The long-term safety of anakinra (Kineret) has been maintained for up to 5 years in patients with the autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS), researchers reported.
In a group of 43 patients followed at the National Institutes of Health in Bethesda, Md., the yearly rate of adverse events has been 7.7 per patient, according to Torbjorn Kullenberg, MD, of Swedish Orphan Biovitrum in Stockholm, and colleagues.
And overall, there was a decrease in adverse events during the years of the study (2003 to 2010), falling from just over 10 per patient to about 5, the researchers reported in Rheumatology.
“CAPS is caused by heterozygous gain-of-function mutations in NLRP3, the gene encoding cryopyrin. Signaling via the interleukin-1 receptor type 1 is crucial for the pathogenesis of CAPS and was first demonstrated by the induction of clinical response in CAPS patients treated with the recombinant IL-1 receptor antagonist anakinra.”
Before the association between IL-1 and CAPS was recognized, mortality during childhood among patients with the most severe form of the disease, neonatal-onset multisystem inflammatory disease (NOMID), was estimated at 20%. However, dramatic and rapid responses were seen in a cohort of NOMID children when anakinra was first tried for this condition.
The cohort has continued to be followed for safety with open-label use of anakinra given as daily subcutaneous injections.
A total of 36 of the patients were diagnosed with NOMID, which is characterized by fevers, rash, headache, aseptic meningitis, hearing loss, visual impairment, and cognitive difficulties. The other seven had overlapping features of NOMID and a milder form of CAPS known as Muckle-Wells syndrome, with features of hearing loss, fever, urticaria, arthralgia, and fatigue.
Most of the patients were under 12 years of age, although the cohort also included seven adults.
Initially, patients were started on dosages of 0.5 to 1.5 mg/kg/day, but this was later increased to 1.5 to 2.5 mg/kg/day. The dose was then adjusted according to clinical response, and the median maintenance dosage at 5 years was 3.1 mg/kg/day.
The total number of adverse events over 5 years for the 43 patients was 1,233. The rate was 9.5 per patient-year for children younger than 2 years, 8.6 per patient-year for those ages 2 to 11, and 9.5 for those older than 18. The rate was only 3.6 per patient-year in the group ages 12 to 17, but that group included only five patients.
During the first 3 years of the study, there was a steady decline in adverse events. However, in the fourth year there was an apparent spike in events, when reporting in patient diaries was changed to include CAPS disease symptoms such as pyrexia, rash, and malaise as adverse events. When those events were removed from the analysis, the overall decrease persisted.
Overall, the most common adverse events were headache, arthralgia, and pyrexia — all of which are common CAPS-associated symptoms and “should be seen as continued disease activity in this patient population with severe CAPS rather than as a side effect of anakinra,” the authors observed.
One patient developed macrophage activation syndrome, which was managed with cyclosporine and prednisone, resolving without sequelae. There were no deaths.
Most events were mild, and only 1% were classified as severe. None required treatment cessation.
Injection site reactions were reported in 10 patients. “As expected,” most of these were in the first month of treatment.
There were 24 serious adverse events, most of which were infections occurring during the first year of treatment. One patient had severe cellulitis and a wound infection and the anakinra was temporarily stopped, which resulted in severe flare. After 8 days, the anakinra was restarted.
Because stopping treatment can trigger disease flares, the authors suggested that continued anakinra treatment should be considered in CAPS patients during infections, “with careful monitoring of the resolution of the infection.”
During most other infections, the anakinra was continued at the same dose. There was no signal for opportunistic infections, and no complications developed.
“In summary, the data presented here show that anakinra is well tolerated during long-term treatment of both children and adults with severe CAPS,” Kullenberg and colleagues concluded.
The study was funded by the Intramural Research Program of the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, and Swedish Orphan Biovitrum.
Several of the coauthors are employees of Swedish Orphan Biovitrum. One also has received research report from SOBI, Regeneron, Novartis, and Eli Lilly.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco