumatoid arthritis treated with rituximab or with a second TNFi after initial TNFi failure: results from The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Abstract Objectives Both TNF inhibitors (TNFi) and rituximab (RTX), a B-cell depleting biologic, can disrupt the immune system in RA. RTX is licensed in Europe for use following TNFi failure. However, safety data on serious infections (SIs) are scarce for RTX in daily practice. This analysis aims to compare the risk of SIs in the first year after a switch to either TNFi or RTX in patients who have failed a first TNFi. Methods This study included patients with RA registered with the British Society for Rheumatology Biologics Register (BSRBR-RA) who switched to either a second TNFi or RTX after failing a first TNFi. Patients were followed until first SI, treatment discontinuation, last recorded follow-up or the end of the first year after the switch, whichever came first. SI was defined as requiring hospitalization, intravenous antibiotics or resulting in death. The risk of first SI was compared between TNFi and RTX using Cox proportional hazard models adjusted using propensity scores using inverse probability of treatment weighting. Results This analysis included 3419 TNFi and 1396 RTX patients contributing 2765 and 1224 person-years (pyrs), respectively. SI occurred in 164 (4.8%) TNFi and 81 (5.8%) RTX patients giving a crude rate of 59 and 66 SI/1000 pyrs, respectively. The adjusted hazard ratio for SI was 1.0 (95% CI: 0.7, 1.4). Conclusion The risk of SIs was comparable over the first year of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi.

Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30‐day and 1‐year mortality after ischemic stroke.

Association between anti-tumour necrosis factor therapy and risk of ischaemic stroke in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Registers-Rheumatoid Arthritis (BSRBR-RA)

Abstract Background People with rheumatoid arthritis are at increased risk of cardiovascular morbidity and mortality, including stroke (cerebrovascular accident [CVA]). Anti-tumour necrosis factor (anti-TNF) therapy may influence the risk of CVA by reducing inflammation. The aim of the analysis was to study the association of anti-TNF therapy with risk of ischaemic CVA in rheumatoid arthritis. Methods The British Society for Rheumatology Biologics Registers-Rheumatoid Arthritis (BSRBR-RA) is an ongoing national prospective observational cohort study. Patients with rheumatoid arthritis recently started on anti-TNF therapy and a biologic-naive comparator group treated only with non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) were recruited to the BSRBR-RA from 2001 to 2008. Patients were followed by physician and patient questionnaires and also linked to the national death register. Incident CVAs were identified from all three sources of follow-up. CVAs were validated against WHO criteria for CVA and further classified as ischaemic CVA using CT brain reports or if ischaemic CVA was reported as the underlying cause of death from death certificates according to International Classification of Diseases 10 (ICD-10) code I63. Patients with a previous CVA were excluded. Risk of ischaemic CVA was compared between the nbDMARD cohort and people ever exposed to anti-TNF using a Cox regression model. Missing baseline data were replaced by multiple imputation. Adjustment was made for confounders using propensity scores stratified by deciles. Findings To Oct 31, 2010, 130 verified incident ischaemic CVAs (21 in 3271 nbDMARD patients, 109 in 11 642 anti-TNF patients) had occurred during 11 973 and 61 226 person-years of observation, respectively (incidence rate 175 vs 178 per 100 000 person-years). After adjustment for confounders, there was no association between ever exposure to anti-TNF and ischaemic CVA risk (hazard ratio 0·88 [95% CI 0·46–1·71]). Interpretation Exposure to anti-TNF therapy does not appear to be associated with risk of ischaemic CVA when compared with nbDMARD therapy. Further follow-up is needed to assess time-varying risk. Funding British Society for Rheumatology.

