Linda Rossi-Semerano

First Clinical Description of an Infant With Interleukin-36-Receptor Antagonist Deficiency Successfully Treated With Anakinra

YM is the first son of Tunisian consanguineous parents who developed, at 2 weeks of life, an erythematous and scaly eruption, with subsequent rapid evolution toward generalized pustular psoriasis. Afterward, cutaneous flares of diffuse erythematous rash and pustules involving the whole body appeared, with a once weekly periodicity. Intense irritability was present during flares without fever. Moreover, since 1 month of age the infant presented with diarrhea, dysphagia, and reduced feeding rate, with failure to thrive. Laboratory tests during acute flares showed marked leukocytosis, thrombocytosis, and anemia without C-reactive protein elevation. Skin biopsy and clinical presentation were consistent with pustular psoriasis; nevertheless, the patient did not respond to high-potency topical corticosteroids and retinoid acid. As the patient presented with repeated skin flares early after birth, as well as serious constitutional distress with failure to thrive, an autoinflammatory syndrome like interleukine-1-receptor antagonist deficiency or interleukin-36-receptor antagonist deficiency (DITRA) was considered. The hypothesis was reinforced by parental consanguinity, and absence of skin lesion improvement under standard topical treatment. Genetic analyses showed a homozygous mutation in the IL36RN gene (L27P), which represents the same mutation recently described in DITRA patients. At age 6 months we started treatment with the recombinant interleukin-1 receptor antagonist anakinra with efficacy both on constitutional symptoms and skin involvement. DITRA is a recently described autoinflammatory disease characterized by repeated flares of generalized pustular psoriasis, high fever, asthenia, and systemic inflammation. We report herein the first exhaustive clinical description of an infant with DITRA who was successfully treated with anakinra.

Tolerance and efficacy of off-label anti-interleukin-1 treatments in France: a nationwide survey

BackgroundDespite their limited licensed indications, anti–interleukin-1 (anti–IL-1) agents are often used in clinical practice for an increasing number of auto-inflammatory diseases. We conducted a national cross-sectional observational study from January 2011 to January 2013 to record the off-label use of such agents in France. We aimed to estimate the off-label use of anti–IL-1 treatments in France, assess their efficacy in rare diseases, and increase the reporting of their possible side effects.MethodsPhysicians answered a questionnaire that covered patient and disease data, anti–IL-1 agent use, efficacy and adverse events. The study involved adult or paediatric patient who had received an anti–IL-1 agent after January 2005 in France.ResultsIn total, 189 patients from 38 centres were included. The main diseases were adult-onset Still’s disease (AOSD) (35), gout (28), systemic juvenile idiopathic arthritis (27), cryopyrin-associated periodic syndrome (CAPS) (21), familial Mediterranean fever (14) and mevalonate kinase deficiency (12). The main off-label used agent was anakinra, used at least once for 185 patients, with canakinumab used for 25. Anakinra was effective in most patients (90%), with higher complete clinical response rates for Schnitzler’s syndrome, gout, CAPS and AOSD. Overall, 58% of patients showed at least one adverse event, mainly minor injection-site reactions. The main reported serious adverse event was severe infection. Injection-site reactions and liver toxicity were significantly more frequent in children than adults. The main non-cutaneous adverse event was liver toxicity, significantly associated with treatment duration. Weight gain was reported in about 10% of patients and was associated with treatment duration and CAPS. Canakinumab was rarely used and showed better cutaneous tolerance than anakinra but similar rates of non-cutaneous and severe adverse events.ConclusionsAnakinra was well tolerated and effective in most patients with various inflammatory diseases. The main adverse events were mild injection-site reactions, especially in children. The survey allowed for collecting limited information on the off-label use of canakinumab.

The French Gaucher’s disease registry: clinical characteristics, complications and treatment of 562 patients

BackgroundClinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described.MethodsAll patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables.ResultsAmong the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%).ConclusionThis registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.

Is Still's Disease an Autoinflammatory Syndrome?

Systemic juvenile idiopathic arthritis (sJIA), formerly called Stills disease, is officially classified as a subset of juvenile idiopathic arthritis (JIA). Beside arthritis, it is characterized by prominent systemic features and a marked inflammatory response. Even if it is still included in the group of juvenile arthritides, sJIA is set apart from all the other forms of JIA. This disorder has markedly distinct clinical and laboratory features suggesting a different pathogenesis. sJIA does not show any association with HLA genes or with autoantibodies and is characterised by an uncontrolled activation of phagocytes with hypersecretion of IL-1 and IL-6. Based on clinical and laboratory features, as well as on new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The new insights on the pathogenesis of sJIA have therefore dramatically changed the approach to treatment, with the development of targeted treatments (anti-IL-1 and anti-IL-6 agents) more effective and safer than earlier medications.

Boundaries between familial Mediterranean fever and juvenile spondyloarthritis: Analysis of three French retrospective cohorts

