Adalimumab as a potential cause of drug-induced thrombocytopaenic microangiopathy

Abstract

We report the case of a 63-year-old male patient admitted to our emergency department for dyspnoea, peripheral oedema, severe diarrhoea and asthenia. History revealed Crohn’s disease (CD) submitted to several intestinal surgical resections in the previous years. He recently started a treatment with adalimumab for the control of CD. Laboratory tests at the admission revealed severe haemolytic anaemia and thrombocytopaenia. Haptoglobin levels were low, schistocyte count was markedly increased. In the suspect of thrombotic microangiopathy, he was admitted to our internal medicine department where we urgently started plasma exchange (PEX). We observed normal ADAMTS-13 activity in absence of Shiga toxin or enterotoxic Escherichia c oli at stool tests. Despite a diagnosis of atypical haemolytic–uraemic syndrome, we observed full platelet count recovery and schistocytes normalisation after the fourth PEX. We then put a diagnosis of adalimumab-induced thrombocytopaenic microangiopathy. Adalimumab was withdrawn. We did not observe relapses in the following 3 months.

Background

Despite a usually aspecific presentation, thrombotic microangiopathies (TMA) must always be considered by the emergency physician. Elements necessary to suspect this group of diseases are microangiopathic haemolytic anaemia, thrombocytopaenia and peripheral schistocytosis associated to end-organ disease.^{1 2} Drug-induced TMA (DI-TMA) can represent a diagnostic dilemma, since it mimics other TMAs, as thrombotic thrombocytopaenic purpura (TTP), atypical uraemic–haemolytic syndrome (aHUS) and enterotoxic uraemic–haemolytic syndrome (STEC-HUS).³ Like other TMA, DI-TMA management requires urgent plasma exchange (PEX) treatment. Immediate withdrawal of suspected drug(s) is strongly recommended. However, since ADAMTS-13 activity is often normal or near normal in DI-TMA, a differential diagnosis with aHUS and STEC-HUS must always be performed, since aHUS typically responds to eculizumab and can be refractory to PEX while STEC-HUS must be treated with specific antibiotics. Several monoclonal antibodies and different classes of drugs can induce DI-TMA but, to our knowledge, only one other case of adalimumab-induced TMA has already been described.^{4 5}

Case presentation

We report the case of a 63-year-old man referring to the emergency department (ED) for confusion, asthenia, dyspnoea on exertion, worsening diarrhoea and peripheral oedemas. He correlated symptoms’ onset with the recent initiation of adalimumab (one single dose) as a new treatment for his Crohn’s disease, 15 days before the admission to our ED. History revealed Crohn’s disease diagnosed 16 years before and complicated with abdominal abscesses which required several surgical interventions of intestinal resection in the previous years. He also complained of hypersensitivity to infliximab and intolerance to azathioprine.

At the admission in the ED he was confused, with no other pathological neurological sign; his skin was pale; cardiac tones were regular but tachycardic, with no added bruits; abdomen was tender, with no evocable pain; liver and spleen were not clinically enlarged; he was dyspnoeic, with regular breath murmurs and some rales; we also observed a modest peripheral oedema; arterial blood pressure was 90/60 mm Hg, cardiac frequency was 102 bpmR (beats per minute, rhythmic), respiratory rate was 22 breaths/min, SpO₂ was 96% while breathing room air.

Investigations

Laboratory examinations performed in the ED showed severe macrocytic anaemia (haemoglobin 53 g/L, mean corpuscular volume (MCV) 127 fL), severe thrombocytopaenia (platelet count (PLT) 25×10⁹/L), normal kidney (creatinine 0.67 mg/dL, estimated glomerular filtration rate (eGFR) 86.19 mL/m) and liver function (aspartate aminotransferase 34 U/L, alanine transaminase 18 U/L, bilirubin 1.2 mg/dL). Chest radiograph showed signs of pulmonary vessels congestion. At the admission to our internal medicine department, the complete white cell count was suggestive of pancytopaenia: leucocytes were 3.24×10⁹/L, haemoglobin was 72 g/L (after packed red cells transfusion), platelets were 16×10⁹/L, reticulocytes were 19.100 u/mmc; thus, we evaluated platelet count in citrate, which a similar result to the standard EDTA test; then, we assessed serum vitamin B₁₂ (0.17 ng/mL) and folate (2.6 ng/mL) levels, which resulted within low-normal limits; antithrombin III levels and coagulation tests (antithrombin-III (AT-III) 73%; prothrombin time (PT) 75%, activated partial thromboplastin time (aPTT) 27 s and d-dimer 310 ng/mL) were normal, thus ruling out a diffused intravascular coagulation; we observed a decreased haptoglobin (<8 mg/dL) and raised lactic dehydrogenase levels (924 U/L), suggesting the presence of intravascular haemolysis. Direct and indirect Coombs test were normal. Antinuclear antibodies, antiplatelet antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant and anticardiolipin antibodies were negative; cytomegalovirus DNA in peripheral blood resulted negative; HIV test was negative. Peripheral blood smear resulted positive, showing 13–15 schistocytes per microscopic field. To further define the diagnosis, we performed ADAMTS-13 activity testing, which resulted normal (>15%), and observed the absence of antibody inhibitor for ADAMTS-13 (<6.5 U/L). Stool test for enterotoxic Escherichia c oli and Shiga toxin were also negative. Colonoscopy underlined multiple colic erosions with ileocolic valve substenosis; brain CT scan showed aspecific signs of leucoencephalopathy; chest CT scan underlined only signs of paraseptal emphysema, while abdomen CT scan showed diffused thickenings of intestinal walls.

