Close to one-fifth of infections in children with juvenile idiopathic arthritis (JIA) on immunosuppressants are caused by opportunistic pathogens — such as microorganisms that take advantage of weakened immune system — according to a large international study.
These infections were most commonly caused by the herpes virus, mycobacterium tuberculosis, and the yeast Candida.
The study, “Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee,” was published in the journal Arthritis Research & Therapy.
The use of immunosuppressants in JIA, including synthetic and biologic disease-modifying rheumatic drugs, is expected to increase the risk for serious and opportunistic infections, such as tuberculosis.
But despite some recent evidence that immunosuppressants are in fact associated with higher infection rates, results are still inconclusive, especially for those caused by opportunistic pathogens.
With this concern in mind, regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency have requested that companies conduct long-term safety assessments of therapies used in late-stage clinical trials.
In response to this request, in 2011, the Paediatric Rheumatology International Trials Organization (PRINTO) created an international registry called Pharmacovigilance in Juvenile Idiopathic Arthritis Patients, or Pharmachild.
As of January 2017, the registry (NCT01399281) included a total of 8,274 patients at 86 PRINTO centers across 32 countries and others belonging to the Paediatric Rheumatology European Society.
In this study, an independent safety adjudication committee set out to determine opportunistic infections in children with JIA by conducting a study based on Pharmachild registry data. The committee was made up of three pediatric rheumatologists and two pediatric infectious disease specialists.
To classify infections, the researchers developed a five-step procedure that included a provisional list of opportunistic infections. Committee members answered five questions regarding infection confirmation, if the infection was common, opportunistic, if treatment was adequate, and if the event could be due to other treatments being taken at the time.
A total of 895 patients (10.8%) enrolled in Pharmachild developed 1,585 infections. From this subset, the researchers evaluated 772 events (48.7%) in 572 individuals — 437 were considered preliminary opportunistic infections and 335 were deemed very severe/severe or serious non-opportunistic events.
After evaluation, there was a consensus for 682 infections, including 119 opportunistic infections (17.4%). The researchers considered the treatment appropriate for 484 events (77.1%).
Among the infections, the association of one biologic — frequently Amgen‘s Enbrel (etanercept) or AbbVie’s Humira (adalimumab) — with one synthetic DMARD was the most reported regimen, accounting for 32% of cases. This was followed by methotrexate (21%) and Enbrel (20.3%) alone, while the combination of one biologic, one synthetic DMARD, and systemic glucocorticoids corresponded to 9% of cases. The use of one synthetic DMARD and systemic glucocorticoids was reported in 3.7% of cases.
After matching the committee’s consensus with the provisional list of infections, 106 were confirmed as opportunistic, which accounts for 15.5%.
Regarding pathogens, herpes virus accounted for 72 events (68% of confirmed opportunistic infections, most commonly herpes zoster), followed by Mycobacterium tuberculosis in 11 events (10.4%), and infections by the yeast Candida in nine events (8.5%).
Less frequent infections included those caused by the papilloma virus (3.8%), pneumocystis — a type of pneumonia caused by the fungus Pneumocystis jirovecii (3.8%) — and cytomegalovirus (2.8%).
“In conclusion, almost 1/5 of all severe and/or serious infections in JIA patients on immunosuppressive therapy are opportunistic,” the researchers wrote.
These findings may serve as reference for future studies in children with JIA on immunosuppressive therapy, “and a list of infections that could possibly display an opportunistic nature related to the patient’s history and/or the pathogen presentation,” they added.