Long-term outcome of anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondyloarthritis.

OBJECTIVES: A significant proportion of patients with juvenile spondyloarthritis (JSpA) are refractory to treatment with established medications. The objective of this study was to assess long-term efficacy of treatment with anti-TNF agents in patients with JSpA. METHODS: An observational study of 16 patients with JSpA from 3 centres treated with infliximab (n=10) and etanercept (n=6) was performed, with a median follow-up period of 7.2 years. Prospective data was collected according to a standardized protocol. Outcomes examined were TEC, TAJC, markers of inflammation (ESR, CRP), functional assessments (C-HAQ, BASDAI, BASFI), and ongoing requirement for anti-TNF treatment. RESULTS: 13/16 patients (83%) had achieved clinical remission 6 months into the treatment. Improvement was sustained over time, with a median TAJC and TEC of 0 at any time point after 6 weeks. 6/16 patients (38%) showed a flare of arthritis after a median of 3.5 years. Two patients with hip disease prior to treatment required an arthroplasty 3 and 8 years post anti-TNF initiation. Patients showed progression of sacroiliitis with median modified New York score of 1 (range 0-3) at time of diagnosis and 3 (range 0-4) at last follow-up (p=0.002). Median BASDAI at last follow up was 1.6, median BASFI 3.1. Two patients developed transient reactions (one generalised, one local); no patient developed other adverse effects during the study. CONCLUSIONS: Anti-TNF treatment in JSpA refractory to standard treatment results in good long-term disease control except for pre-existing hip disease. However, radiographic evidence suggests inferior efficacy for control of sacroiliac joint disease.

A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network.

Clinical evaluation of a young woman with subcutaneous fibrotic nodules, progressive distal joint contractures and marfanoid stature revealed a previously unrecognized fibrotic disorder characterized by several unique phenotypic features and some features overlapping with known disorders. Mutational analysis of the FBN1 and FBN2 genes excluded Marfan syndrome and congenital contractural arachnodactyly. MMP2 gene sequence analysis excluded multicentric osteolysis, nodulosis and arthropathy. The lack of mutations within the MAGP2 gene also excluded an MAGP2-associated disorder. In order to establish the mechanistic basis for the severe skin pathology noted in this patient, we performed transcriptional profiling of dermal fibroblasts, and candidate gene expression studies in conjunction with immunocytochemistry and cell-based and functional assays. Data from these experiments have further excluded any previously recognized fibrotic disorder and identified a unique pattern of gene expression in this patient consistent with progressive fibrosis. The pathogenic mechanisms included persistent proliferation of dermal fibroblasts in coexistence with a disarray of the microfibrillar network. Collagen accumulation, moreover, could be linked to extensive crosslinking resulting from increased activities of lysyl oxidases (LOX and LOXL), and lack of remodelling due to deficiencies in collagenolytic matrix metalloproteinases. The disorder may represent a novel syndrome in which transforming growth factor-ß1-independent dermal fibrosis, unlike known microfibrillar disorders caused by single gene deficiencies, associates with a disarray of the microfibrillar network.

Clinical features and outcome of pediatric Wegener's granulomatosis.

OBJECTIVE: Wegener's granulomatosis (WG) is a predominantly small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). There are few reports describing its clinical features and outcome in children. We report on the experience at a single tertiary referral center over 21 years. METHODS: We conducted a retrospective chart review of all patients diagnosed with WG at The Hospital for Sick Children between 1984 and 2005. RESULTS: Twenty-five patients were identified. Median age at diagnosis and median followup were 14.5 years and 32.7 months, respectively. Male-to-female ratio was 1:4. Median duration of symptoms before diagnosis was 2 months. Of 22 patients, 21 were ANCA positive during their disease course (classic ANCA 78.9%). Constitutional symptoms were the most common clinical feature at presentation (24 of 25). Glomerulonephritis was present in 22 patients at presentation. Only 1 of 11 patients who presented with or developed renal impairment had normalization of serum creatinine. Upper airway involvement occurred in 21 patients at presentation and 24 over followup; only 1 had subglottic stenosis. Twenty patients had initial pulmonary involvement, most commonly nodules (44%) and pulmonary hemorrhage (44%). Five patients required ventilation for pulmonary hemorrhage. Four patients (16%) had venous thrombotic events (VTEs). Treatment included prednisone (100%), cyclophosphamide (76%), azathioprine (40%), and methotrexate (32%). CONCLUSION: Pediatric WG typically presents in adolescence and has a female predominance. Glomerulonephritis and pulmonary disease are common at diagnosis and frequently present as a pulmonary-renal syndrome. Loss of renal function is common and rarely completely reversible. As in adults, children with WG are at risk of VTEs.

Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFalpha agents.

