Chronic Use of Adalimumab as Potential Cause of Severe Thrombocytopenia in Psoriatic Arthritis Patient : The Need for Regular Monitoring of Cytopenias

C l i n M e d International Library Citation: Pereira VC, Costa KH, de Oliveira LR (2016) Chronic Use of Adalimumab as Potential Cause of Severe Thrombocytopenia in Psoriatic Arthritis Patient: The Need for Regular Monitoring of Cytopenias. Int J Blood Res Disord 3:020 Received: March 24, 2016: Accepted: May 25, 2016: Published: May 28, 2016 Copyright: © 2016 Pereira VC, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pereira et al. Int J Blood Res Disord 2016, 3:020


Introduction
Anti-tumor necrosis factor alpha (anti-TNFα) agents are increasingly used to treat intestinal, skin and rheumatic inflammatory diseases with proven efficacy and safety [1].Hematologic adverse events are described as potentially fatal when they are severe or belatedly detected [1].
The current study presents the evolution of a patient presenting acute and severe thrombocytopenia, which was probably induced by adalimumab using criteria for drug-induced thrombocytopenia described by George et al. [2].The medication use was discontinued and after the patient was treated with corticosteroids, human intravenous immunoglobulin (IVIG) and rituximab he presented platelet count recovery.

Case Report
The current study reports the case of a 58-year-old male

Abstract
Anti-tumor necrosis factor alpha (anti-TNFα) agents are used to treat inflammatory diseases with recognized safety and efficacy.Although they are rare, severe hematologic adverse effects are described and may be fatal.The current study describes the case of a patient presenting psoriatic arthritis, and under prolonged treatment with adalimumab.His condition worsened due to severe acute thrombocytopenia and severe hemorrhagic manifestations.Adalimumab was considered to be the probable cause of the thrombocytopenia and, therefore, its use was discontinued.The treatment consisted of corticosteroids, human immunoglobulin, rituximab and transfusion support.The regular monitoring of cytopenias in patients using anti-TNFα agents may be a safe measure for the early detection of severe hematologic adverse events.It is worth conducting additional studies to better characterize the interaction between anti-TNFα agents and the hematopoietic and immune systems.After extensive laboratory evaluation, adalimumab was considered to be the potential cause of thrombocytopenia and, therefore, the medication use was discontinued and the other chronic use medications were kept.Treatment consisted of intravenous corticotherapy (methylprednisolone -1 g/day for three days) followed by oral prednisone (1 mg/kg/day) and platelet transfusion.However, the treatment result showed unfavorable platelet increase, persistent digestive bleeding and hemoglobin decrease (> 2 g/dL).IGIV therapy (1 g/kg on D1 and D3) was then applied and it resulted in satisfactory platelet increment (39 × 109/L) and bleeding control.After four days of IGIV and corticosteroid therapy, the patient showed new platelet count decrease (12 × 109/L).Thus, it was made the option for using intravenous rituximab (100 mg every seven days for four weeks).Platelet transfusions were administered for control of bleeding when platelet count was lower than 10 × 109/L.The patient's condition improved with sustained normalization of platelet count 18 days after the onset of symptoms and eight days after the beginning of the treatment with rituximab, without the reintroduction of adalimumab.

Discussion
Anti-TNFα agents are used in a myriad of inflammatory diseases, especially in rheumatoid arthritis, psoriasis/psoriatic arthritis and crohn's disease [1,3].Although they are safe and show limited hematological toxicity, several unusual hematologic adverse events were reported in association with these medications, especially thrombocytopenia, neutropenia, pancytopenia, hypercoagulability and aplastic anemia [1,[4][5][6][7][8].Most guidelines about the use of anti-TNFα agents do not recommend the regular monitoring of cytopenias [1].
Thrombocytopenia associated with anti-TNFα agents is considered to be rare, with actual unknown occurrence and it is apparently less frequent in patients treated with adalimumab in comparison to those treated with other anti-TNFα agents [1,6,7].Brunasso et al. found 5.97% occurrence of platelet counts below 50 × 109/L whereas Chen et al. did not report such finding [4,7].Despite the known role of TNFα in the control of hematopoiesis in association with other cytokines, the exact mechanism of this association remains unknown, fact that leads to some assumptions: • The production of medication-associated antibodies that bind to platelet glycoproteins and induce platelet destruction; [6,7] • The formation of immune complexes that bind to the platelet surface with consequent destruction by the activation of the complement system; [6] • The Th1 lymphocyte apoptosis induction by the relatively increasing Th2 lymphocytes and by stimulating the production of platelet antibodies; [6,7] • Blocking stem cell differentiation [5,7,9].
Platelet recovery after the discontinuation of these medications and the recurrence of thrombocytopenia upon the re-exposure to them indicate the causal relationship between anti-TNFα agents and thrombocytopenia [2,4].The mean time between the beginning of the medication use and thrombocytopenia considerably varies and it may extend up to three years [4,10].Thrombocytopenia intensity may be discreet (with no clinical consequences) or severe (with or without hemorrhagic manifestations).However, thrombocytopenia has been pointed out as an idiosyncratic reaction rather than an event related to the class of anti-TNFα agents [5,7,11].
The management of thrombocytopenia is defined according to its intensity and to the occurrence of hemorrhagic manifestations.Mild-moderate thrombocytopenia (> 50 × 109/L) may be managed by simply discontinuing the medication use and by clinical and laboratory follow-up.On the other hand, the most serious cases of severe thrombocytopenia (< 30-50 × 109/L) may require specific treatment in addition to medication use discontinuity, especially when these cases are associated with bleeding events.
The pharmacological management of adalimumab-related thrombocytopenia resembles ITP treatment, since they are conditions in which the immune mechanism is implicated in the pathophysiology [4].The first-line treatment consists of using corticosteroids.Severe cases requiring rapid platelet increment or non-responsive corticotherapy cases may be treated with IVIG.There are few case reports describing the use of other medications such as mycophenolate mofetil and rituximab [4].
The probable causal relationship between thrombocytopenia and adalimumab in the current case is supported by the fact that thrombocytopenia was detected after the patient was exposed to adalimumab and that he showed sustained platelet count recovery after the discontinuation of the anti-TNFα agent.In addition, the other medications used by the patient were excluded as cause of thrombocytopenia since their continuity did not affect platelet recovery.Other possible causes of thrombocytopenia were also excluded.In this case, there is no definitive evidence supporting the effective role rituximab plays in the platelet count recovery due to the concomitant use of other medications (corticosteroids and IVIG) and to the short time interval (eight days) from the beginning of rituximab use to platelet recovery.
In conclusion, despite the established safety of the anti-TNFα agents, it is suggested that the regular monitoring of cytopenias should be taken into consideration in patients taking this type of medication.Additional studies should be conducted to allow better understanding the interaction mechanisms between these agents and the hematopoietic and immune systems.