The Turkish Journal of Gastroenterology
Turk J Gastroenterol 2011; 22 (5): 537-539
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|Infliximab- and azathioprine-related severe
neutropenia and thrombocytopenia in a case with
|Ali Rıza KÖKSAL1, Canan ALKIM1, Engin ALTINKAYA1, Mehmet Sait BUĞDACI1, Osman ÖZDOĞAN1,
Salih BOĞA1, Hüseyin ALKIM2, Mehmet SÖKMEN1
|Department of 1Gastroenterology, Şişli Etfal Training and Research Hospital, İstanbul
Department of 2Gastroenterology, Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul
|Keywords: Crohns disease, infliximab, neutropenia, thrombocytopenia, azathioprine.
A 25-year-old female patient with Crohns disease had been using azathioprine and metronidazole for an extended period because
of recurrent perianal and rectovaginal fistulae. Infliximab was added to the treatment regimen following postoperative recurrence
of a rectovaginal fistula. Upon the development of severe neutropenia and thrombocytopenia after the third dose of infliximab, azathioprine and infliximab were stopped. Neutropenia work-up did not reveal any other cause. Neutropenia was ameliorated with use
of granulocyte colony-stimulating factor. Treatment was restarted with infliximab alone upon leakage from the rectovaginal fistula
with no hematologic toxicity. This case was considered as a serious adverse effect of infliximab and azathioprine combination therapy.
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that is released in response to infectious or inflammatory stimuli. The TNF-α antagonists infliximab, etanercept and adalimumab
are successfully used in the treatment of rheumatoid diseases such as rheumatoid arthritis and
ankylosing spondylitis, and in Crohns disease refractory to standard therapy (1). Generally well-tolerated, the most common side effects related to
TNF-α inhibitors are reactions at the injection site, dyspnea, urticaria, and headache. Infusion reactions, anaphylaxis, development of tuberculosis
and opportunistic fungal infections, congestive heart failure, and triggering of multiple myeloma attacks have also been reported (2). Although the
mechanism of action is unclear, aplastic anemia,
neutropenia and pancytopenia have been reported
in association with anti-TNF-α treatment (2-4).
Infliximab-related neutropenia is not common,
and exists in the literature as case reports (3,5-7).
Azathioprine (AZA) and its active metabolite 6mercaptopurine (6-MP) have been extensively
used in the treatment of steroid-resistant Crohns
disease. A significant side effect of these drugs
that inhibit DNA synthesis is bone marrow toxicity. This side effect usually occurs after doses
greater than 2 mg/kg/day. This dose-dependent
myelosuppression generally improves with lowering of the dose or suspension of treatment (8). However, an idiosyncratic severe myelosuppression
may rarely occur with these drugs. Previous studies have not reported an increase in the prevalence
of any adverse effect, including bone marrow toxicity, during combination therapy with AZA and
A 25-year-old female patient was first admitted to
our clinic 7 years ago with the complaint of abdominal pain and diarrhea. After clinical, endoscopic
and histologic examinations, an ileocolonic
Crohn's disease was diagnosed. Her Crohns Disease Activity Index (CDAI) score was 530, and a
clinical remission was achieved with mesalazine 3
g/day and a prednisolone course of 40 mg/day. She
remained in remission for one year with mesalazine. After one year, a perianal fistula developed,
and AZA 2 mg/kg/day was started together with a
six-week metronidazole course. Following two years in remission, a rectovaginal fistula developed
and the patient was operated. Postoperative metronidazole was started for non-closure of the fistula and the development of new perianal fistulae.
Being well-tolerated, the AZA dose was increased
to 3 mg/kg/day in order to obtain more effective
therapeutic effect, and later discontinued due to
mild bone marrow suppression [white blood cell
count (WBC): 3000/mm3, polymorphonuclear neutrophils (PMNs): 1450/mm3, hemoglobin (Hb): 10.9
g/dl, platelet count: 155.000/mm3)]. Treatment
with AZA was restarted after three months, up to
100 mg (nearly 2 mg/kg - the patients body weight
was 54 kg at that time) with increments of 25 mg.
