Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials.

OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: Patients (2-19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population. RESULTS: 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed. CONCLUSION: Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab. TRIAL REGISTRATION NUMBERS: NCT00886769, NCT00889863, NCT00426218 and NCT00891046.

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.).

Late cardiac assessment in children diagnosed with post-streptococcal reactive arthritis: a long term study.

OBJECTIVES: Unlike rheumatic fever (RF), the association of post-streptococcal reactive arthritis (PSRA) and carditis is controversial. The American Heart Association recommends anti-streptococcal prophylaxis for PSRA for one year, repeating echocardiogram and discontinuation of prophylaxis if normal. In this study the possibility of late cardiac involvement was investigated in a cohort of children with PSRA. METHODS: Children diagnosed with PSRA and followed at the Paediatric Rheumatology Units at two medical centres in Israel had echocardiography carried out by a paediatric cardiologist, at least 1 year following diagnosis. RESULTS: 146 patients with PSRA met the study criteria. Of these, 69 had undergone echocardiography 1-6.9 years (mean 3.6 years ± 1.5 years) after diagnosis. All had normal major parameters. Twenty (29.0%) patients had minimal cardiac findings, including 5 (7.2%) mild mitral insufficiency, 12 (17.4%) minimal mitral insufficiency, 2 (2.9%) mild tricuspid insufficiency and one patient (1.4%) had very mild, aortic insufficiency. Of the 77 patients who did not have echocardiography, 31 were randomly excluded from the initial study list, 26 refused to undergo echocardiography, and 20 were lost to follow-up. All were asymptomatic according to their medical record or telephone questionnaire. There were no significant differences in clinical or demographic data between those with or without echocardiography. CONCLUSIONS: No late cardiac involvement was found in our paediatric PSRA patients. Therefore, different approaches to antibiotic prophylaxis for PSRA and ARF are probably suggested. A prospective, controlled study is needed to definitively assess the necessity of prophylaxis in PSRA.

A longitudinal PRINTO study on growth and puberty in juvenile systemic lupus erythematosus.

OBJECTIVE: To obtain longitudinal data on growth/puberty in a large-scale, multi-national prospective cohort of juvenile systemic lupus erythematosus (SLE). METHODS: Data from 331/557 (59.4%) patients ≤18 years old with juvenile SLE in active phase, with anthropometric data available at four follow-up visits, were studied. RESULTS: There was a significant reduction in parent-adjusted height z score with time in females and males (p<0.0001), with a significant gender difference (p<0.0001) and with male height being most affected. Median body mass index z score peaked at 6 months and was still significantly above baseline after 26 months (p<0.01), with no gender difference. Standardised height reduction was inversely related to age at onset. Females with onset age <12 years had a median parent-adjusted height z score of -0.87 with no catch-up growth. At the end of the study, growth failure was seen in 14.7% of the females and 24.5% of the males. Height deflection (less than -0.25/year) was found in 20.7% of the females and 45.5% of the males. Delayed pubertal onset was seen in 15.3% and 24% of the females and males, respectively, and delayed/absent menarche was seen in 21.9%, while 36.1% of the females and 44% of the males had some degree of delayed pubertal development. Growth failure baseline determinants were previous growth failure (OR: 56.6), age at first visit ≤13.4 years (OR: 4.2) and cumulative steroid dose >426 mg/kg (OR: 3.6). CONCLUSIONS: The children at risk of having a negative effect on height and pubertal development are prepubertal and peripubertal children treated with >400 mg/kg cumulative dose of corticosteroids.

Performance of Birmingham Vasculitis Activity Score and disease extent index in childhood vasculitides.

