Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: A prospective cohort study

Abstract

Background Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions. Methods We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti–thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months. Findings Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73–31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity. Interpretation Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation. Fund German Ministry of Education, Science, Research and Technology and the German Research foundation.

Mitigating alemtuzumab-associated autoimmunity in MS

“…Secondary humoral autoimmunity resulting in hyper- or hypothyroidism, thrombocytopenia or renal disease are well known risks following alemtuzumab treatment of MS. 5 , 6 We hypothesize that anti-CD20 B-cell depletion after alemtuzumab administration may mitigate the risk of secondary autoimmunity and have investigated this possibility. Our initial results suggest that anti-CD20 B-cell depletion is safe and potentially efficacious.…”

“… 3 , 4 Antibody-mediated secondary autoimmune disease in patients with MS treated with alemtuzumab approaches an incidence of 40%–50% in prolonged follow-up, with a peak incidence by the third year following treatment initiation and waning incidence thereafter. 5 – 16 …”

“…The most common secondary autoimmune disorder is antibody-mediated thyroid disease; with autoimmune hyperthyroidism being the most common and exceeding those developing hypothyroidism. 5 , 6 Other antibody-mediated autoimmune diseases have been reported, including idiopathic thrombocytopenic purpura, anti–glomerular basement membrane (GBM) disease, neutropenia, hemolytic anemia, and vitiligo, among others. T cell–mediated autoimmunity and granulomatous inflammatory diseases (principally sarcoidosis) occur at a considerably lower incidence.…”

Signatures of immune reprogramming in anti-CD52 therapy of MS: markers for risk stratification and treatment response

“…The most common adverse effects of alemtuzumab are infusion-associated reactions and infections, which occur at the highest rate after the first treatment course. Most relevant are secondary autoimmune events, including thyroid disease, immune thrombocytopenia and nephropathy [ 7 ]. The experiences of these trials led to the implementation of an extensive safety measures allowing for early recognition and therapy of adverse events.…”

Anti-thyroid autoantibodies as biomarkers for alemtuzumab associated thyroid autoimmunity

“…In this article of EBioMedicine , Tobias Ruck and colleagues demonstrate that anti-thyroid autoantibodies are possible biomarkers for thyroid secondary autoimmune disorders in alemtuzumab treated people with relapsing-remitting multiple sclerosis [1]. Alemtuzumab, a humanized monoclonal antibody against CD52, is a highly effective treatment for multiple sclerosis [[2], [3], [4]].…”