Evaluating the real-world benefits and risks of anti-tumor necrosis factor therapies

The discovery of tumor necrosis factor-α (TNF-α) as the pivotal cytokine in the inflammatory pathway and the development of drugs specifically targeted at this molecule has revolutionized our treatment of patients with rheumatoid arthritis (RA) and other inflammatory arthritides over the past decade. Trial after trial, investigators have consistently demonstrated efficacy in reducing disease activity, inflammation, and radiographic progression with anti-TNF therapy1. However, questions remain regarding the longterm safety of anti-TNF therapy because of the pleiotropic effects of TNF-α in immune system regulation. Such questions cannot always be answered in the context of a randomized controlled trial (RCT). By its very nature, an RCT is an experiment, an attempt to replicate a controlled laboratory environment using a homogeneous population of study subjects, with preset questions. This limits the generalizability of the results to the wider population of patients we see in routine clinical practice2. Also, some questions, especially about longterm safety, cannot always be answered because the duration of an RCT is relatively short. Observational studies can go some way toward answering these pertinent questions. Over the past decade, a number of biologic registers and other observational studies of “real-world” anti-TNF use have been established and have started to address important questions regarding treatment benefits3,4, longterm treatment persistence5, and safety, with a focus on serious infections6,7,8 and malignancy9,10,11. Many of these studies have been based in large healthcare claims databases, which gather details about patient interactions with the healthcare system12. These studies have the advantage of large sample sizes but can be limited in the detail … Address correspondence to Dr. Hyrich; E-mail: kimme.hyrich{at}manchester.ac.uk

FRI0146 The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy - results from the british society for rheumatology biologics register (BSRBR)

Objectives To evaluate the risk of gastrointestinal perforation (GIP) in subjects with RA treated with anti-TNF therapy compared to non-biological disease-modifying antirheumatic drugs (nbDMARDs). Methods The analysis was conducted in the British Society for Rheumatology Biologics Register (BSRBR), a prospective cohort study. Patients with RA starting treatment with the TNF inhibitors etanercept (ETA), infliximab (INF) or adalimumab (ADA) and a biologic-naïve comparison cohort exposed to nbDMARDs were recruited between 2001-2009. Subjects were followed until 31/3/2011 or death, whichever came first. Events were ascribed to anti-TNF if they occurred while the patient was receiving anti-TNF therapy or within 90 days of the first missed dose. Events were attributed to the most recent drug received in patients who switched anti-TNF therapy. Cox proportional hazards model were developed to compare the rates of GIP between cohorts. A propensity score was used to balance covariates between treatment groups and included age, gender, weight, comorbidity, smoking, indexes of disease severity, use of steroids, NSAIDs, and gastroprotective drugs. Stratification by deciles of propensity score for treatment was used to adjust for confounding between the groups. Current steroid use was entered into the model as a time-varying covariate. Results There were 58 (upper: 25, lower: 33) GI perforations: 5 in the nbDMARD cohort, 37 in the anti-TNF cohort (on drug + 90 days), and 16 in the anti-TNF cohort (off drug). In univariate analyses higher HAQ, history of hypertension, and smoking were associated with the risk of lower GIP, and use of nonselective NSAIDs at baseline and low weight with the risk of upper GIP, irrespective of anti-TNF exposure. After adjustment, treatment with TNF antagonists was associated with hazard ratio (HR) of 1.6 (95% CI 0.4 to 6.0) for all perforations, 2.7 (95% CI 0.4 to 18.1) for lower and 0.9 (95% CI 0.1 to 5.8) for upper GI perforations. Current use of steroids was the single most important predictor of GIP with adjusted HR of 2.9 (95% CI 1.5 to 5.4), but this increase of risk was confined to lower GIPs (HR 8.0, 95% CI 2.6 to 24.1). Table 1 DMARD (N=3393) Anti-TNF (N=11881) Etanercept (N=4129) Infliximab (N=3483) Adalimumab (N=4269) Follow-up (pyrs) 13168 51748 22518 12516 16713 All GIPs: N 5 37 19 8 10 All GIPs: Rate per 100000 pyrs 38 (12, 89) 72 (50, 99) 84 (51, 132) 64 (28, 126) 60 (29, 110) All GIPs: Adjusted HR Referent 1.6 (0.4, 6.0) 1.8 (0.5, 7.5) 1.4 (0.3, 6.0) 1.4 (0.3, 5.8) Lower GIPs: N 2 20 12 3 5 Lower GIPs: Rate per 100000 pyrs 15 (2, 55) 39 (24, 60) 53 (28, 93) 24 (5, 70) 30 (10, 70) Lower GIPs: Adjusted HR Referent 2.7 (0.4, 18.1) 3.9 (0.6, 27.3) 1.6 (0.2, 14.5) 2.2 (0.3, 17.0) Upper GIPs: N 3 17 7 5 5 Upper GIPs: Rate per 100000 pyrs 23 (5, 67) 33 (19, 53) 31 (13, 64) 40 (13, 93) 30 (10, 70) Upper GIPs: Adjusted HR Referent 0.9 (0.1, 5.8) 0.8 (0.1, 5.9) 1.0 (0.1, 7.9) 0.9 (0.1, 6.3) Conclusions Anti-TNF therapy was not associated with statistically significant increase of all GI perforations, although there was a signal of possible increased risk of lower GI perforations. Current use of steroids was the single most important risk factor for lower GI perforations. Disclosure of Interest None Declared