OBJECTIVES Children with Familial Mediterranean fever may suffer from musculoskeletal involvement, somewhat difficult to distinguish from juvenile spondyloarthritis. The association of these two diseases has been scarcely reported in children. Objective of this work was to define the association of familial Mediterranean fever and juvenile spondyloarthritis in France. METHODS Three cohorts of children with familial Mediterranean fever, juvenile spondyloarthritis, familial Mediterranean fever related juvenile spondyloarthritis, were retrospectively identified in the French reference center of auto-inflammatory diseases. Familial Mediterranean fever was defined according to Tel-Hashomer or Turkish pediatric criteria with at least one exon-10 MEFV-gene mutation. Juvenile spondyloarthritis was defined according to ILAR criteria. Patients with familial Mediterranean fever or juvenile spondyloarthritis were respectively compared to familial Mediterranean fever related juvenile spondyloarthritis patients. RESULTS Sixteen children were identified as having familial Mediterranean fever related juvenile spondyloarthritis. The male/female-ratio was 0.6, with median age at spondyloarthritis onset of 7.5years (3-16years). All carried at least one M694V variant in MEFV gene; 16.7% were HLA-B27-carriers. Compared to 83 familial Mediterranean fever patients, familial Mediterranean fever related juvenile spondyloarthritis patients had less frequently fever (P<0.01) and more frequently arthritis (P<0.05), enthesitis (P<0.001), inflammatory back pain (P<0.001), inadequate response to colchicine (P<0.05). Compared to 20 juvenile spondyloarthritis patients, familial Mediterranean fever related juvenile spondyloarthritis patients less often received non-steroidal anti-inflammatory drugs (P<0.01) and anti-tumor necrosis factor drugs (P<0.001). CONCLUSIONS Familial Mediterranean fever may be associated with typical pattern of juvenile spondyloarthritis. These patients, with less response to colchicine, should be diagnosed earlier and treated as for jSpA.

Conventional radiography in juvenile idiopathic arthritis: Joint recommendations from the French societies for rheumatology, radiology and paediatric rheumatology

BackgroundJuvenile idiopathic arthritis (JIA) can cause structural damage. However, data on conventional radiography (CR) in JIA are scant.ObjectiveTo provide pragmatic guidelines on CR in each non-systemic JIA subtype.MethodsA multidisciplinary task force of 16 French experts (rheumatologists, paediatricians, radiologists and one patient representative) formulated research questions on CR assessments in each non-systemic JIA subtype. A systematic literature review was conducted to identify studies providing detailed information on structural joint damage. Recommendations, based on the evidence found, were evaluated using two Delphi rounds and a review by an independent committee.Results74 original articles were included. The task force developed four principles and 31 recommendations with grades ranging from B to D. The experts felt strongly that patients should be selected for CR based on the risk of structural damage, with routine CR of the hands and feet in rheumatoid factor-positive polyarticular JIA but not in oligoarticular non-extensive JIA.ConclusionThese first pragmatic recommendations on CR in JIA rely chiefly on expert opinion, given the dearth of scientific evidence. CR deserves to be viewed as a valuable tool in many situations in patients with JIA.Key Points• CR is a valuable imaging technique in selected indications.• CR is routinely recommended for peripheral joints, when damage risk is high.• CR is recommended according to the damage risk, depending on JIA subtype.• CR is not the first-line technique for imaging of the axial skeleton.

Clinical predictors of magnetic resonance imaging-detected sacroiliitis in children with enthesitis related arthritis

OBJECTIVES To determine the predictors of sacroiliitis detected by magnetic resonance imaging (MRI) in children with enthesitis-related arthritis. METHODS In this retrospective, longitudinal study, we retrieved clinical and laboratory data from the charts of patients with confirmed enthesitis related arthritis and evaluated their association with magnetic sacroiliitis detected at first MRI after disease onset. The MRI images of sacroiliac joints were read by 2 independent radiologists and validated against those from 25 age- and sex-matched subjects with known non-rheumatologic conditions. RESULTS We reviewed the clinical records of 20 patients with enthesitis-related arthritis for whom MRI images of sacroiliac joints were available. Five had bilateral MRI sacroiliitis, 3 unilateral sacroiliitis while 12 had no sacroiliitis. All MRI images of sacroiliiitis showed bone-marrow oedema but no erosions, sclerosis or sacroiliac enthesitis. Personal history of buttock pain or abnormal physical examination of sacroiliac joints predicted MRI sacroiliitis with a positive predictive value of 0.75 (95% confidence interval 0.35-0.95). In the absence of these clinical elements, MRI sacroiliitis was unlikely to be found (negative predictive value 0.83; 95% confidence interval 0.50-0.97). CONCLUSION In children with enthesitis-related arthritis the presence of buttock pain or of abnormal sacroiliac joint examination is a strong predictor of magnetic sacroiliitis.

Resrip: a network dedicated to children and adolescents suffering from chronic rheumatic diseases in the Ile-de-France region

Introduction: chronic rheumatic diseases affect around 2000 children in the Ile-de-France region. Most patients suffer from juvenile idiopathic arthritis (JIA) that leads to chronic pain, fatigue and structural damage responsible for short- and long-term disability. Several physicians and health professionals may be involved in the treatment and care of these patients. This multidisciplinary approach is particularly important in managing paediatric rheumatic diseases, since many symptoms are chronic and change in severity over time. The RESRIP (Reseau pour les Rhumatismes Inflammatoires Pediatriques) network has been created to improve and personalize patient care coordination.

PW02-012 - First clinical description of an infant with DITRA

Interleukin-36-receptor antagonist deficiency (DITRA) is a recently described auto-inflammatory disease1, characterized by repeated flares of generalized pustular psoriasis, high fever, asthenia and systemic inflammation. This condition is caused by homozygous missense mutation in the IL36RN gene, encoding the interleukin-36-receptor antagonist (IL-36Ra), an anti-inflammatory cytokine. We report herein the first exhaustive clinical description of an infant with DITRA, who was successfully treated with anakinra.

PW03-019 – Survey of off-label ANTI-IL1 treatments in France.

Despite their limited licensed indications, anti-IL1 agents are often used in real-life practice for an increasing number of diseases. A national survey to record their off-label use in France was started in January 2011. The survey is coordinated by the French National Reference Centre for Auto-inflammatory Diseases, under the aegis of the “Club Rhumatisme et Inflammation” (CRI).