Differential diagnosis

The patient was admitted to the ED with vague and aspecific signs and symptoms. History was positive for Crohn’s disease (CD), several intestinal resections and a recent treatment with adalimumab. The first laboratory tests underlined a severe macrocytic anaemia with thrombocytopaenia. The most common cause of macrocytic anaemia in patients with CD is B₁₂ or folate deficiency due to reduced enteric absorption. This condition affects up to 18.4% of patients with CD, particularly those with prior surgery and need for ongoing medical therapy.⁶ In this subject, serum vitamin levels were within low-normal limits, but reticulocyte count at the admission was low, considering the severe anaemia, suggesting a reduced bone-marrow production reflecting the malabsorption. Another common cause of macrocytic anaemia in CD is drug toxicity due to mesalazine, sulfasalazine, azathioprine and mercaptopurine treatment, which was excluded by history. Autoimmune haemolytic anaemia is very rare in CD, with only few cases reported in literature⁷ and was ruled out by Coombs tests. Autoimmune thrombocytopaenia overlapping CD is not frequent,⁸ but it has been reported both in CD and in anti-TNFa-treated patients with CD.⁹ In this subject, however, we observed absence of antiplatelet autoantibodies and peripheral schistocytosis, which was more suggestive of TMA; lupus-like syndromes can overlap CD or be induced by anti-TNFa treatment but were excluded by absence of antinuclear antibodies; secondary forms due to malignancy, particularly lymphoma, were ruled out by instrumental tests; few cases of TMA have been described in CD.¹⁰ Often, these cases are described as autoimmune, mimicking thrombotic thrombocytopaenic purpura¹¹ with an autoimmune mechanism. In this report, a normal ADAMTS-13 activity and absence of ADAMTS-13 antibody inhibitor suggested more a toxic or a complement-mediated damage, which resolved with drug withdrawal and plasma exchange.

Treatment

Patients underwent immediate transfusion of three units of packed red cells and required two further units during the hospital stay. Adalimumab was withdrawn immediately. We promptly started PEX, with a gradual increase of both platelet count and haptoglobin and a progressive reduction of lactic dehydrogenase and schistocyte count (figure 1), with normalisation after the fourth plasma exchange. Vitamin B₁₂ was also added at the dose of 1000 μg/day for 3 days with increase of reticulocyte count and improvement of pancytopaenia.

Figure 1.

Peripheral blood smear after the second plasmapheresis showing schistocytes reduction (four per field).

Outcome and follow-up

The patient was discharged in the 13th day, with complete recover: at discharge, his haemoglobin level was 97 g/L, MCV 102 fL, platelets were 209×10⁹/L, reticulocytes were 163.400 u/mmc, lactic dehydrogenase was 204 U/L, haptoglobin was 60 mg/dL, with normal renal function (creatinine 0.61 mg/dL, eGFR 94.67 mg/dL) and normal hepatic function.

On discharge, he was oriented with no pathological neurological signs; cardiac tones were regular, with no added bruits; abdomen was tender, with no evocable pain; diarrhoea was absent; liver and spleen were not clinically enlarged; he breathed regularly, breath murmurs were regular, with no pleural effusion or added sounds; peripheral oedema was no more appreciable; systolic blood pressure was 130/80 mm Hg, cardiac frequency was 80 bpmR, SpO₂ 99% while breathing room air.

He underwent to further three PEX in second, fourth and ninth day after discharge. We continued the clinical and instrumental follow-up for 3 months, without any evidence of DI-TMA relapse. The patient was then referred to our gastroenterologic department for the follow-up of his Crohn’s disease, with the indication of avoiding adalimumab use.

Discussion

There is only one other report describing a DI-TMA secondary to adalimumab use,⁵ underlining the rarity of this manifestation. TMA must be always suspected in presence of haemolytic anaemia and thrombocytopaenia with end-organ damage,¹² which, in our case, was represented by confusion, dyspnoea with lung and peripheral oedema and worsening diarrhoea. Laboratory examinations suggest a toxic or complement-mediated damage, resembling more aHUS than a TTP, with normal ADAMTS-13 activity and absence of anti-ADAMTS-13 antibodies. Literature reports that DI-TMA can be induced or by toxic or immune-mediated mechanisms. However, it is usually difficult to differentiate the two forms. Currently, guidelines on treatment of TMAs recommend starting PEX. Further treatment depends on the TMA subtype: TTP typically responds to plasma exchange, while aHUS must be treated with eculizumab once the diagnosis is established. In our case, laboratory tests were suggestive of aHUS, but the patient responded optimally to plasma exchange and drug withdrawal.

Learning points.

• Drug-induced thrombotic microangiopathies (DI-TMA) presentation is highly aspecific, and there are no specific diagnostic tests for this entity.

• DI-TMA diagnosis is difficult, since ADAMTS-13 activity is typically normal, as in atypical uraemic–haemolytic sundrome (aHUS), but plasma exchange is effective, as in thrombotic thrombocytopaenic purpura (TTP).

• A complete workup to differentiate DI-TMA from TTP, aHUS andenterotoxic uraemic–haemolytic syndrome is necessary for a correct management.

• DI-TMA requires immediate withdrawal of the suspected drug(s).

• Adalimumab-induced TMA are rare but must be considered when clinical and laboratory findings are consistent with this diagnosis.