Anja Strangfeld

Risk of Herpes Zoster in Patients With Rheumatoid Arthritis Treated With Anti–TNF-α Agents

CONTEXT The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor alpha (TNF-alpha). Little is known about the reactivation of latent viral infections during treatment with TNF-alpha inhibitors. OBJECTIVE To investigate whether TNF-alpha inhibitors together as a class, or separately as either monoclonal anti-TNF-alpha antibodies (adalimumab, infliximab) or a fusion protein (etanercept), are related to higher rates of herpes zoster in patients with rheumatoid arthritis. DESIGN, SETTING, AND PATIENTS Patients were enrolled in the German biologics register RABBIT, a prospective cohort, between May 2001 and December 2006 at the initiation of treatment with infliximab, etanercept, adalimumab, or anakinra, or when they changed conventional disease-modifying antirheumatic drug (DMARD). Treatment, clinical status, and adverse events were assessed by rheumatologists at fixed points during follow-up. MAIN OUTCOME MEASURES Hazard ratio (HR) of herpes zoster episodes following anti-TNF-alpha treatment. Study aims were to detect a clinically significant difference (HR, 2.0) between TNF-alpha inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-alpha inhibitors, the monoclonal antibodies or the fusion protein, compared with conventional DMARDs. RESULTS Among 5040 patients receiving TNF-alpha inhibitors or conventional DMARDs, 86 episodes of herpes zoster occurred in 82 patients. Thirty-nine occurrences could be attributed to treatment with anti-TNF-alpha antibodies, 23 to etanercept, and 24 to conventional DMARDs. The crude incidence rate per 1000 patient-years was 11.1 (95% confidence interval [CI], 7.9-15.1) for the monoclonal antibodies, 8.9 (95% CI, 5.6-13.3) for etanercept, and 5.6 (95% CI, 3.6-8.3) for conventional DMARDs. Adjusted for age, rheumatoid arthritis severity, and glucocorticoid use, a significantly increased risk was observed for treatment with the monoclonal antibodies (HR, 1.82 [95% CI, 1.05-3.15]), although this risk was lower than the threshold for clinical significance. No significant associations were found for etanercept use (HR, 1.36 [95% CI, 0.73-2.55]) or for anti-TNF-alpha treatment (HR, 1.63 [95% CI, 0.97-2.74]) as a class. CONCLUSION Treatment with monoclonal anti-TNF-alpha antibodies may be associated with increased risk of herpes zoster, but this requires further study.

Does Tumor Necrosis Factor α Inhibition Promote or Prevent Heart Failure in Patients With Rheumatoid Arthritis

OBJECTIVE To determine the hazard risk of developing or worsening heart failure in rheumatoid arthritis (RA) patients treated with tumor necrosis factor alpha (TNFalpha) inhibitors. METHODS RA patients ages 18-75 years who started treatment with infliximab, etanercept, or adalimumab (n = 2,757), or conventional disease-modifying antirheumatic drugs (controls; n = 1,491) at the time of enrollment in a German biologics register were studied. Cox proportional hazards models were applied to investigate the influence of disease-related and treatment-specific risk factors on the incidence or worsening of heart failure. RESULTS The 3-year incidence rates of heart failure in patients with and patients without cardiovascular disease at the start of treatment were 2.2% and 0.4%, respectively. After adjustment for traditional cardiovascular risk factors, an increased risk of developing heart failure was found in patients who had a higher 28-joint Disease Activity Score at followup (hazard ratio [HR] 1.47 [95% confidence interval 1.07-2.02], P = 0.019). A residual nonsignificant risk related to treatment with TNFalpha inhibitors remained (adjusted HR 1.66 [95% confidence interval 0.67-4.1], P = 0.28). This residual risk was balanced by the efficacy of the anti-TNF treatment. When only baseline characteristics were taken into account, the HR related to TNFalpha inhibitor treatment decreased to 0.70 (95% confidence interval 0.27-1.84). CONCLUSION The findings of this study indicate that TNFalpha inhibitor treatment that effectively reduces the inflammatory activity of RA is more likely to be beneficial than harmful with regard to the risk of heart failure, especially if there is no concomitant therapy with glucocorticoids or cyclooxygenase 2 inhibitors. Furthermore, the data suggest that TNFalpha inhibition does not increase the risk of worsening of prevalent heart failure.

Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab

Objectives To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival. Methods Data of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking. Results During 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28  > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2). Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor α (TNFα) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNFα inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97). Conclusions Patients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNFα inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.

Comparative effectiveness of tumour necrosis factor α inhibitors in combination with either methotrexate or leflunomide

Objective: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor α (TNFα) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. Methods: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFα inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n  =  1375) or leflunomide (n  =  394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. Results: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. Conclusion: The current clinical practice is to use methotrexate as a first choice for the combination with TNFα antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

Evaluation of the RABBIT Risk Score for serious infections

Objective To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA). Methods The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample. Results The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor α (TNFα) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk. Conclusions The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.

Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers

Objectives Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. Methods Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. Results Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). Conclusions This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs

Objective To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). Methods In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. Results 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2−0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. Conclusions The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis

Objective This observational cohort study investigated the impact of biological (b) disease-modifying antirheumatic drugs (DMARDs) on the outcomes of serious infections (SIs) in patients with rheumatoid arthritis. Methods We investigated outcomes of SIs observed in 947 patients enrolled in the German biologics register RABBIT(Rheumatoid arthritis: observation of biologic therapy). Outcomes were (1) recovery without complication, (2) sepsis following SI (≤30 days), and (3) death after SI without known sepsis (≤90 days). We applied a multinomial generalised estimating equation model for longitudinal data to evaluate the risks of sepsis and death simultaneously. Results Sepsis within 30 days after SI was reported in 135 out of 947 patients, 85 of these had a fatal outcome. Fifty-three patients died within 90 days after SI without known sepsis. The adjusted risk of developing sepsis increased with age and was higher in patients with chronic renal disease. Compared with conventional synthetic (cs)DMARDs, the risk was significantly lower when patients were exposed to bDMARDs at the time of SI (OR: 0.56, 95% CI 0.38 to 0.81). Risk factors of fatal SI were higher age, use of glucocorticoids at higher doses and heart failure. Patients treated with bDMARDs and those with better physical function had a significantly lower mortality risk. Conclusions These results suggest a beneficial effect of bDMARDs on the risk of sepsis after SI and the risk of a fatal outcome. Successful immunosuppression may prevent an unregulated host response to SI, that is, the escalation to sepsis. Further investigation is needed to validate these results.

Health-related quality of life in patients with long-standing rheumatoid arthritis in the era of biologics: data from the German biologics register RABBIT

Objective. To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care. Methods. Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients’ HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores. Results. All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%. Conclusion. Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population.

Sustainability of Rituximab Therapy in Different Treatment Strategies: Results of a 3‐Year Followup of a German Biologics Register

To compare the approved treatment of rheumatoid arthritis using rituximab + methotrexate (RTX + MTX) versus the off‐label treatment variants of RTX in monotherapy or RTX in combination with leflunomide (RTX + LEF).