Venous and arterial thromboembolic events in adalimumab‐treated patients with antiadalimumab antibodies: A case series and cohort study

Abstract

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 adalimumabtreated 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.Biologic therapeutics have revolutionized the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis, and inflammatory bowel disease (1). Therapeutic monoclonal antibodies (mAb) that block tumor necrosis factor (TNF) have been shown to be powerful, effective, and safe, but they can induce antidrug antibodies (2,3). TheThe clinical part of the study was partially financed by Abbott (Hoofddorp, The Netherlands). Wyeth (Hoofddorp, The Netherlands) finances a project on immunogenicity assessments in the same patients, the results of which were used for the present study.

Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical Recommendations

“…Anti-drug antibodies (ADA) have been implicated in infusion reactions and anaphylaxis (6,7) as well as immune complex-mediated diseases (8,9). ADA have also caused secondary treatment failures (loss of efficacy) (10)(11)(12) and, in rare occasions, more serious adverse events such as deficiency syndromes for instance thrombocytopenia and pure red cell aplasia (13,14).…”

Infliximab Therapy for Plaque Psoriasis: The UCL Experience

“…It could even be deleterious, by analogy with other observations (Korswagen et al, 2011). Among patients with relapse (complete or partial, severe and resistant), 16 were treated with ustekinumab: after a minimum of 10 months, 5 responses at 100%, 7 satisfactory responses (50-99%), and 4 failures were observed.…”

Acute renal artery occlusion following infliximab infusion

“…Anti-adalimumab antibodies were detected in four of these eight patients. The incidence rate of TEE was respectively 26/1000 and 8.4/1000 persons per year for patients with and without anti-adalimumab antibodies, with an adjusted hazard ratio of 7.6 and a median period of occurrence of 78 and 156 wk respectively for patients with and without antiadalimumab antibodies [1] . Mehta et al [2] described a right common femoral artery thrombosis 3 d after a second dose of infliximab in a patient with Crohn's disease.…”

“…Urgences chu rouen MI, and a transient ischemic attack) [1] . Anti-adalimumab antibodies were detected in four of these eight patients.…”

“…A statistically significant increase in frequency is seen for Immunoglobulin M and Immunoglobulin G aCL after 3 mo of treatment with infliximab [13] . However, there is no established link between the presence of antibodies and the degree of activation of systemic inflammation responsible for risk of embolism [1] . TNF-α inhibitors may also impact the vascular system through other mechanisms.…”