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.

Chronic Nonbacterial Osteomyelitis in Children: Exploring the Interplay of Sleep, Pain, Quality of Life, and Disease Activity.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that most commonly affects children and adolescents.1 Pain is a common problem in pediatric rheumatic diseases, with adolescents reporting reduced physical functioning, school absenteeism, anxiety, and depression.2.

Atypical Presentations of Pediatric-Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) in children is a rare, severe thrombotic microangiopathy. This condition is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia due to reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. METHODS: A retrospective case series evaluating data collected from the medical files of 4 children diagnosed with iTTP. RESULTS: The presented case series depicts a variety of iTTP presentations: 1 case of primary iTTP, 1 case induced by Shiga toxin, 1 associated with RAS-associated autoimmune leukoproliferative disease (RALD), and 1 initial manifestation of systemic lupus erythematosus (SLE). Notably, 2 patients recovered without undergoing plasma exchange. CONCLUSION: Early ADAMTS13 testing in children with unexplained hemolysis or thrombocytopenia is crucial. The diverse underlying causes, including infections and autoimmune disorders, underscore the complexity of iTTP in the pediatric population. These cases highlight the necessity for personalized treatment approaches that consider each patient's unique clinical situation and potential alternatives or modifications to conventional therapeutic regimens.

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine among adolescents with juvenile-onset inflammatory rheumatic diseases.

OBJECTIVES: The effectiveness of the BNT162b2 mRNA COVID-19 vaccine for adolescents with juvenile-onset inflammatory or immune rheumatic diseases (IRDs) is unknown. Several studies have suggested attenuated immunogenicity in patients with IRD. This study evaluated the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing COVID-19 infection in adolescents with juvenile-onset IRD compared with controls without immune rheumatic disease. METHODS: We used data from Clalit Health Services, the largest health-care organization in Israel, to conduct an observational cohort study from February to December 2021, involving 12-18 year-old adolescents diagnosed with IRD. Study outcomes included documented COVID-19 infection in relation to vaccination status and immunomodulatory therapy. We estimated vaccine effectiveness as one minus the risk ratio. Adolescents aged 12-18 years without immune rheumatic disease served as controls. RESULTS: A total of 1639 adolescents with IRD (juvenile idiopathic arthritis, SLE, or familial Mediterranean fever) were included and compared with 524 471 adolescents in the same age range without IRD. There was no difference in COVID-19 infection rates after the second dose of vaccine between those with IRD and controls (2.1% vs 2.1% respectively, P = 0.99). The estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose. CONCLUSION: We found that the BNT162b2 mRNA vaccine was similarly effective against COVID-19 infection in adolescents with and without IRD. Immunomodulatory therapy did not affect its effectiveness. These results can encourage adolescents with IRD to get vaccinated against COVID-19.

Measuring the knowledge of juvenile idiopathic arthritis among Israeli paediatricians and paediatric orthopaedic surgeons: what needs to be improved?

OBJECTIVES: Approximately 1 child in 1,000 is affected by juvenile idiopathic arthritis (JIA). Persistent, undiagnosed JIA with high disease activity interferes with daily life and carries a risk of irreversible physical and psychosocial damage. Due to its relative rarity, primary care physicians often do not recognise it. Consequently, diagnosis and referral to paediatric rheumatologists are delayed. We aimed to evaluate the knowledge of Israeli paediatricians and paediatric orthopaedic surgeons regarding the epidemiology, clinical manifestations, laboratory parameters and treatment of JIA. METHODS: An 11-item, online questionnaire regarding JIA was sent to Israeli paediatricians and paediatric orthopaedic surgeons. The questionnaire was completed by 318 paediatricians and 30 paediatric orthopaedic surgeons (total response rate 22.5%). RESULTS: The average score was 67/100 points and the pass rate was 70.1% (set at 60 points). Several factors were associated with better overall scores: paediatric residents compared to senior physicians, exposure to rheumatology during residency, and seeing more patients with JIA in the past 5 years. No significant difference was found between paediatricians and paediatric orthopaedic surgeons. The true incidence of JIA was underestimated by 40% of participants, 30-45% were not familiar with its clinical presentation (age of onset, pain characteristics, chronic uveitis symptoms), and 60% were not familiar with up-to-date treatments. CONCLUSIONS: Paediatricians and paediatric orthopaedic surgeons in Israel have gaps in knowledge regarding JIA. This could result in delayed referral and treatment, which might affect outcomes. The results of this study highlight the need for better education and exposure to a rheumatologist, to improve knowledge and recognition of JIA.

[A REPORT ON THE PRACTICALITIES OF THE JOINT FELLOWSHIP IN PEDIATRIC RHEUMATOLOGY IN ISRAEL].

BACKGROUND: The field of pediatric rheumatology was only recently recognized in Israel as a sub-specialty. To enable a fellowship program in this field comprising mainly uncommon diseases, the Meir and Shaare Zedek medical centers were authorized to implement a joint fellowship program, in which the trainees split their time between the two medical centers. OBJECTIVES: This article presents the unique experience as a trainee in the joint fellowship program in pediatric rheumatology, while relating to the different characteristics of these centers, patient populations and variable disease exposure. METHODS: Assessment of the extent of clinical and procedural exposure was achieved by comparing the exposure data of the fellow during the first two years of the joint fellowship to the published data derived from questionnaires answered by 44 fellows in the United States. RESULTS: All requirements for successfully completing the Israeli fellowship program were fulfilled, but also those of the North American and European programs. We have shown that the extent of both clinical and procedural exposure is high in the joint fellowship program. We also show the differences in the variety of diseases seen in both centers. DISCUSSION: Possible explanations for these observations are provided in this article. The experience of this joint fellowship can set an example for other fellowship programs in medical areas dealing with uncommon diseases.

Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency.

The E3 subunit of the pyruvate dehydrogenase complex (dihydrolipoamide dehydrogenase/dihydrolipoyl dehydrogenase/DLD/lipoamide dehydrogenase/LAD), is a mitochondrial matrix enzyme and also a part of the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. DLD deficiency (MIM #246900), is relatively frequent in the Ashkenazi Jewish population but occurs in other populations as well. Early diagnosis is important to prevent episodes of metabolic decompensation, liver failure, and encephalopathy. The clinical presentations are varied and may include Reye-like syndrome, hepatic failure, myopathy, and myoglobinuria. Laboratory markers, such as elevated urinary alpha-ketoglutarate, blood pyruvate, lactate, and ammonia, are mostly nonspecific and not always present, making the diagnosis difficult. Since we observed elevated plasma citrulline levels in a number of confirmed cases, we retrospectively examined the value of citrulline as a biochemical marker for DLD deficiency. Data was gathered from the files of 17 pediatric patients with DLD deficiency, confirmed by enzymatic and genetic analysis. The control group included 19 patients in whom urea cycle defects were ruled out but DLD deficiency was suspected. Seven of the DLD-deficient patients presented with elevated plasma citrulline levels (median value 205 µM, range 59-282 µM) (normal range 1-45 µM) while none in the control patient group. In five patients, elevated citrulline was associated with elevated plasma glutamine and metabolic acidosis. Interestingly, elevated plasma citrulline was associated with the common G229C mutation. In conclusion, we suggest that elevated plasma citrulline in the absence of urea cycle defects warrants an investigation for DLD deficiency.

Obstacles in Early Diagnosis of Children With Juvenile Idiopathic Arthritis: A Nationwide Israeli Retrospective Study.

OBJECTIVE: Characterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel. METHODS: This is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts. RESULTS: Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis (P < 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P < 0.05). CONCLUSION: This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment.

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.

Juvenile polymyositis associated with ureteral necrosis: a diagnostic and therapeutic dilemma-case report and review of the literature.

We describe an 11-year-old girl, diagnosed with juvenile polymyositis (JPM), who developed right ureteral obstruction secondary to necrosis. We emphasize the dilemmas regarding optimal timing for surgical intervention and medical treatment. Vascular involvement, which could be a part of juvenile dermatomyositis, may also be a feature of JPM. We discuss the association between vasculopathy and ureteral necrosis and review the literature regarding similar conditions. Whether the ureteral necrosis is a specific feature of vasculopathy, or a result of visceral calcinosis, needs to be further explored.

Canakinumab investigated for treating familial Mediterranean fever.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. The treatment of choice is colchicine. However, ~40% of patients are only partial responders and 5-10% are non-responders. Advances in the understanding of the role of pyrin in the regulation of interleukin (IL)-1ß activation has led to use of anti-IL-1 agents for colchicine-resistant FMF. AREAS COVERED: The authors performed a literature search of anti-IL-1 treatment for FMF, particularly canakinumab, a humanized IL-1ß antibody, by searching PubMed/Medline/Scopus since 2001 and proceedings of major rheumatologic conferences since 2011 for unpublished studies. EXPERT OPINION: Many reports of successful treatments with anti-IL-1 agents were published since 2007. In 2011, the first case reports of successful treatment with canakinumab were reported. Successful phase II trials reported in 2014 and 2015 led to a double-blind, randomized, placebo-controlled phase III trial in patients with colchicine-resistant FMF. Significantly more canakinumab treated patients attained the very stringent primary outcome measure and secondary outcomes vs. those treated with placebo. The safety profile was similar to canakinumab trials for other indications. Canakinumab appears to be an excellent alternative for the vast majority of patients with colchicine-resistant FMF, with an adequate safety profile.

Cutaneous polyarteritis nodosa successfully treated with topical diflucortolone valerate: a case report & review of the literature.

Cutaneous Polyarteritis Nodosa (cPAN) was first described in 1931. cPAN is considered a rare disease, its true incidence is unknown. The age of onset is diverse. Most studies have shown no significant gender predominance. cPAN presents with distinct skin findings, such as a maculopapular rash, subcutaneous nodules, livedoid vasculitis, panniculitis, ischemic finger lesions, or erythematous patchy rash. Etiology is unclear. It is still believed to be an immune complex-mediated disease, although a possible mechanism recently proposed relates a familial form of the disease to impaired activity of Adenosine Deaminase 2. cPAN may reflect an underlying disease, infection or medical treatment. There is no consensus as to initial treatment, dosage and length of treatment. Patients with constitutional symptoms, visceral involvement, a more severe course of the disease, or high acute phase reactants, were treated mainly with systemic corticosteroids and/or cytotoxic agents for varying durations. However, persistence of cutaneous lesions has been documented. We describe a 14 year old male suffering from persistent cPAN, with no constitutional symptoms or involvement of internal organs. The patient was treated with a local corticosteroid-based ointment during exacerbations, until complete remission. Although reported in only one study, treatment with topical corticosteroid compound may result in significant improvement or complete regression of skin lesions in cPAN patients.