Tocilizumab is a humanized monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist and belongs to an important group of biological agents that has revolutionized anti-inflammatory therapy for rheumatoid arthritis. However, the use of medicinal products that block IL-6 has reportedly been associated with an increased risk of gastrointestinal perforation, mainly of the intestine. Gastrointestinal perforation associated with tocilizumab was identified as a potential signal during screening of the WHO global database VigiBase. As of March 2020, VigiBase contained 20 unique cases (compared with 3 expected) from nine countries that reported gastrointestinal perforation in which tocilizumab was the suspected medicinal product. Seventeen of the 20 cases (85%) were assessed as serious, one of them fatal. The time to onset of the adverse reaction ranged from 0,5 to 36 months (on average 5 months). The indication for the use of tocilizumab (specified in 18 cases) was rheumatoid arthritis (16 reports) and giant cell arteritis (2 reports). The outcome of the adverse reaction was unknown in 7 cases, but 11 patients recovered or were recovering, including 4 patients who underwent surgery, and 2 patients did not recover, including a fatal case. In 10 patients, known risk factors for gastrointestinal perforation were present, including concomitant diseases or a history of gastrointestinal disorders, smoking, and concomitant use of methotrexate, rituximab, steroids, NSAIDs, or a combination of these. It is assumed that perforation occurred more often in patients with higher body weight than in those with lower body weight (in cases where information was available). Given the seriousness of this reaction, it would be advisable to recommend careful monitoring of patients receiving tocilizumab, particularly those with risk factors for gastrointestinal perforation, as well as individuals with high body weight, since the dose of the medicinal product depends on the patient's weight.
Tocilizumab is a humanized monoclonal antibody that acts as an interleukin6 (IL-6) receptor antagonist. Thus, it is an immunosuppressive and interleukin-suppressing drug indicated for the treatment of severe active and progressive rheumatoid arthritis in adults, especially in combination with methotrexate, and giant cell arteritis. Tocilizumab is often prescribed to patients who respond inadequately to or are intolerant of previous therapy with drugs for the treatment of rheumatism or therapy with tumor necrosis factor antagonists. In addition, tocilizumab may be prescribed as monotherapy in case of intolerance to or inappropriate continuation of treatment with glucocorticoids and/or methotrexate. Tocilizumab reduces the rate of progression of joint damage and improves physical function when used in combination with methotrexate. It is also indicated for the treatment of juvenile idiopathic polyarthritis in patients aged 2 years and older who have not responded to previous therapy with methotrexate. Recently, tocilizumab has been discussed and tested as an alternative treatment for patients with COVID-19 at risk of a cytokine storm, since IL-6 is proposed as one of the most important cytokines in the storm.
Gastrointestinal perforation is a hole in the wall of the gastrointestinal tract (esophagus, stomach, small and large intestine). The main causes of gastrointestinal perforation may be gastric and duodenal ulcers, appendicitis, gastrointestinal cancer, diverticulitis, inflammatory bowel diseases and the use of medicinal products (NSAIDs). Perforation usually requires surgical intervention; conservative treatment is indicated only in selected patients who are clinically stable.
Gastrointestinal perforation is mentioned in the medical use instructions in the EMA and FDA. However, the instructions list intestinal perforation as a complication of diverticulitis. Therefore, gastrointestinal perforation was identified as a potential signal during VigiBase screening.
The aim of this study was to analyze the pattern of clinical features of gastrointestinal perforation associated with the use of tocilizumab in VigiBase case reports and to assess causality alongside findings from the literature.
Case analysis
A clinical review was conducted of reports of gastrointestinal perforation associated with tocilizumab received by VigiBase up to March 2020.
VigiBase contained 20 unique cases (3 expected) reporting gastrointestinal perforation or stomach perforation with tocilizumab as a suspect or interacting medicinal product. Reports were received from 9 countries (Japan, the USA, Colombia, Austria, the United Kingdom, Ireland, Greece, Portugal and Hungary). The indications for tocilizumab use were rheumatoid arthritis (16 cases) and giant cell arteritis (2 cases), and in 2 cases the information was absent. By gender – 13 women, 6 men and in 1 case the sex was unknown. The patient’s age ranged from 37 to 83 (mean 61 years). The vast majority of reports were reported by physicians (n = 16). Of 20 cases, 17 (85%) were serious, including four life-threatening and one fatal case. In 11 cases (55%) there were narratives, although some of them were considered less informative.
In addition to gastrointestinal perforation, 7 cases also reported acute coronary syndrome, pulmonary embolism, cerebrovascular accident, neutropenia, elevated transaminases, respiratory or urinary tract infections, with multiple concomitant manifestations in some patients. In 15 cases (75%), tocilizumab was the only suspected drug. In the remaining 5 reports, the suspected medicinal products also included methotrexate, prednisolone, hormones (unspecified) and celecoxib, and in two of these patients, who were using NSAIDs or steroids, gastroprotection (for example, antacids) was not mentioned. In the reports where information was provided, concomitant therapy was used in 12 patients.
In eight cases, information on tocilizumab dosing was provided: the mean dose corresponding to four-week intervals was 7,9 mg/kg, ranging from 6,0 to 10,0 mg/kg, based on the highest dose when different doses were administered. Where information was available (n = 8), the mean body weight was 80 kg, with weight ranging from 49 to 114 kg.
Conclusions
Gastrointestinal perforation is an important identified risk of treatment with tocilizumab, which can be life-threatening. However, at present the instruction for medical use lists intestinal perforation as a complication of diverticulitis. VigiBase contained cases of gastrointestinal perforation, in particular in patients with concomitant medicinal products known to cause gastrointestinal perforation, and with high body weight. Healthcare professionals should be aware of this possible risk and monitor closely patients, in particular those with risk factors for gastrointestinal perforation, as well as patients with high body weight, during treatment with tocilizumab, which is dosed according to total body weight.
More detailed information on cases of gastrointestinal perforation from VigiBase and the literature is described in the original document “Gastric perforation due to Tocilizumab” (184 KB) (Uploaded: 25.01.2021 08:42:49).
List of medicinal products containing tocilizumab that are authorized for medical use in Ukraine (according to the State Register of Ukraine as of 19.06.2020) (10 KB) (Uploaded: 25.01.2021 08:42:50).