OBJECTIVE: To determine whether treatment with tumor necrosis factor alpha (TNFalpha)-blocking agents alters the incidence of new-onset uveitis in patients with juvenile idiopathic arthritis (JIA). STUDY DESIGN: Cohort study based on retrospective chart review. The charts of all 1109 patients with a diagnosis of JIA seen between January 1, 1996, and June 30, 2003, at our clinic were reviewed for diagnosis of uveitis and treatment with TNFalpha inhibitors. Cox regression analysis was performed with anti-TNFalpha treatment as a time-dependent covariate for risk of development of uveitis. RESULTS: We identified 70 patients treated with anti-TNFalpha without a prior diagnosis of uveitis. Two of these 70 patients (2.9%), both treated with etanercept, had development of new-onset uveitis during anti-TNFalpha therapy. One had juvenile psoriatic arthritis diagnosed 4.1 years before onset of uveitis. The other had extended oligoarticular JIA diagnosed 6.4 years before onset of uveitis. We found no statistically significant difference in the risk for development of uveitis between patients with or without anti-TNFalpha treatment. CONCLUSIONS: In our patients with JIA, anti-TNFalpha treatment did not alter the risk for development of new-onset uveitis. However, anti-TNFalpha therapy with etanercept did not prevent the development of uveitis in 2 patients.

Tumour necrosis factor alpha inhibitors in the treatment of childhood uveitis.

OBJECTIVE: To describe the efficacy of anti-TNF-alpha agents in the treatment of childhood uveitis. METHODS: We performed a retrospective chart review of all children with uveitis treated with TNF-alpha blockers at The Hospital for Sick Children, Toronto. RESULTS: Twenty-one children with uveitis were treated with the anti-TNF-alpha agents etanercept (11 patients) and infliximab (13 patients), resulting in 24 treatment courses. All patients had persistently active uveitis despite treatment with at least one standard immunosuppressive drug before the start of anti-TNF-alpha therapy. Six of 21 patients (29%) had idiopathic uveitis. In the other 15 patients, the underlying disease was juvenile idiopathic arthritis in 12 (57%), Behçet disease in two (9%) and sarcoidosis in one (5%). Response to etanercept treatment was good in 27%, moderate in 27% and poor in 45% of patients. Response to infliximab treatment was good in 38%, moderate in 54% and poor in 8% of patients. The difference in the percentage of patients with a moderate or good response was statistically significant (P = 0.0481). We also observed a lower rate of complications, such as new-onset or worsening glaucoma or cataract in the infliximab-treated group. CONCLUSION: Anti-TNF-alpha treatment was beneficial in a high percentage of patients with childhood uveitis refractory to standard immunosuppressive treatment. Infliximab resulted in better clinical responses with less ocular complications than etanercept.

Autologous stem cell transplantation for pediatric rheumatic diseases.

The National Institute of Allergy and Infectious Disease, National Institutes of Health, convened a workshop entitled The Next Step: Protocol Development for Autologous Stem Cell Transplantation for Pediatric Rheumatic Disease, June 2000, co-chaired by Drs. Karyl Barron and Carol Wallace. The goal of the workshop was to focus on the scientific rationale for stem cell transplantation therapy in the pediatric diseases, unique aspects of this therapy in the pediatric rheumatic diseases, transplantation issues and options, regulatory issues, and development of a DNA repository for these diseases.

Inflammatory linear verrucous epidermal nevus and arthritis: a new association.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare, chronic skin condition that begins in early childhood. We present two children with ILVEN and arthritis, a previously undescribed association. We discuss the relevance of this association and suggest appropriate management for this arthritis.

Tubulointerstitial nephritis and uveitis in children and adolescents. Four new cases and a review of the literature.

We identified 35 cases of tubulointerstitial nephritis and uveitis (TINU), 31 from a MEDLINE search (1966-1996) of the English literature and 4 from our hospital records (1988-1996). To meet the case definition, the patient had to be less than 18 years old and have TINU of unknown cause. Common presenting symptoms included fatigue, weight loss, fever, and abdominal pain. The uveitis was usually anterior and could occur at any time with respect to the onset of the renal disease. Common laboratory features included anemia, increased erythrocyte sedimentation rate, and decreased creatinine clearance. Most patients (33 of 35) had renal biopsies that commonly revealed an intense inflammatory interstitial infiltrate, glomerular sparing, and negative immunofluorescence studies. Of the 35 patients, 26 received systemic corticosteroid therapy (5 of 26 for eye disease); 22 had follow-up for at least 1 year; 13 of 35 patients had a recurrence of their uveitis. The outcome in all 35 cases was normal renal function with no documented visual loss. In conclusion, TINU is a unique syndrome with characteristic clinical features, laboratory changes, and renal biopsy results. Treatment is controversial, and the outcome in children, even if untreated, is excellent.

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1.