SAT0148 Does depression affect response to anti-tumour necrosis factor-α therapy in patients with rheumatoid arthritis (RA)? Results from the british society for rheumatology biologics register (BSRBR)

Background Depression is widely reported in RA, with prevalence estimates at 14-46%. Several studies have suggested that RA patients with persistent depression have poorer response to anti-TNF therapy. Objectives To investigate the effects of depression status at baseline in patients with RA on (1) response to anti-TNF therapy at 6 months, and (2) survival rates on first anti-TNF drug. Methods 8899 patients with RA starting their first anti-TNF and enrolled in the BSRBR were included in this analysis. Data was collected at baseline and 6 monthly for 3 years from the hospital (including 28 joint count disease activity score (DAS28)), comorbidity, anti-rheumatic drug use (start/stop dates and reasons for discontinuation) and current medication use) and the patients (Health Assessment Questionnaire (HAQ)). Depression was defined at baseline as no history (ND), depression history without current medication (D), or depression with current medication (CM). Response to anti-TNF at 6-months was defined using (1) EULAR response criteria (none versus moderate or good) and (2) achieving >0.22 improvement in HAQ. Multivariate logistic regression was used to study the effect of depression on response. Discontinuation of anti-TNF was compared using Cox Regression. Results Depressed patients were younger, proportionally more female with similar disease severity (Table). Co-morbidity rates were higher in depressed patients, particularly those taking medication. There was no difference in overall DAS28 response between the groups. However, depressed patients were less likely to achieve a clinically significant improvement in HAQ. Survival rates on drug were not affected by depression D HR 1.01 (0.92, 1.12) CM HR 1.00 (0.88, 1.13). Table 1. Baseline depression and effect on 6 month response and drug survival ND D CM* Subjects (n) 7292 967 640 Age ± SD 57±12 56±11 56±12 Gender, % female 76 81 84 Co-morbidities, n (%)  0 3953 (53) 501 (52) 291 (45)  1 2311 (32) 314 (32) 225 (35)  2 785 (11) 117 (12) 79 (12)  3 196 (3) 28 (3) 39 (6)  4+ 47 (1) 7 (1) 6 (1) DAS28 score, mean ± SD 6.5±1.0 6.6±0.9 6.6±1.0 HAQ score, mean ± SD 2.0±0.6 2.1±0.5 2.1±0.5 Adjusted OR DAS response (95% CI)** ref 1.03[0.85,1.25] 0.90[0.73,1.13] Adjusted OR HAQ** ref 0.79[0.68,0.92] 0.74[0.62,0.89] Adjusted HR discontinuation of 1st anti-TNF** ref 1.01[0.92,1.12] 1.00[0.88,1.13] Conclusions Patients with baseline depression were less likely to achieve a clinically important improvement in HAQ at 6 months, with no difference in DAS28 response, suggesting it may be subjective measures of disease and ultimately response that are affected by patient depression. Drug survival was not affected by depression suggesting that anti-TNF therapy is still effective in these patients. Disclosure of Interest None Declared