Elisabetta Cortis

Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central-nervous-system involvement, and arthropathy. In the present study, we report, in seven unrelated patients with CINCA syndrome, distinct missense mutations within the nucleotide-binding site of CIAS1, a gene encoding cryopyrin and previously shown to cause Muckle-Wells syndrome and familial cold urticaria. Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes. These findings demonstrate that CIAS1 missense mutations can result in distinct phenotypes with only a few overlapping symptoms and suggest that this gene may function as a potential inducer of apoptosis.

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series

OBJECTIVE To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

Long-term outcome and prognostic factors of juvenile dermatomyositis: A multinational, multicenter study of 490 patients

To investigate the long‐term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study.

Differentiating PFAPA syndrome from monogenic periodic fevers

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

Abatacept improves health‐related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis

To assess health‐related quality of life (HRQOL) in abatacept‐treated children/adolescents with juvenile idiopathic arthritis (JIA).

Macrophage activation syndrome in juvenile idiopathic arthritis.

UNLABELLED Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept. CONCLUSION Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A.

Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age

Objective. To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age. Methods. Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18–48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement. Results. Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported. Conclusion. In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

Infliximab therapy in pediatric Takayasu’s arteritis: report of two cases

Takayasu arteritis (TA) is a chronic vasculitis of unknown etiology. Experience with anti-tumor necrosis factor alpha (anti-TNF) agents in difficult-to-treat patients with TA is limited and refers to adult patients. Here, we present two cases of pediatric TA treated with infliximab, in which clinical remission was observed. Anti-TNF treatment represents a useful therapy in pediatric Takayasu arteritis too, especially to avoid the risk of long-term corticosteroids toxicity.

Validation of the Childhood Health Assessment Questionnaire in active juvenile systemic lupus erythematosus.

OBJECTIVE To validate the Childhood Health Assessment Questionnaire (C-HAQ) as a measure of disability in patients with active juvenile systemic lupus erythematosus (SLE). METHODS Of 557 patients with juvenile SLE included in the Paediatric Rheumatology International Trials Organisation (PRINTO) database, 504 (90.5%) were included in the present study and underwent C-HAQ assessment at the time of a major therapeutic intervention and then after 6 months. Validation procedures, according to the Outcome Measures in Rheumatology Clinical Trials filter for outcome measures in rheumatology, included assessment of responsiveness, feasibility, internal consistency, construct validity, collinearity, and discriminative ability. Response to therapy was evaluated with the PRINTO/American College of Rheumatology (ACR) juvenile SLE definition of improvement. RESULTS At baseline, patients showed a high level of disease activity (mean physician global 5.8) and moderate disability (mean C-HAQ 0.83); both disease activity and disability improved after 6 months of treatment. The change in C-HAQ score correlated moderately with the Systemic Lupus Activity Measure (r(s) = 0.42), parents global assessment of pain and well-being (r(s) = 0.55 and 0.53, respectively), and the physical summary score of the Child Health Questionnaire (r(s) = -0.61), and poorly with other clinical and laboratory parameters. The absolute change in C-HAQ demonstrated a significant ability to discriminate between patients who improved and those who did not improve based on the PRINTO/ACR definition of improvement. Responsiveness of the C-HAQ was moderate (standardized response mean 0.74). Internal consistency was excellent (Cronbachs alpha = 0.96). CONCLUSION The C-HAQ showed moderate responsiveness to clinical change, construct validity, good feasibility, internal consistency, and discriminative ability. These findings demonstrate that the C-HAQ represents a good measure to capture disability in patients with active juvenile SLE.

Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study

OBJECTIVES The aim of the study is to assess the rate of atypical manifestations at onset in pediatric systemic lupus erythematosus (SLE) and to evaluate their effect on disease outcome. STUDY DESIGN This is a multicenter retrospective cohort study. A manifestation was considered atypical if it was not included in the American College Rheumatology classification criteria for SLE but was reported in literature as associated with SLE. Unfavorable outcome was considered presence of organ damage in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index at the last available evaluation. RESULTS One hundred patients were enrolled in the study; 24% presented atypical clinical features at onset. Univariate analysis showed a significant association of worse outcome variables with the presence of atypical manifestations at onset (P = .004), as well as renal involvement (P = .027). A multivariate logistic regression analysis showed that atypical manifestations at onset (P = .018), renal involvement at onset or during follow up (P = .024), and central nervous system disease involvement during follow up (P = .021) were independent predictors of poor prognosis. CONCLUSIONS Our data support a relatively high rate of atypical onset in pediatric SLE. Presence of atypical manifestations at presentation and early kidney disease correlate with poor outcome. Similarly, during follow-up, kidney and central nervous system diseases are associated with worse outcome.