Antibody development and disease severity of COVID-19 in non-immunised patients with rheumatic immune-mediated inflammatory diseases: data from a prospective cohort study.

BACKGROUND: Research on the disease severity of COVID-19 in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) has been inconclusive, and long-term prospective data on the development of SARS-CoV-2 antibodies in these patients are lacking. METHODS: Adult patients with rheumatic IMIDs from the Amsterdam Rheumatology and Immunology Center, Amsterdam were invited to participate. All patients were asked to recruit their own sex-matched and age-matched control subject. Clinical data were collected via online questionnaires (at baseline, and after 1-4 and 5-9 months of follow-up). Serum samples were collected twice and analysed for the presence of SARS-CoV-2-specific antibodies. Subsequently, IgG titres were quantified in samples with a positive test result. FINDINGS: In total, 3080 consecutive patients and 1102 controls with comparable age and sex distribution were included for analyses. Patients were more frequently hospitalised compared with controls when infected with SARS-CoV-2; 7% vs 0.7% (adjusted OR: 7.33, 95% CI: 0.96 to 55.77). Only treatment with B-cell targeting therapy was independently associated with an increased risk of COVID-19-related hospitalisation (adjusted OR: 14.62, 95% CI: 2.31 to 92.39). IgG antibody titres were higher in hospitalised compared with non-hospitalised patients, and slowly declined with time in similar patterns for patients in all treatment subgroups and controls. INTERPRETATION: We observed that patients with rheumatic IMIDs, especially those treated with B-cell targeting therapy, were more likely to be hospitalised when infected with SARS-CoV-2. Treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs other than B-cell targeting agents is unlikely to have negative effects on the development of long-lasting humoral immunity against SARS-CoV-2.

Adherence to etanercept therapy in rheumatoid arthritis patients during 3 years of follow-up.

OBJECTIVES: To determine the percentage non-adherence to etanercept in patients with rheumatoid arthritis during three years of follow-up. METHODS: During study visits in this prospective cohort study, blood samples were taken to determine serum etanercept concentrations using ELISA and patients were asked if they had missed an etanercept dose, at which date and for what reason. Non-adherence was defined as serum etanercept concentration <0.1 µg/mL and no valid reason to miss the prescribed etanercept dose. RESULTS: In total, 292 consecutive patients treated with etanercept were included. Most patients had a valid reason to miss their etanercept dose (25/37). In total 12 out of 292 patients (4.1%, 95% confidence interval 2.2-7.2) were non-adherent during the 3 year period. In a small percentage of patients (3.4%, 95% confidence interval 0.8-10.4) who failed to respond to etanercept therapy, according to their rheumatologist, this was associated with inadequate exposure to etanercept and thus non-adherence. CONCLUSION: In this study, adherence to etanercept therapy was measured using serum etanercept concentration. In most patients an absent etanercept concentration was due to a medical reason. Furthermore, the majority of patients were adherent to etanercept therapy and had adequate drug exposure. In total, only 12 out of 292 patients (4.1%) were non-adherent during 3 years of follow-up. These findings highlight that only a small minority of patients are non-adherent to etanercept treatment, especially compared to adherence rates of other drugs. However, physicians should be aware that in patients failing to respond to treatment, non-adherence is a possible cause.

Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up.

BACKGROUND: Previous data have shown that etanercept levels are associated with clinical response in rheumatoid arthritis. However, for ankylosing spondylitis (AS), data regarding this topic are inconclusive. OBJECTIVES: To investigate the relationship between etanercept levels and clinical response in patients with AS. METHODS: Observational prospective cohort study of 162 patients with AS =treated with etanercept, monitored during 24 weeks of treatment. Etanercept trough levels were determined, retrospectively, using an ELISA. Disease activity was measured using AS Disease Activity Score (ASDAS), including C-reactive protein (CRP) and Bath AS Disease Activity index (BASDAI). Active disease was defined as ASDAS≥2.1. Since etanercept is a drug administered at home there might have been some variation in trough level sampling. RESULTS: At 24 weeks etanercept levels were significantly higher in patients with ASDAS<2.1, (3.8 mg/L; IQR 2.5-5.2) compared with patients with ASDAS≥2.1 (2.3 mg/L; IQR 1.2-3.4; p≤0.001). Generalised estimating equation analysis demonstrated a statistically significant association between etanercept levels and ASDAS, BASDAI, CRP and erythrocyte sedimentation rate (all p<0.001). When patients were categorised into quartiles according to etanercept levels, the lowest quartile (etanercept<1.80 mg/L) comprised 35% of all patients with ASDAS≥2.1 while the highest quartile comprised only 14%. CONCLUSIONS: Disease activity and inflammation are associated with etanercept levels in patients with AS at 24 weeks of treatment. Measuring etanercept levels might help in identifying overtreatment and undertreatment and optimise etanercept therapy in AS.

Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects.

OBJECTIVE: To evaluate the cost-effectiveness of personalised treatment for rheumatoid arthritis (RA) using clinical response and serum adalimumab levels. METHODS: A personalised treatment algorithm defined, based on clinical (European League Against Rheumatism) response and drug levels at 6 months, whether adalimumab treatment should be continued in a specific dose or discontinued and/or switched to a next biological. Outcomes were simulated using a patient level Markov model, with 3 months cycles, based on a cohort of 272 adalimumab-treated patients with RA for 3 years and data of patients from the Utrecht Rheumatoid Arthritis Cohort. Costs, clinical effectiveness and quality adjusted life years (QALYs) were compared with outcomes as observed in usual care and incremental cost-effectiveness ratios were calculated. Analyses were performed probabilistically. RESULTS: Clinical effectiveness was higher for the cohort simulated to receive personalised care compared with usual care; the average difference in QALYs was 3.84 (95 percentile range -8.39 to 16.20). Costs were saved on drugs: €2 314 354. Testing costs amounted to €10 872. Mean total savings were €2 561 648 (95 percentile range -3 252 529 to -1 898 087), resulting in an incremental cost-effectiveness ratio of €666 500 or €646 266 saved per QALY gained from a societal or healthcare perspective, respectively. In 72% of simulations personalised care saved costs and resulted in more QALYs, in 28% it was cost saving with lower QALYs. Scenario analyses showed cost saving along with QALYs gain or limited loss. CONCLUSIONS: Tailoring biological treatment to individual patients with RA starting adalimumab using drug levels and short-term outcome is cost-effective. Results underscore the potential merit of personalised biological treatment in RA.

Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients.

OBJECTIVE: To investigate the relationship between serum etanercept levels and clinical response. METHODS: In 292 etanercept-treated patients with rheumatoid arthritis clinical and pharmacological data were determined at baseline and after 1, 4 and 6 months of etanercept treatment. Differences in etanercept levels between good, moderate and European League Against Rheumatism (EULAR) non-responders were assessed after 6 months of therapy. RESULTS: After 6 months of therapy etanercept levels were significantly higher in good responders (median (IQR) 3.78 (2.53-5.17)) compared with both moderate 3.10 (2.12-4.47) and EULAR non-responders 2.80 (1.27-3.93) (all p<0.05). There was a significant association between clinical response and serum etanercept levels (regression coefficient 0.54, 95% CI 0.21 to 0.86, p=0.001). When patients were categorised into quartiles according to the height of etanercept levels, the lowest quartile (etanercept level <2.1 mg/l) comprised 40% of all non-responders. The highest quartile (etanercept level >4.7 mg/l) comprised 35% of all good EULAR responders. Anti-etanercept antibodies were detected in none of the sera. CONCLUSION: The authors demonstrated that lower etanercept levels were associated with non-response. Therapeutic drug monitoring and the possibility of the adjusted dosing regimes in the selected groups of patients should be investigated further as a possible tool to optimise treatment with etanercept.

Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study.

OBJECTIVE: We observed 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab, 2 of whom had rheumatoid arthritis (RA) and 1 of whom had psoriatic arthritis. Antiadalimumab antibodies were detected in all 3 patients. We undertook this study to determine whether the development of antiadalimumab antibodies was associated with thromboembolic events during adalimumab treatment. METHODS: A retrospective search (with blinding with regard to antiadalimumab antibody status) for thromboembolic events was performed in a prospective cohort of 272 consecutively included adalimumab-treated RA patients. Incidence rates were calculated and hazard ratios (HRs) were estimated using Cox regression. None of the index patients were part of the cohort. RESULTS: Antiadalimumab antibodies were detected in 76 of 272 patients (28%). Eight thromboembolic events were found, 4 of which had occurred in patients with antiadalimumab antibodies. The incidence rate was 26.9/1,000 person-years for patients with antiadalimumab antibodies and 8.4/1,000 person-years for patients without those antibodies (HR 3.8 [95% confidence interval 0.9-15.3], P = 0.064). After adjustment for duration of followup, age, body mass index, erythrocyte sedimentation rate, and prior thromboembolic events, the HR was 7.6 (95% confidence interval 1.3-45.1) (P = 0.025). CONCLUSION: These findings suggest that the occurrence of venous and arterial thromboembolic events during adalimumab treatment is higher in patients with antiadalimumab antibodies than in those without antiadalimumab antibodies. Patient numbers were relatively small; therefore, validation in other cohorts is mandatory.