OBJECTIVES: To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) v3 and the Disease Extent Index (DEI) for the assessment of disease activity in 4 primary childhood (c-) systemic vasculitides. METHODS: Patients fulfilling the EULAR/PRINTO/PRES (Ankara) c-vasculitis classification criteria for Henoch-Schönlein purpura (HSP), childhood (c) polyarteritis nodosa (c-PAN), c-Wegener's granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) with disease duration at the time of diagnosis ≤3 months were extracted from the PRINTO database. The performance of the BVAS and DEI were examined by assessing convergent validity, the pattern of disease involvement, and responsiveness. We also evaluated alternative unweighted scoring methods for both tools. RESULTS: The analysis set included 796 patients with 669 HSP, 80 c-PAN, 25 c-WG and 22 c-TA. The median age at diagnosis was 6.9 years (6.6-12) and median delay in making the diagnosis from the onset of signs/symptoms was 0.01 (0.003-0.027) years. A strong correlation was found between the BVAS and DEI (rs=0.78) while correlation with the physician global assessment was moderate (rs=0.48) with BVAS and poor with DEI (rs=0.25). Both the BVAS and DEI sub-scores and total scores were able to descrive the disease involvement in the 4 childhood vasculitides. Responsiveness was large (>1.5) for both tools. The performance characteristics of the BVAS and DEI with the unweighted methods were comparable. CONCLUSIONS: This study demonstrates that both the BVAS and DEI are valid tools for the assessment of the level of disease activity in a large cohort of childhood acute and chronic vasculitides.

Differentiation of post-streptococcal reactive arthritis from acute rheumatic fever.

OBJECTIVE: To perform a retrospective study comparing clinical and laboratory aspects of patients with acute rheumatic fever (ARF) and patients with post-streptococcal reactive arthritis (PSRA), to discern whether these are 2 separate entities or varying clinical manifestations of the same disease. STUDY DESIGN: We located the records of 68 patients with ARF and 159 patients with PSRA, whose diseases were diagnosed with standardized criteria and treated by 8 pediatric rheumatologists in 7 medical centers, using the Israeli internet-based pediatric rheumatology registry. The medical records of these patients were reviewed for demographic, clinical, and laboratory variables, and the data were compared and analyzed with univariate, multivariate, and discriminatory analysis. RESULTS: Four variables were found to differ significantly between ARF and PSRA and serve also as predictors: sedimentation rate, C-reactive protein, duration of joint symptoms after starting anti-inflammatory treatment, and relapse of joint symptoms after cessation of treatment. A discriminative equation was derived that enabled us to correctly classify >80% of the patients. CONCLUSION: On the basis of simple clinical and laboratory variables, we were able to differentiate ARF from PSRA and correctly classify >80% of the patients. It appears that ARF and PSRA are distinct entities.

Familial Mediterranean fever and growth: effect of disease severity and colchicine treatment.

OBJECTIVE: To evaluate the effect of disease severity and colchicine treatment on height and weight parameters in children with familial Mediterranean fever (FMF). METHODS: Thirty prepubertal children (19 M, 11 F) were studied retrospectively. Z-score values of height, growth velocity, weight and body mass index were obtained over 1.84 +/- 1.14 years before and 2.58 +/- 1.55 years during colchicine therapy. Disease severity was evaluated by a specific score for FMF. RESULTS: By comparison to growth before treatment, during colchicine therapy height SDS increased from -1.00 +/- 1.17 to -0.54 +/- 0.96 (p < 0.001) and weight SDS increased from -0.74 +/- 1.09 to -0.47 +/- 1.06 (p = 0.008). An effect of disease severity on growth pattern could not be detected. Height SDS during therapy was negatively correlated with age at colchicine initiation. CONCLUSIONS: Colchicine therapy has a positive effect on both height and weight parameters in children with FMF. Early initiation of treatment is beneficial for height gain.

Optic neuritis associated with etanercept therapy for juvenile arthritis.

