NEW YORK – Evidence has accumulated in recent years that IL-1-beta-mediated inflammation and a dysregulation of the innate immune system is common to many autoinflammatory disorders that involve bouts of seemingly unprovoked recurrent inflammation and no indication of malignancy or infection, according to Dr. Jonathan Samuels.
These findings have opened up new therapeutic targets for these disorders, and some recent clinical studies suggest that investigators are on the right track, said Dr. Samuels, a rheumatologist affiliated with the Center for Musculoskeletal Care at NYU Langone Medical Center, New York.
Dr. Jonathan Samuels
The term "autoinflammation" was coined in 1999 following the discovery of the genes responsible for Familial Mediterranean Fever (FMF), a disease characterized by recurrent episodes of fever and abdominal pain, along with pleurisy, arthritis, and other symptoms. Patients feel normal between bouts and are unresponsive to corticosteroids. Like other patients with autoinflammatory diseases, FMF patients show no evidence of autoantibodies or antigen-specific T-cell reactivity, suggesting instead disordered regulation of the innate immune system, Dr. Samuels said at a meeting sponsored by New York University.
IL-1 has been identified as one of the most potent proinflammatory cytokines of the innate immune system, and is being recognized as a likely therapeutic target. "Many molecular cascades from various autoinflammatory diseases converge at IL-1, with oversecretion (as in the case of neonatal-onset multisystem inflammatory disease or NOMID) or uninhibited signaling (as in the case of deficiency of the interleukin-1-receptor antagonist or DIRA)," Dr. Samuels said.
For example, while colchicine has been shown to prevent acute attacks of FMF by 75% and decrease symptoms in 95%, there are no proven alternative therapies for patients with FMF who are resistant or intolerant to colchicine. Dr. Samuels was a coinvestigator of a recent randomized, double-blind placebo-controlled trial in which 14 patients with FMF who were colchicine resistant or intolerant were treated with the IL-1 antagonist rilonacept (2.2 mg/kg, maximum 160 mg) given by weekly subcutaneous injection for two 3-month courses. Rilonacept resulted in a significant reduction in the number of attacks per month (0.77 vs. 2.00, P = .027) and there were more treatment courses without attacks with rilonacept, compared with placebo. Rilonacept did not affect the duration of attacks (Ann. Intern. Med. 2012;157:533-41).
The cryopyrin-associated periodic syndromes, commonly known as CAPS, are a group of autosomal dominant autoinflammatory diseases that have been linked to mutations in the same gene. All three cryopyrinopathies have an early onset and present with urticarial rash and fever, although they span a spectrum of severity, according to Dr. Samuels. The mildest form is familial cold autoinflammatory syndrome (FCAS), which involves episodes generally lasting less than 24 hours, and is accompanied by headache and polyarthralgia. Muckle-Wells syndrome lasts 24-48 hours, and may cause deafness, optic disk edema, oligoarthritis, and polyarthralgia, as well as abdominal pain. Patients with NOMID are the most severely affected, with almost-continuous episodes, chronic meningitis, mental retardation, deafness, blindness, epiphyseal/patellar overgrowth, and intermittent chronic arthritis.
All three CAPS syndromes have been shown to respond to anti-IL-1 agents, according to Dr. Samuels. For example, in 2012, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases found in an open-label cohort study of 26 patients with NOMID that the IL-1 inhibitor anakinra yielded long-term improvements in measures such as global scores of disease activity, pain, CNS inflammation, and hearing for up to 5 years as long as escalating doses were used (Arthritis Rheum. 2012;64:2375-86).
Treatment with anakinra also has been beneficial for neonates with DIRA, which involves an autosomal recessive mutation on chromosome 2q that leads to uncontrolled IL-1 binding and causes crusting, erythema, pustulosis, and osteolytic lesions.
"This is a very complex group of disorders," Dr. Samuels said. Diagnosis should take into account ethnicity, inheritance pattern, cytokines, attack duration, treatment response, age of onset, triggers, and amyloid frequency. He referred audience members to a helpful diagnostic algorithm (Cleveland Clinic J. Med. 2012;79:569-81).
Dr. Samuels reported no relevant financial disclosures.