Infliximab, etanercept and adalimumab are tumor necrosis factor (TNF)-α inhibitors, mainly used for the treatment of chronic inflammatory diseases. TNF-α inhibitors modulate disease activity in a growing number of chronic inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, as well as inflammatory bowel diseases. Lymphomatoid papulosis is characterized by a chronic course of recurrent, self-healing papulonecrotic or nodular skin lesions. This condition has an indolent clinical behavior, and its malignant potential is uncertain. Statistical screening of the WHO global database VigiBase revealed disproportionate reporting of the term “lymphomatoid papulosis” associated with adalimumab. A broader search was conducted to include other TNF-α inhibitors, such as infliximab and etanercept. In the case series, including adalimumab, infliximab and etanercept, a consistent time to onset of the reaction was identified, and there is biological plausibility supporting the signal. Reporting of this signal is justified because, in some high-risk patients, lymphomatoid papulosis may be considered a precursor condition closely associated with other malignant lymphoproliferative disorders.
Infliximab, etanercept and adalimumab are biological medicinal products. Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (TNF)-α, and etanercept is a soluble p75 receptor protein of TNF-α.
TNF-α inhibitors have had a considerable effect on disease activity as the number of chronic inflammatory diseases has grown, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, as well as inflammatory bowel disease.
Lymphomatoid papulosis is characterized by a chronic course of recurrent, self-healing papulonecrotic or nodular skin lesions. The histological picture of lymphomatoid papulosis is extremely variable and may resemble various types of cutaneous T-cell lymphomas. The current WHO classification of the European Organisation for Research and Treatment of Cancer (EORTC) lists lymphomatoid papulosis as a primary cutaneous CD30+ lymphoproliferative disorder.
Lymphomatoid papulosis has an indolent clinical course, and its malignant potential is uncertain. The frequency of association between lymphomatoid papulosis and the development of other malignant conditions, such as lymphoma, CD30 + anaplastic large cell lymphoma, mycosis fungoides or Hodgkin's disease, remains unclear in the literature. Some studies suggest a frequency of 10 to 20%, while others suggest a cumulative risk of up to 60 – 80% after a follow-up period of 20 to 30 years. For this reason, long-term follow-up of patients with lymphomatoid papulosis is strongly recommended.
As of January 2020, 15 reports with the term “lymphomatoid papulosis” associated with adalimumab had been registered in the database, compared with approximately 3 expected cases. The search was extended to other medicines of the same therapeutic class, revealing 11 cases associated with etanercept (3 expected cases) and 5 cases associated with infliximab (1 expected case). There were no reports of lymphomatoid papulosis associated with the use of golimumab and certolizumab.
31 reports (adalimumab 15, etanercept 11, infliximab 5) were received from 9 countries – the USA, the United Kingdom, Hungary, Spain, France, Germany, Greece, Austria and Canada. Nine cases were published in the scientific literature. By gender, the distribution is as follows – 18 men, 12 women, and in 1 case the sex was not specified. Age range – 16-82 years.
In 14 patients, the time to onset of clinical manifestations was determined, with a mean of 739,5 days (slightly more than two years); the median was 485 days (16 months), with a range from 24 days to 10 years. In 27 reports, the event was considered serious. Skin lesions were described as patches, plaques, or erythematous nodules on the extremities and sometimes on the trunk. In 24 reports, a TNF-α inhibitor was the only suspected medicinal product.
Reports in VigiBase indicate that this may be a signal of an association of adalimumab, etanercept and infliximab with lymphomatoid papulosis.
Conclusions
Reports in VigiBase revealed a pattern between the occurrence of lymphomatoid papulosis and the use of adalimumab, etanercept and infliximab. These TNF-α inhibitors were the only suspected medicinal product in 24 of 31 cases. The median time to onset of the adverse reaction was 16 months, and this was related to the nature of the adverse reaction and the mechanism of action of the medicine. Lymphomatoid papulosis or cutaneous T-cell lymphoma is not mentioned in the package leaflets of these medicines, although there are literature data supporting this signal. For these reasons, it is possible to include lymphomatoid papulosis in the package leaflets of medicinal products containing the active substance adalimumab, etanercept and infliximab so that doctors and patients are aware of this condition during treatment with these medicines.
More detailed information on infliximab, etanercept, and adalimumab, on lymphomatoid papulosis, and a description of the cases are given in the original document “Lymphomatoid papulosis and tumor necrosis factos-α inhibitors: infliximab, etanercept and adalimumab” (225 KB) (Uploaded: 25.01.2021 08:42:49).
List of medicinal products containing infliximab, etanercept, and adalimumab and registered in Ukraine (according to the State Register of Ukraine as of 10.06.2020).
