Discussion
Anti-TNFα induced thrombocytopenia has been reported previously in patients with rheumatoid arthritis (2), psoriasis (3,4) and CD (5-7). Patients were treated with both etanercept and infliximab (2), infliximab monotherapy (5) or adalimumab monotherapy (3,4, 6,7). Of note, most of these reports have not reported on the presence of specific autoantibodies against platelets. Furthermore, only two of the aforementioned reports involved patients with CD who developed thrombocytopenia associated with exposure to adalimumab (6,7). Salar et al. (7) describe a patient with CD who received both infliximab and adalimumab. A thrombocytopenia of 44×109/L occurred with platelet-associated IgG detected with a (undefined) platelet antibody test. More recently, Casanova et al. (6) reported a patient with CD who developed severe thrombocytopenia of 25×109/L after rechallenge treatment with adalimumab. Tests for the presence of antibodies were not performed. In accordance with the two patients with CD (6,7) our patient showed an increased number of megakaryocytes in the bone marrow supporting an ITP-related mechanism. Although an ITP-related mechanism has been speculated on in other reports, our report with confirmed GPIIb/IIIa and GV platelet autoantibodies provides conclusive evidence for this notion.
Our patient developed thrombocytopenia after three weeks of treatment. In other reports, the time between the first exposure of the anti-TNFα agent varied and extended up to >2 years. Some reports (3,6,7) showed an asymptomatic thrombocytopenia detected by routine blood samples, while other cases presented with bleeding symptoms (1).
Drug-induced thrombocytopenia can be classified into nonimmune and immune-mediated thrombocytopenia. Drug-induced immune-thrombocytopenia (ITP) can be categorized into several mechanisms including the formation of drug-specific antibodies or drug-dependent antibodies (e.g. quinine) and production of autoantibodies specific to platelets (e.g. gold) (8).
The exact pathophysiological mechanism of adalimumab-induced ITP is not known. A possible explanation, analogous to Aster et al. (8), is that adalimumab interacts with the platelets membrane GPIIb/IIIa and GPV through bridging interactions resulting in removal from the immune system. Another possible mechanism is that binding of adalimumab to the platelets membrane can cause a conformational change of the GPIIb/IIIa and GPV resulting in a neo-epitope which stimulates the formation of antibodies against platelets. Finally, previous reports hypothesized that anti-TNFα agents could induce apoptosis of Th1 lymphocytes leading to a relative excess of Th2 lymphocytes that could in turn lead to the production of antibodies (6,7).
This report adds to a general understanding of drug-induced thrombocytopenia induced by adalimumab, which could lead to a better recognition of this potential fatal phenomenon. Adalimumab-induced immune-thrombocytopenia is a rare cause of thrombocytopenia reversible upon adalimumab discontinuation. We report antibodies against multiple epitopes including GPIIb/IIIa and GPV without bone marrow suppression. MAIPA assay testing, if available, can be used to determine the platelet glycoprotein target(s). In order to prevent serious adverse events we recommend to monitor thrombocyte levels closely after initiation of anti-TNFα therapy. Although specific studies are lacking for drug-induced ITP, standard ITP treatment with intravenous immunoglobulins and/or steroids may be considered if interventions are clinically warranted.
Acknowledgement : not applicable.
Conflict of interest: all authors state that they have no conflict of interest
Funding: none.
Data availability statement: the data that support the findings of this study are available from the corresponding author upon reasonable request.