Evidence Mounts in Support of IL-1 Inhibition for Recurrent Pericarditis

Recent data from trials of two separate medications for treatment of refractory recurrent pericarditis are bolstering the prospects of interleukin-1 (IL-1) inhibition in the management of the debilitating autoinflammatory condition.

“Interleukin-1 plays an essential role in the development of cardiac inflammation and pathogenesis across a wide range of conditions, including recurrent pericarditis,” says Allan L. Klein, MD, Director of Cleveland Clinic’s Center for the Diagnosis and Treatment of Pericardial Diseases and a coinvestigator in the studies. “These promising efficacy and safety results with two different IL-1 inhibitors — anakinra and rilonacept — raise hope for a new treatment approach to refractory recurrent pericarditis.”

Background: Refining the role of immunosuppression

Pericarditis recurs in about 30% of cases of acute idiopathic pericarditis and in about half of such cases not treated with colchicine. The first episode often arises after a viral illness, in which the virus attacks pericardial cells. The cells react by releasing interleukin-1α and -1β from inflammasomes, exacerbating inflammation. In many cases, a self-sustained autoinflammatory response is believed to develop.

While some patients respond to standard therapy with NSAIDs, colchicine and corticosteroids, some do not or are unable to be tapered off steroids. In addition to experiencing frequent recurrences accompanied by often-disabling chest pain, patients with recurrent disease may develop severe side effects from chronic glucocorticoid therapy.

Increased understanding of the underlying physiology of recurrent pericarditis has generated interest in possible therapy with IL-1 blockade, specifically with two recombinant IL-1 inhibitors already approved for other autoinflammatory diseases — anakinra and rilonacept.

Registry study of anakinra

Use of anakinra for recurrent pericarditis has been reported in several case studies, small single-center case series and a randomized controlled trial (AIRTRIP) involving 21 patients. Results have been encouraging but have lacked robust statistical power, and evidence for optimal treatment protocols has been lacking.

This was the backdrop for the International Registry of Anakinra for Pericarditis (IRAP) study, which became the largest reported investigation of anakinra for the condition to date when recently published by the European Journal of Preventive Cardiology (2019 Oct 15 [Epub ahead of print]).

The single-arm observational study enrolled 224 consecutive patients between 2014 and 2018 from the registry, which includes 14 pericardial disease referral centers in six countries, including Cleveland Clinic. All patients had corticosteroid-dependent, colchicine-refractory recurrent pericarditis. Median disease duration was 17 months; 75% of cases were idiopathic.

Patients were treated with anakinra 100 mg once daily by subcutaneous injection for a median of six months followed by tapering for a median of three months.

The study, which compared health measures between baseline and the end of therapy, found anakinra to be associated with the following effects:

• Pericarditis recurrences fell. After median treatment of six months (range, 3-12 months), pericarditis recurrences were reduced to one-sixth of their baseline rate, i.e., from 2.33 to 0.39 flares per patient per year (P < 0.001). This translates to a mean of one recurrence every 939 days with therapy, down from one every 157 days at baseline — a reduction of 83%.
• Emergency department admissions and hospitalizations plummeted. Emergency department admissions were reduced to less than one-tenth of their baseline rate (from 1.08 to 0.10/patient/year), and hospitalizations dropped to one-seventh of their initial rate (from 0.99 to 0.13/patient/year) (both P < 0.001).
• Corticosteroid dependence was substantially reduced. All patients had been corticosteroid dependent at some time; 180 (80%) were still dependent at enrollment. At the end of anakinra therapy, just 61 remained on glucocorticoids (P < 0.001). NSAID use was also discontinued in most patients (from 170 to 54 patients). While colchicine use also declined, most patients still remained on it after anakinra therapy (from 198 to 131).

Therapy was well tolerated in the vast majority of patients. While adverse events occurred in 99 patients (44%), most were transient skin reactions at the injection site, and no serious events occurred.

Notably, outcomes were dependent on therapy duration. Lower risk of recurrence was associated with full-dose treatment for at least three months, with longer full-dose treatment and longer tapering associated with increasingly better outcomes.

“This study provides real-world data to support the use of anakinra for refractory recurrent pericarditis,” says Dr. Klein, a senior author of the study who, along with co-author Paul Cremer, MD, made Cleveland Clinic the study’s top-enrolling site. “The dramatic patient improvement strongly supports the hypothesis that interleukin-1 plays a critical role in refractory recurrent pericarditis and provides support for further investigation of IL-1 inhibition for this condition.”

All eyes on rilonacept

Based on these registry findings and previous data, anakinra is actively considered for off-label use in cases of refractory recurrent pericarditis, Dr. Klein notes. Meanwhile, attention is increasing around another IL-1 inhibitor under active investigation for a potential indication for recurrent pericarditis — rilonacept, which is administered by once-weekly subcutaneous injection, in contrast to anakinra’s once-daily dosing.

The primary venue for that investigation is the ongoing phase 3 RHAPSODY trial (NCT03737110), a global investigation for which Dr. Klein is one of two co-principal investigators. The placebo-controlled investigation is using a randomized withdrawal design to determine time to first recurrence in the randomized withdrawal period.

Interest in rilonacept’s potential was boosted by a poster presented by Dr. Klein at the American Heart Association 2019 Scientific Sessions in November. The poster reported final results of an open-label phase 2 study of rilonacept among 25 patients.

The study showed that rilonacept —160 mg weekly by subcutaneous injection for 6 weeks plus an optional 18-week extension — was associated with a rapid and sustained resolution of recurrent pericarditis episodes, with the annualized incidence of episodes falling from 3.9/year at baseline to 0.18/year during treatment. Patients also had significant improvements in overall quality-of-life scores, and all patients were able to either stop or taper corticosteroid therapy without pericarditis recurrence. The drug was generally well tolerated, with an adverse event profile consistent with its FDA-approved labeling.

“These final phase 2 data show a sustained clinical response over six months of treatment with rilonacept, supporting tapering of corticosteroids while on therapy,” notes Dr. Klein. “These findings affirm the efficacy results of the interim analysis reported at the American College of Cardiology Scientific Sessions in March 2018. We look forward to results from the randomized investigation of rilonacept in the ongoing phase 3 trial.”