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Abstract
Autoimmune haemolytic anaemia (AIHA), autoimmune destruction of erythrocytes is most commonly secondary to immunomodulated conditions. The association between AIHA and inflammatory bowel disease (IBD) has been poorly investigated. We aim to report a case of AIHA in a patient with ulcerative colitis (UC) treated with vedolizumab.
A case of a woman in her 30s with UC that after the initiation of vedolizumab developed severe anaemia. Due to the absence of visible blood losses and a positive Coombs direct test, the diagnosis of AIHA was established. The patient initially initiated prednisolone with no response. Rituximab had to be introduced. After a few days with this therapy, there was a clinical and analytical improvement.
AIHA must be taken into account as a possible cause of anaemia in patients with IBD. The differential diagnosis between IBD or drug-related (namely vedolizumab) as the cause of the AIHA is complex and almost impossible to establish.
- Gastrointestinal system
- Haematology (drugs and medicines)
- Drugs: gastrointestinal system
- Ulcerative colitis
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- Gastrointestinal system
- Haematology (drugs and medicines)
- Drugs: gastrointestinal system
- Ulcerative colitis
Background
Autoimmune haemolytic anaemia (AIHA) is a blood disorder characterised by autoimmune (immunoglobulin G and/or immunoglobulin M mediated) destruction of red blood cells. With an incidence of 1 per 100 000/year, this disease is most commonly secondary to an immunomodulated condition.1 Anaemia is, in fact, common in patients with inflammatory bowel disease (IBD).2 3 Additionally, the incidence of AIHA in patients with IBD has been recognised to be higher than in the general population. As a matter of fact, AIHA has been considered an extraintestinal manifestation of IBD,4 resulting from a cross-reactivity between autoantibodies against intestinal and luminal substances and red blood cell surface antigens.5
Vedolizumab is a monoclonal antibody approved for the treatment of IBD. Targeting the migration of T lymphocytes through the colonic wall, this agent is effective in both Crohn’s disease and ulcerative colitis (UC). In fact, this agent is one of the safest options for patients with UC according to the most recent meta-analysis.6 7 The association between vedolizumab and AIHA has been scarcely described.8 9 In the cases reported in the literature, AIHA develops either a few weeks or months after the initiation of vedolizumab. Moreover, there is a severe case of IgA AIHA described in a Crohn’s disease patient initially thought to be associated with the administration of vedolizumab. This AIHA was also treated with rituximab. However, after a thorough evaluation of the patient’s medical records, a prior episode of AIHA was discovered, occurring before vedolizumab was initiated, leading to the association being discarded and to the reintroduction of Vedolizumab.10 There has even been a case report of AIHA successfully treated with vedolizumab,11 making the putative role of vedolizumab as a causative agent of AIHA in IBD controversy. We, thus, aim to report a case of severe refractory AIHA in a patient with UC treated with vedolizumab.
Case presentation
We report a case of a woman in her 30s with UC diagnosed 4 years before, due to complaints of haematochezia and diarrhoea. The patient had also a medical history of various episodes of acute pancreatitis of undetermined aetiology and sarcoidosis.
At the time of the diagnosis, an endoscopic evaluation was performed and the disease extended only to the left colon and had a Mayo endoscopic subscore 3. The patient was first medicated with messalazine 4 g daily orally. After a period of 3 years in clinical and endoscopic remission, the patient had a reactivation of the disease and initiated infliximab. Nevertheless, due to the absence of clinical response, the antitumour necrosis alfa agent was suspended. Vedolizumab was then initiated. After this introduction, clinical remission was achieved but endoscopic activity (Mayo endoscopic subscore 2) persisted. Analytical evaluations during the first months of therapy were completely normal regarding haemoglobin (Hb) and C reactive protein. Faecal calprotectin remained elevated.
Nine months after the initiation of the anti-integrin receptor antagonist, the patient started having symptoms of severe fatigue and pallor. At that time, the patient had 3–4 dejections daily without blood. Due to an episode of lipothymia, the patient was admitted to day hospital care and a laboratory workup was performed. A value of 58 g/L of Hb was found. Due to the absence of visible blood losses, other causes of anaemia were suspected. The case was discussed with the haematology department. The absence of a history of any other new medications or over-the-counter supplements was confirmed. The patient also denied consumption of alcohol, tobacco or recreational drugs. Additionally, allergies and other relevant history events such as surgeries were denied. No relevant family history was reported.
