Long-term use of interleukin-1 inhibitors reduce flare activity in patients with fibrodysplasia ossificans progressiva

Abstract

Objectives: Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy.

Methods: Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres.

Results: All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales.

Conclusion: This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO.

Funding: RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III.

Keywords: IL-1; IL-1β; anakinra; canakinumab; fibrodysplasia ossificans progressiva; heterotopic ossification; interleukin.

Figure 1.

Flare rates of patients with FOP treated with anti-IL-1 therapy. (A) Individual patient flare-up rates per month before initiation of therapy, during therapy, during a pause and after restarting it. (B) Average flare-up rates/month for all treatment phases without anti-IL-1 vs with anti-IL-1. *P < 0.01

Figure 2.

Images of the right knee and surrounding area of patient 1, before the surgical repair of his right patella (A) and 3.5 months after (B), with no radiological signs of heterotopic ossification

Figure 3.

IL-1β plasma levels in FOP Patients 1 and 2 on canakinumab treatment. IL-1β levels were measured by ELISA in plasma samples collected during treatment with canakinumab from patient 1 (four samples during flares and one during remission) and patient 2 (three samples during flares and one during remission). IL-1β levels were also measured in plasma samples from patients with IL-1-driven monogenic auto-inflammatory diseases, including cryopyrin-associated periodic syndrome (n = 5, triangles), FMF (n = 1, square), TNF-associated periodic syndrome (n = 2, asterisks) and mevalonate kinase deficiency (n = 1, diamond) who were undergoing treatment with canakinumab