PURPOSE: We sought to describe cases of optic neuritis associated with etanercept therapy. METHODS: A retrospective chart review was undertaken on all patients that developed uveitis or optic neuritis associated with etanercept therapy between January 2003 and January 2005 in 2 medical centers: Assaf Harofeh Medical Center, and Kaplan Medical Center, Israel. RESULTS: Four patients (3 girls, 1 boy) treated with etanercept for juvenile idiopathic arthritis (JIA) are presented. The 3 girls had oligoarticular-onset JRA. The boy had HLA-B27-positive juvenile spondyloarthropathy and bilateral uveitis. After a mean follow-up of 10 months (range, 2.5-18 months) all 4 patients had reduced visual acuity due to optic neuritis, which was accompanied by vitreitis in 2 eyes. In 3 patients, the discontinuation of etanercept, together with steroid treatment, resulted in resolution of the inflammation. The fourth patient elected to continue etanercept treatment and experienced no further deterioration in visual acuity. CONCLUSION: Optic neuritis is a potentially sight-threatening complication of etanercept therapy. Patients with JRA who are candidates for therapy should be examined by an ophthalmologist before starting treatment and then regularly thereafter. Ophthalmologists and rheumatologists should be aware of this hazard and be cautious when using etanercept in this patient population.

Corticosteroid treatment in patients with Sydenham's chorea.

Sydenham's chorea occurs in approximately 10% of acute rheumatic fever and is one of its major manifestations. The disease may last for weeks or months, with a high risk of recurrence; usually only supportive treatment is recommended. This report describes five children diagnosed with Sydenham's chorea and treated with a short course of corticosteroids. Marked improvement of the involuntary movements was observed within 24-48 hours, with complete resolution within 7-12 days after commencement of treatment; there were no relapses. Larger, possibly comparative studies are necessary, but in the meantime treatment with corticosteroids in patients with Sydenham's chorea should be considered.

Tumor necrosis factor (TNF)alpha and its soluble receptor (sTNFR) p75 during acute human parvovirus B19 infection in children.

Human parvovirus B19 (HPV) has been shown to be involved in the pathogenesis of various connective tissue and autoimmune diseases. In order to gain more information on HPV possible role in these diseases, we have investigated some immune responses in patients with acute HPV infection, mainly the secretion of the proinflammatory cytokine tumor necrosis factor (TNF)alpha and it's antagonist--the soluble TNF receptor (sTNFR) p75. Thirteen children with acute HPV infection and 13 healthy volunteers were investigated for the presence of autoantibodies, lymphocyte subpopulation counts, levels of total immunoglobulins, IgG subclasses and complement. The levels of TNFalpha and sTNFR p75 were determined in serum and conditioned medium (CM) from unstimulated and LPS stimulated peripheral blood mononuclear cell (PBMC) cultures. There was no difference between patients and controls regarding autoantibodies, lymphocytes, immunoglobulins, IgG subclasses and complement. A significant imbalance between TNFalpha and sTNFR p75 was found in the patients group. TNFalpha concentrations were significantly higher both in sera and in CM from the patients as compared with the controls. The levels of sTNFR concentrations were either similar (in sera) or significantly lower (in CM) in the patients compared with the controls. The TNF index, representing the biologically available TNFalpha, was significantly higher in patient's sera and CMs. In view of these results, it is conceivable that infection with human HPV in otherwise healthy children may lead to a proinflammatory state. The presence of high levels of biologically available TNFalpha, in susceptible individuals, may in turn play a role in the pathogenesis of systemic autoimmune diseases in HPV infected individuals.

Human parvovirus B19 infection in children: uncommon clinical presentations.