There was no decrease in leukocyte count. The perianal disease did not improve after six months of
therapy with AZA. Furthermore, new perianal fistulae and fissures developed, and leakage from the
patients rectovaginal fistula persisted. Infliximab
was therefore added to the treatment at 5 mg/kg
on weeks 0, 2 and 6. The patient presented with
complaints of fatigue, fever and diarrhea 10 days
after the third infliximab dose. Fever was 39°C,
WBC: 350/mm3, PMNs: 130/mm3, platelet:
34000/mm3, and Hb: 10.8 g/dl. The patient was
hospitalized and placed under therapy with widespectrum antibiotics, and AZA was discontinued.
On day 5, the patient still had high fever, and neutropenia and thrombocytopenia had not improved. Granulocyte colony-stimulating factor (GCSF) was administered at doses 30 MU/day for five days. Blood counts started to increase after the
second day of G-CSF treatment. Cultures were negative. Testing for the other possible etiologies of
neutropenia and thrombocytopenia showed no
pathologies (antinuclear antibody (ANA), antiDNA, extractable nuclear antigens (ENA) profile,
anti-neutrophil cytoplasmic antibody (ANCA),
Epstein-Barr virus (EBV), cytomegalovirus
(CMV), and parvovirus tests were all negative).
The patient was discharged on mesalazine alone
with normal temperature and blood count. Upon
leakage from the rectovaginal fistula two months
after discharge, treatment with infliximab alone
at a dose of 3 mg/kg was initiated. The patients
hemogram was normal, and the third dose was administered as 5 mg/kg. No hematologic toxicity
was observed after the eighth dose of infliximab
treatment. There was marked improvement in the
rectovaginal and perianal fistulae.
The known risk of severe myelosuppression in patients with inflammatory bowel disease using thiopurine therapy warrants monitoring the patients
during their first two months of therapy. Manufacturers recommend weekly WBCs for the first eight
weeks of therapy followed by blood tests at least
every three months. Less frequent monitoring
(weekly within the first 4 weeks of the therapy
and every 612 weeks thereafter) may be sufficient. It is just as important to advise patients to report promptly should a sore throat or other sign of
infection occur. Tailoring or optimization of thiopurine therapy can occur before or during treatment. Clinicians should aim for a maintenance dose of AZA of 22.5 mg/kg/day and of 6-MP of 11.5
mg/kg/day in both ulcerative colitis and Crohns
disease. The maximum dose will differ between individuals, and effectivity means that level at
which leukopenia develops (11).
Drug-induced bone marrow suppression is related
to infectious complications and increased mortality (12). Although bone marrow suppression is
quite rare with infliximab, it is a more common side effect with AZA. In our case, the previous AZArelated mild neutropenia had improved upon discontinuation of the drug, and was not observed
with dose increase in small increments up to the 2
mg/kg of body weight. Thus, we think that our patients first myelotoxicity was related to the highdose of AZA. After the third dose of infliximab, neutropenia persisted despite discontinuation of
AZA and infliximab. The neutropenia reported by
Montané et al. (3) within 2-3 weeks of etanercept
treatment only improved 1-2 months after discontinuation of the drug. Treatment could not be resumed, as similar side effects were observed with
repeated doses of etanercept, and later with infliximab. Favalli et al. (5) reported serious neutropenia following the second dose of infliximab in a patient with enteropathic spondyloarthropathy.
Marchesoni et al. (13) described an additive effect
of potentially myelosuppressive agents such as allopurinol and leflunomide being co-administered
with infliximab in relation with a case with rheumatoid arthritis who developed neutropenia. Vidal et al. (6) also mentioned an additive effect in
their report of severe neutropenia and thrombocytopenia in a patient with rheumatoid arthritis after the third dose of infliximab in combination
with methotrexate. We also suggest that our patients second myelotoxicity was related to the coadministration of AZA and infliximab, because the
patient had no myelotoxicity with separate uses of
AZA 100 mg/day and/or infliximab. There is no data in the literature regarding the two drugs interaction during metabolism (14). However, myelosuppression, a side effect of both drugs, is enhanced in combined use. As our patients need for anti-TNF treatment continued, AZA was discontinued and infliximab dosage was increased in small
increments, thereby avoiding bone marrow toxicity.
In conclusion, infliximab treatment in Crohns disease in combination with AZA can cause serious
myelosuppression. Patients under treatment with
this combination should be closely monitored for
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