The physical examination was normal with the exception of pale skin and mucosa.
Investigations
Laboratory evaluation revealed an elevation of ferritin (505 ng/mL) and slightly elevated lactate dehydrogenase (LDH) level (252 U/L) with normal bilirubin and haptoglobin levels. Due to a positive result in the Coombs direct test result, the diagnosis of AIHA was established.
Other serological tests to exclude other possible causes were performed: viral hepatitis A, B and C, cytomegalovirus and Epstein-Barr virus, herpes simplex and varicella-zoster virus and HIV. Quantiferon test was negative.
Differential diagnosis
After a clinical discussion with the haematology team, vedolizumab was considered to be the most probable cause of the severe AIHA. In spite of this, a causative relationship with IBD activity could not be excluded.
Treatment
The patient initiated prednisolone first in a dose of 1 mg/kg per day and after with 1.5 mg/kg per day with no response, with progressively clinical and laboratory worsening. The patient started having palpitations and severe fatigue. The value of Hb was 4.9 g/dL and LDH, bilirubin and reticulocytes values were visibly deteriorating (figure 1). Five days after treatment escalation to 2 mg/kg per day of prednisolone without improvement, the patient started rituximab.
Evolution of the levels of lactate dehydrogenase (LDH) and reticulocytes based on the therapies administered.
Outcome and follow-up
After four cycles of rituximab, Hb level, erythrocytes and reticulocytes were within the normal range. The patient soon, after 2 months, returned to normal daily life. In 1 year of follow-up with monthly appointments, no signs of relapse were detected.
Discussion
AIHA is characterised by erythrocyte destruction mediated by autoantibodies.5 The diagnosis of an AIHA is based on the presence of anaemia, haemolysis (hyper-reticulocytosis, elevation of indirect bilirubin, decrease of haptoglobin levels and high levels of LDH) and an autoimmune mechanism assessed by the Coombs direct test. In most cases, AIHA is secondary to the activity of another immune-mediated disorder.1 4
Extraintestinal manifestations are common in patients with IBD.12 The association between UC and AIHA has been scarcely reported and in the majority of cases are characterised by a disease in an active stage. Moreover, a few reports have already described an association between AIHA and infliximab infusion.13–16 By contrary, to the best of our knowledge, there have been only two cases of AIHA possibly associated with vedolizumab.8 9 The presumptive diagnosis of a drug induced AIHA is made if there is a response to withdrawal of the drug. This was not present in our case, but there was also no response to corticosteroids, as there is in the majority of cases of AIHA.
Indeed, following clinical deliberation with the haematology team, vedolizumab emerged as the likely culprit. Nevertheless, a definitive association with IBD activity could not be ruled out. Furthermore, since neither discontinuation of vedolizumab nor corticosteroid therapy elicited a response, a conclusive diagnosis remains elusive.
This report highlights the importance of a high index of suspicion in patients with severe anaemia and active IBD being treated with biologics. The differential diagnosis between inflammatory immunomodulated activity or vedolizumab as the cause of the haemolytic anaemia is complex and almost impossible to establish.
Patient’s perspective
The journey I underwent was a tumultuous ride of emotions, ranging from fear and anguish to anxiety and panic. The weeks without a diagnosis were arduous and challenging, taking a toll on both my physical and psychological well-being. Experiencing a myriad of physical symptoms, including dizziness, fainting, profound fatigue, an accelerated heart rate, low haemoglobin levels, and undergoing blood transfusions, along with an initial therapy that proved ineffective, is an ordeal that will forever remain etched in my memory. Equally unforgettable is the invaluable support I received from dedicated professionals who stood by me, never letting go of my hand. Their unwavering commitment made all the difference in my recovery.
Learning points
In inflammatory bowel disease patients’, the major cause of anaemia is iron deficiency. Nevertheless, other causes should be searched mainly in cases in which blood loss is not visible.
Drug-induced haemolysis should always be a differential diagnosis of autoimmune haemolytic anaemia, even if the disease is in the active stage and even months after the introduction of therapies.
In spite of the fact that vedolizumab is considered a safe drug, some adverse events are possible and should be taken into account.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: MJT, SL, FP and PF. The following authors gave final approval of the manuscript: MJT, SL, FP and PF.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.