Mesalazine-Associated Agranulocytosis

To the Editor: Mesalazine is a member of the drug class 5-aminosalicylates, and its potential mechanism of action involves the inhibition of the cycloxygenase pathway and the suppression of local prostaglandin production in the colon.1,2 As the first-line drug for the treatment of ulcerative colitis (UC) and Crohn disease (CD), mesalazine is more effective than conventional sulfasalazine (SASP) that has a relatively superior safety and tolerability profile.3 The most commonly reported adverse reactions associated with mesalazine are headache, nausea, abdominal pain, diarrhea, and abdominal distension3,4; adverse effects resulting in agranulocytosis are exceedingly rare. This article presents a patient with CD who developed severe agranulocytosis after using mesalazine in the Chinese population. We will also conduct a systematic review of published cases to analyze the clinical characteristics of this rare condition, with the aim of providing a reference for the safer use of mesalazine in the clinic. A 62-year-old woman, 61 kg, was diagnosed with CD after recurrent abdominal pain and intestinal obstruction, with no prior medical history and normal blood counts. After more than 2 months of receiving oral mesalazine granules 1 g 4 times per day, the patient's blood routine showed a white blood cell of 0.40 × 109/L, and an absolute neutrophil count (ANC) of 0.40 × 109/L and the use of mesalazine was discontinued. Three days later, the ANC decreased to 0.01 × 109/L simultaneously developed a mass in the right inguinal area. The patient was admitted for agranulocytosis. After receiving treatment of ceftazidime and recombinant human granulocyte stimulating factor (G-CSF) 300 μg for 8 days, the patient's blood routine was white blood cell of 82.28 × 109/L, ANC of 72.72 × 109/L, and the infection improving, which led to the discontinuation of G-CSF and antibiotics. During the patient's hospitalization, the most prevalent causes of agranulocytosis were systematically eliminated,5 such as hematological disorders (bone marrow examination suggestive of myeloproliferative hypoplasia, with morphology tentatively free of primitive and pathologic hematopoietic alterations), infections, CD activity, vitamin deficiencies, immune factors, and other drug-related factors. After being discharged from the hospital, the patient's blood counts returned to normal within 5 months of discontinuing mesalazine (Table 1). The Naranjo score was 8, suggesting that the correlation between mesalazine and neutropenia was probable. Table 1. - Laboratory results after administering mesalazine. Days after admission WBC (/mm3) ANC (/mm3) 0 3.92 6 5.67 4.28 12* 5.05 3.52 84† 0.40 0.11 87 0.29 0.01 90 0.25 0.03 92 0.34 0.04 90‡ 0.84 0.10 94§ 82.28 72.72 97 41.28 35.37 229 3.63 2.69 240 3.33 2.39 *The patient was initiated on mesalazine.†The patient discontinued mesalazine.‡The patient receive human G-CSF treatment.§The patient discontinued G-CSF.WBC, white blood cell. In our case, agranulocytosis (defined as ANC < 0.5 × 109/L) occurred after mesalazine treatment, which was discontinued and returned to normal around 5 months after symptomatic management with anti-infection and G-CSF, suggesting a possible diagnosis of granulocyte deficiency because of mesalazine. Mesalazine is a well-tolerated drug; hematologic adverse reactions, such as agranulocytosis and pancytopenia, occur rarely (<1/10,000), and the adverse reactions that cause severe agranulocytosis are even more rare. The keywords “neutropenia,” “granulocyte deficiency,” “agranulocytosis,” and “mesalazine” were used in the databases of PubMed, Web of Science, Medline, China Knowledge Network Infrastructure, and Wanfang up to June 30, 2024. Only 10 relevant cases were identified domestically and internationally (Table 2). Table 2. - Published reports of agranulocytosis induced by mesalazine. Author (year) Age (years)/sex Diagnosis Therapeutic regimen The time of adverse reactions Level of WBC/ANC after medication Treatment Recovery time of the WBC and ANC (after discontinuation) Clinical outcome Freire González et al6 (2018) 82/F UC Oral mesalazine 4 g and topical mesalazine 4 g 3 months WBC 1.8 × 109/LANC 0.03 × 109/L Antibiotics and GSF 10 days Recover Frattini et al7 (2013) 64/F UC Mesalazine 14 months WBC 0.8 × 109/LANC 0.01 × 109/L Antibiotics and GSF 20 daysANC 1.6 × 109/L Recover Fowler et al8 (2010) 73/M UC Asacol 5 months ANC 0 NR 4 months ANC 2.3 × 109/L8 months ANC 3.4 × 109/L Recover Akbal