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

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-1ß (IL-1ß). 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-1ß levels during a FOP flare, further supporting a role of IL-1ß 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-1ß levels comparable to those in IL-1ß-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.

Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: Multicenter, retrospective data collection.

PURPOSE: To collect retrospective data of patients with Juvenile Idiopathic Arthritis (JIA) and other rheumatic diseases who received live attenuated booster measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMR/V) during treatment with immunosuppressive therapy. RESULTS: Data from 13 pediatric rheumatology centers in 10 countries, including 234 patients, were collected. Mean age at diagnosis was 5 ± 2.7 years, 67% were girls. Among them, 211 (90.2%) had JIA and 110 (47%) were in remission on medication. Disease activity was low in 37%, high in 8%, and moderate in 8%. One hundred-twenty-four received MMR/V booster while on methotrexate (MTX); 3 reported local mild adverse events (AE). Among 62 on MTX + biologics and 9 patients who received a combination of 2 disease modifying antirheumatic drugs (DMARDs), 9 reported mild AE. Among 39 on biologics, 1 reported fever one day after booster vaccination. No vaccine-related infection of measles, rubella, mumps or varicella was reported, none of the patients developed disease flare, including those with high disease activity. CONCLUSIONS: In this retrospective study, live-attenuated MMR/V booster vaccines were safe for children with rheumatic diseases, on immunosuppressive therapies. This strengthens the Paediatric Rheumatology European Society (PReS) recommendation that vaccination with live attenuated vaccines in patients on immunosuppressive therapies can be considered individually, weighing the benefit of vaccination against the risk of inducing infection through vaccination. These data provide the basis for a prospective data collection study, planned by the PReS vaccination study group.

Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome?

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1ß (IL-1ß) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions. CASE PRESENTATION: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1ß were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1ß plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents. CONCLUSIONS: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1ß plasma levels during a paroxysm support a role for IL-1ß in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.

Disease activity, overweight, physical activity and screen time in a cohort of patients with juvenile idiopathic arthritis.

OBJECTIVES: Physical activity is an important part of children's health and social development. Juvenile idiopathic arthritis (JIA) can lead to decreased physical activity and quality of life. This study characterised clinical aspects, physical activity rates, obesity, and screen time in a group of JIA patients. METHODS: Ninety-seven JIA patients in the Paediatric Rheumatology Clinic at Meir Medical Center were evaluated over a 6-month period and compared by statistical methods to 98 age-matched healthy controls. Information on disease activity, type and amount of physical activity (using the Modified Godin Leisure-Time Exercise Questionnaire), and daily screen time hours were collected. RESULTS: Among the JIA patients, 56% had oligoarthritis, 22% polyarthritis and 17% systemic disease. Disease activity among all JIA sub-groups was low (average of 1.7/10), two-thirds of patients had disease activity lower than 3, only 4% over 5, and 56% were in clinical remission. Obesity rates in the patient and control groups were 21.5% and 19.4%, respectively. Physical activity levels were similar in both groups. Age at onset of disease and physical activity rate were negatively correlated (r=-0.288, p=0.004). Total weekly leisure activity of the control group was higher (46.9 vs. 38.4 hours, respectively), while daily screen time was similar (3.2 vs. 2.9 hours, respectively). CONCLUSIONS: Physical activity, obesity rates and screen time hours were similar between JIA patients and controls. This lack of difference could be attributed to clinical remission following early, aggressive, treat-to-target therapy.