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

Ruby Haviv; Leonid Zeitlin; Veronica Moshe; Amit Ziv; Noa Rabinowicz; Fabrizio De Benedetti; Giusi Prencipe; Valentina Matteo; Carmen Laura De Cunto; Edward C Hsiao; Yosef Uziel

doi:10.1093/rheumatology/keae255

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

Rheumatology (Oxford). 2024 May 11:keae255. doi: 10.1093/rheumatology/keae255. Online ahead of print.

Authors

Ruby Haviv^{1

2}, Leonid Zeitlin^{2

3}, Veronica Moshe¹, Amit Ziv^{1

2}, Noa Rabinowicz¹, Fabrizio De Benedetti⁴, Giusi Prencipe⁴, Valentina Matteo⁴, Carmen Laura De Cunto⁵, Edward C Hsiao⁶, Yosef Uziel^{1

2}

Affiliations

¹ Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Center, Kfar Saba, Israel.
² Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ Pediatric Orthopedic Department, Dana-Dwek Children's Hospital, Sourasky Medical Center, Tel Aviv, Israel.
⁴ Division of Rheumatology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
⁵ Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
⁶ Division of Endocrinology and Metabolism, Institute for Human Genetics, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, USA.

PMID: 38733591
DOI: 10.1093/rheumatology/keae255

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 interleukin-1β (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 centers.

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 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 formation 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: Fibrodysplasia ossificans progressiva; IL-1; IL-1β; anakinra; canakinumab; heterotopic ossification; interleukin.