Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Complex regional pain syndromes in children and adolescents.

BACKGROUND: The purpose of the present paper was to assess efficiency of treatment and long-term functional outcome of complex regional pain syndromes (CRPS) in children who were treated in the chronic pain clinic at a major tertiary hospital in Israel. METHODS: The files of 14 children with CRPS were analyzed retrospectively. Demographic data, initiating event, referring source, time needed for referral to pain clinic, clinical evaluation, treatment, recurrence and complications were recorded. RESULTS: Fourteen children with CRPS types I and II were included in the study. Girls were affected in 71%. Lower extremities were affected in 57%. The median time from onset of symptoms to seeking medical help was 4.46 weeks (range 2-82 weeks). The median time to referral to pain clinic was 24.51 weeks (range 1.2-94). In 45% the referral source was the pediatrician. A total of 85.8% of patients were referred to various consultations before the pain clinic. Most children had reduced pain and improved function on non-invasive treatment approach. Invasive treatments were used in 28.5%. Full or partial recovery was accomplished in 93%. Recurrence was observed in 29%. CONCLUSIONS: CRPS in children and adolescents is still underdiagnosed, although many of the epidemiologic features of pediatric CRPS are similar in different countries/cultures. Early recognition and management is the major factor in improving outcome and preventing resistant CRPS, but even children with delayed diagnosis still have a good outcome. The management of this disease by an experienced multidisciplinary team is recommended. Because psychosocial factors play an important role, it is recommended to provide psychological evaluation and cognitive behavioral treatment as soon as possible.

Intravitreal injections of triamcinolone acetonide for severe vitritis in patients with incomplete Behcet's disease.

PURPOSE: To report our experience with intravitreal triamcinolone acetonide (IVTA) injections for the treatment of sight-threatening vitritis. DESIGN: Interventional case series. METHODS: Three patients with acute severe exacerbations of noninfectious panuveitis and vitritis were treated with IVTA injections alone or as an adjunct to systemic immunosuppressive agents. RESULTS: Rapid clearance of the vitreous inflammation with improvement in visual acuity was observed 1 to 2 weeks after injection. The effect lasted 2 to 6 months, with the shortest duration in the vitrectomized eye of Patient 1. Repeated injections were required in all patients. CONCLUSION: Intravitreal triamcinolone acetonide may be beneficial in selected cases of vitritis. This treatment modality has a rapid effect and may lower the use of systemic agents.

Peripheral neuropathy in pediatric systemic lupus erythematosus.

Peripheral neuropathy is an uncommon manifestation of systemic lupus erythematosus and has not yet been characterized in pediatric patients. We report the clinical and electrophysiologic features of peripheral neuropathy in one child and three adolescents with lupus erythematosus. There were three females and one male. The peripheral neuropathy followed the onset of lupus erythematosus by a mean of 3 years. The onset of the neuropathy correlated with lupus erythematosus activity and presented with either severe pain or dropfoot. Nerve conduction studies revealed sensory and motor polyneuropathy in all patients and mononeuritis multiplex in two patients. Only one patient had associated central nervous system involvement at that time. All patients were positive for IgM and IgG anticardiolipin antibodies. Patients were treated with steroids, gabapentin, carbamazepine, azathioprine, and cyclophosphamide. Response to treatment was variable: two patients recovered and two had a partial response. Although an unusual manifestation, peripheral neuropathy should be kept in mind as part of the neurologic spectrum in lupus erythematosus. It is not necessarily associated with central nervous system disease. A role for antiphospholipid antibodies in the pathogenesis is suggested.

Presence of D8/17 B-cell marker in patients with poststreptococcal reactive arthritis.

An elevated expression of the alloantigen D8/17 on B lymphocytes has been previously proposed as a susceptibility marker in rheumatic fever. The aim of the study was to investigate the presence of the D8/17 marker on B lymphocytes in poststreptococcal reactive arthritis (PSRA). The study sample included 19 patients (15 boys, 4 girls; mean age 11.7 +/- 5.4 years) who were diagnosed with PSRA (mean age at diagnosis, 9.4 +/- 5.6 years) and 18 healthy controls (10 boys and 8 girls) matched for ethnic background. B-cell D8/17 expression was tested by flow cytometry assay using monoclonal antibodies. Laboratory results showed a higher expression of D8/17 in the patient group (23.1 +/- 10.4%, range 11.6-51.9%) than in the control group (17.1 +/- 8.2%, range 7.1-35.7) in controls; this difference was statistically significant after log transformation of the data (P = 0.035). The high rate of expression of the D8/17 marker in patients with PSRA suggests that RF and PSRA share the same genetic susceptibility.

Localized scleroderma in childhood is not just a skin disease.

OBJECTIVE: Juvenile localized scleroderma is usually considered a disease that is confined to the skin and subcutaneous tissue. We studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma. METHODS: Data from a multinational study on juvenile scleroderma was used for this in-depth study. Clinical features of patients with extracutaneous manifestations were compared with those of patients who had exclusively skin involvement. RESULTS: Seven hundred fifty patients entered the study. One hundred sixty-eight patients (22.4%) presented with a total of 193 extracutaneous manifestations, as follows: articular (47.2%), neurologic (17.1%), vascular (9.3%), ocular (8.3%), gastrointestinal (6.2%), respiratory (2.6%), cardiac (1%), and renal (1%). Other autoimmune conditions were present in 7.3% of patients. Neurologic involvement consisted of epilepsy, central nervous system vasculitis, peripheral neuropathy, vascular malformations, headache, and neuroimaging abnormalities. Ocular manifestations were episcleritis, uveitis, xerophthalmia, glaucoma, and papilledema. In more than one-fourth of these children, articular, neurologic, and ocular involvements were unrelated to the site of skin lesions. Raynaud's phenomenon was reported in 16 patients. Respiratory involvement consisted essentially of restrictive lung disease. Gastrointestinal involvement was reported in 12 patients and consisted exclusively of gastroesophageal reflux. Thirty patients (4%) had multiple extracutaneous features, but systemic sclerosis (SSc) developed in only 1 patient. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 and anticentromere, markers of SSc, were not significantly increased. CONCLUSION: Extracutaneous manifestations of juvenile localized scleroderma developed in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully.

The Pediatric Rheumatology International Trials Organization criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the disease activity core set.

OBJECTIVE: To validate and promulgate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile systemic lupus erythematosus (SLE). METHODS: In 2001, a preliminary consensus-derived core set of measures for evaluating the response to therapy in juvenile SLE was established. In the present study, the core set was validated through an evidence-based, large-scale data collection process that led to the enrollment of 557 patients from 39 different countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, agreement in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response. RESULTS: The following clinical measures were found to be feasible and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physician's global assessment of disease activity, 2) global disease activity measure, 3) 24-hour proteinuria, 4) parent's global assessment of the patient's overall well-being, and 5) health-related quality of life assessment. CONCLUSION: The members of PRINTO propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a patient with juvenile SLE has responded adequately to therapy.