BACKGROUND: Human parvovirus B19 is responsible for a variety of clinical syndromes, such as erythema infectiosum, non-immune hydrops fetalis, transient aplastic anemia, and arthropathies. HPV is also suspected of playing a role in the pathogenesis of various chronic inflammatory and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Kawasaki disease and multiple sclerosis. OBJECTIVES: To study the age distribution and clinical presentation of patients hospitalized for human parvovirus B19 infection. METHOD: We reviewed the case records of all pediatric patients with serologic evidence of HPV infection who were admitted during a 20 month period to a major community hospital. RESULTS: Of 128 children tested for HPV, 48 had evidence of acute infection based on the presence of immunoglobulin M antibodies; 8 patients who also had positive IgM for other viruses were excluded, thus 40 case records were studied. The mean age of the patients was 5.21 years, but 22 patients were under 4. The clinical presentations included 25 patients with fever, either recurrent or prolonged, accompanied in some by enlarged spleen, liver and lymph nodes, skin rash and arthropathy; the remaining patients were investigated for anemia, skin rash, joint complaints and hepatitis. In addition, HPV infection was documented in several well-defined clinical conditions, such as SLE, vasculitic skin lesions, acute lymphoblastic leukemia, pure red cell aplasia, and optic neuritis. CONCLUSIONS: In a group of 40 pediatric patients exhibiting anti-HPV IgM antibodies, a younger age and less common clinical presentations were observed, furthermore 5 patients had clinical syndromes in which the causative role of HPV infection was not clear.

Rheumatic Fever and post-group a streptococcal arthritis in children.

There are several diseases associated with group A beta hemolytic streptococcal infection; the two most common are acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PsRA). Epidemiological and clinical data for both diseases are described, as well as current recommendations for treatment and prevention. There is an ongoing debate as to whether these two are different diseases or are parts of the spectrum of the same disease. There are some reports of carditis developing after PsRA, suggesting that PsRA may be part of the spectrum of ARF. However, since there are substantial clinical, immunological, and genetic differences between PsRA and ARF, we believe PsRA to be a distinct entity.

Post-streptococcal reactive arthritis in children: a distinct entity from acute rheumatic fever.

There is a debate whether post-streptococcal reactive arthritis (PSRA) is a separate entity or a condition on the spectrum of acute rheumatic fever (ARF). We believe that PSRA is a distinct entity and in this paper we review the substantial differences between PSRA and ARF. We show how the demographic, clinical, genetic and treatment characteristics of PSRA differ from ARF. We review diagnostic criteria and regression formulas that attempt to classify patients with PSRA as opposed to ARF. The important implication of these findings may relate to the issue of prophylactic antibiotics after PSRA. However, future trials will be necessary to conclusively answer that question.

Recurrent transient synovitis of the hip in childhood. Longterm outcome among 39 patients.

OBJECTIVE: To describe the outcome of children with recurrent transient synovitis (TS) of the hip. METHODS: A retrospective chart review of children with at least 2 separate episodes of TS between 1986 and 2003. We described the diagnostic investigations and outcome of these patients. A followup telephone survey for disability and pain scores was performed in 2004. RESULTS: We studied 39 children, 26 boys and 13 girls, from 6 pediatric rheumatology centers. The mean age at initial episode was 6 +/- 2.6 years. There were a total of 102 episodes (mean 2.9 +/- 1.6, median 2, range 2-10). All but 2 children had normal plain radiographs of the hip. All patients were contacted 4.2 +/- 2.5 years after the first episode. None developed clinical Perthes disease or other chronic orthopedic condition. Three (8%) patients developed chronic disease: one had familial Mediterranean fever and 2 developed spondyloarthropathies, 0.5, 2, and 6 years after presentation. At followup 26 of 36 patients were asymptomatic, and 10 reported rare hip pain after intensive physical effort. CONCLUSION: Children with recurrent TS usually have a benign course. In some patients recurrent TS may be the presenting feature of a chronic inflammatory condition. No progression to chronic orthopedic conditions was observed.

Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial.

We performed a prospective, randomized, open-label equivalence study comparing the use of naproxen to aspirin in 33 patients with rheumatic fever. The mean time until resolution of arthritis was 2.9+/-2.9 days in both groups. Liver enzyme elevations were more frequent in the aspirin group (P=.002). We conclude that naproxen is as effective, is easier to use, and is safer than aspirin in the treatment of the arthritis of rheumatic fever.