et al9 (2010) 37/F CD Oral mesalazine 4 g/day and azathioprine 100 mg/day 2 weeks WBC 0.9 × 109/LANC 0.1 × 109/L NR 7 days Recover Bhidayasiri et al10 (2000) 60/M CD Mesalazine 800 mg t.i.d. and oral prednisone 2 months WBC 0.6 × 109/LANC 0.02 × 109/L Antibiotics and high-dose G-CSF (10 μg/kg·d) 2 weeksANC 3.4 × 109/L Recover Otsubo et al11 (1998) 20/M UC NR 4 months NR Antithymocyte globulin, cyclosporine, and G-CSF NR NR Kotanagi et al12 (1998) 23/M CD Pentasa 3.0 g/d and prednisolone 2 weeks WBC 0.7 × 109/L Received blood transfusion and G-CSF 7 days Recover Thalhammer et al13 (1997) 41/F CD Mesalazine 1000 mg t.i.d. and prednisolone 50 mg 3 months WBC 1.0 × 109/LANC 0.3 × 109/L Antibiotics and GSF NR Recovery with persisting harm Abboudi et al14 (1994) 71/M UC Mesalazine 800 mg b.i.d. 5 months WBC 1.3 × 109/LANC 0.4 × 109/L ATG regular red cell and platelet transfusions NR Death Wyatt et al15 (1993) 75/M UC Mesalazine 400 mg t.i.d. 4 months WBC 0.8 × 109/L Broad-spectrum antibiotics and G-CSF NR Death NR, not reported; WBC, white blood cell. To our knowledge, this is the first published report of agranulocytosis associated with mesalazine use in a Chinese population. Previously reported cases (including the present case) included 5 female and 6 male patients, most of them recovered after receiving symptomatic management, with 2 fatal cases observed in patients with UC who were using a low dose of mesalazine (<2 g/d). Santos et al16 have suggested that leukopenia is related to age and drug dosage, independent of gender and diagnosis. Agranulocytosis caused by mesalazine is predominantly observed in older patients (>60 years), as the case with the patient we reported, consistent with previous studies. Further research is necessary to determine whether its occurrence is linked to UC disease itself. The United Nations Commission on Safety of Medicines reported 46 cases of hematologic abnormalities associated with mesalazine between 1980 and 1993, most of which involved oral mesalazine doses of more than 1 g per day but did not demonstrate a dose-dependent correlation.17 The results of our literature review also indicate that the hematologic abnormalities caused by mesalazine may not be strongly correlated with the dosage of mesalazine used, which needs further investigation. Previously reported granulocyte deficiency has ranged from 2 weeks to a year later after mesalazine treatment, with the majority of cases appearing around 3 months of treatment. It is noteworthy that although mesalazine and its major metabolites have relatively short apparent terminal half-lives averaging 7–9 and 8–12 hours. After discontinuing mesalazine, previous cases, including the present patient, have demonstrated that patients tend to exhibit no significant signs of recovery of ANC in the short term. Therefore, early screening is generally challenging, which may result in delayed treatment, especially when combined with other factors that contribute to granulocyte deficiency (eg, combined use of azathioprine9). Because patients with agranulocytosis are at a significantly increased risk of infection,14 most of the documented cases were treated with broad-spectrum antibiotics and G-CSF, and the recovery period of ANC in these patients with G-CSF was approximately 7–20 days. There was only 1 case who did not use pharmacologic interventions such as G-CSF, and although the ANC of this patient recovered spontaneously, the recovery period was relatively long. Currently, the mechanism by which mesalazine causes agranulocytosis is unclear. Freire González et al6 suggest that it is an idiosyncratic response, possibly because of a damaging effect at the level of the stem cells or an immune system-mediated destruction of peripheral blood cells. Frattini et al7 propose that the recovery of hematology is usually slow, possibly because of a central, immune-remediated mechanism of toxicity, and may trigger severe infections. Therefore, discontinuation of mesalazine alone may not be sufficient in exceptional cases. There is currently no standardized management of neutropenia due to mesalazine. Clinicians should be aware that regular monitoring of blood counts is necessary when using mesalazine, particularly within the first 3 months of treatment, in older age groups, and in individuals receiving concomitant azathioprine. When neutropenia occurs, the utilization of G-CSF may be a therapeutic option to reduce the duration of granulocyte deficiency and decrease the incidence of complications.18,19