OBJECTIVE: To delineate the clinical features in patients with the autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) and to determine the location of the involved gene. METHODS: Eight affected individuals (ages 2-15 years) with CACP from 4 consanguineous kindreds were clinically evaluated. Four patients are newly described and 4 have been reported previously. Findings were compared with those in 21 other previously reported cases. DNA obtained from the 8 affected patients and their available siblings and parents was used in a genome-wide search for linkage. RESULTS: Congenital camptodactyly and childhood-onset noninflammatory arthropathy were present in all affected patients. Seven patients developed bilateral coxa vara deformity, and 1 developed coxa magna with cystic erosions. Two of the patients also had symptoms or signs of pericarditis. A genome-wide search for linkage identified homozygosity for a series of genetic markers on human chromosome 1q in all affected patients. The marker D1S191 yielded a maximum logarithm of the odds ratio (LOD score) of 3.3 at theta = 0. The CACP gene lies within a 1.9-cM candidate interval defined by the markers D1S2107 and D1S222. CONCLUSION: The principal features of the CACP syndrome are congenital or early-onset camptodactyly and childhood-onset noninflammatory arthropathy. Coxa vara deformity or other dysplasia associated with progressive hip disease may develop over time. Clinical pericarditis may also occur. A locus responsible for causing CACP syndrome is assigned to a 1.9-cM interval on human chromosome 1q25-31 by homozygosity mapping. This now facilitates the identification of the responsible gene and permits testing for locus homogeneity in other CACP kindreds.

Systemic onset juvenile rheumatoid arthritis.

Systemic onset juvenile rheumatoid arthritis (SoJRA) accounts for 10-20% of all JRA, affecting males and females equally and occurring most frequently under the age of 5 years. It is characterized by arthritis, daily spiking fever, an evanescent rash, serositis and a variety of other extra-articular features. Exclusion of systemic infections, malignancies and connective tissue diseases is most important in establishing the diagnosis. The disease has a wide range of severity from a short monocyclic course to a prolonged chronic course with severe destructive arthritis in approximately one third of patients. Destructive arthritis, secondary amyloidosis and treatment complications including infections, osteoporosis, growth retardation and the macrophage activation syndrome account for the significant morbidity and mortality associated with the disease. Pharmacological management includes non-steroidal anti-inflammatory drugs, corticosteroids, methotrexate and an emerging role for cyclosporine A and cytotoxic drug therapy. Elucidation of the immunopathogenetic mechanisms may lead to new targeted therapy.

CT appearance of pulmonary vasculitis in children.

OBJECTIVE: The aim of this study was to determine whether a CT pattern that may represent early or subtle changes of pulmonary vasculitis in children exists. MATERIALS AND METHODS: High-resolution CT scans of the chest for 107 children were retrospectively reviewed by two radiologists who were unaware of the original study findings. Chest CT scans (conventional) for another 54 children who had symptoms or a diagnosis of vasculitis also were reviewed. RESULTS: We identified hazy or fluffy centrilobular, perivascular densities in 10 children, two of whom had small airways disease and eight of whom had vasculitis (Wegener's granulomatosis [n = 5], systemic lupus erythematosus [n = 1], scleroderma-polymyositis overlap syndrome [n = 1], and Churg-Strauss syndrome [n = 1]). The latter eight children underwent 35 scans, 17 of which were positive for these perivascular densities. All positive scans were associated with active disease of new onset (5/17) or with clinical exacerbation of preexisting systemic disease (12/17). The positive scans also were associated with an elevated erythrocyte sedimentation rate (13/17) and biopsy evidence of vasculitis from a variety of sites, including the lungs (n = 1), kidneys (n = 7), oropharynx (n = 5), skin (n = 9), lymph nodes (n = 1), and myocardium (n = 2). The single lung biopsy showed an angiocentric inflammatory-hemorrhagic process. Of the five patients who had positive scans, underwent therapy, and then had repeat studies, four patients had scans revert to normal in association with inactive disease. The remaining patient whose scan did not normalize failed to respond to treatment. CONCLUSION: The fluffy centrilobular pattern likely represents subtle changes of pulmonary vasculitis. In the appropriate clinical setting, such a finding may obviate the need for a lung biopsy.

Clinical significance of specific autoantibodies in juvenile dermatomyositis.

OBJECTIVE: To determine the prevalence and clinical association of myositis specific antibodies in an unselected group of patients with juvenile dermatomyositis (DM). METHODS: The sera of 42 subjects, representing an unselected group of patients from a single center, with juvenile DM and 7 others with idiopathic inflammatory myopathy (IIM) were examined for the presence of myositis specific antibodies by immunodiffusion against calf thymus extract and immunoprecipitation with HeLa extract. RESULTS: Of the subjects with juvenile DM, only 2 had evidence of antibodies specific to myositis (anti-Mi2). Three other patients with juvenile DM had defined autoantibodies not usually considered to be specific to myositis. Two of the 3 subjects had anti-PM-Scl; both developed features of scleroderma after the juvenile DM remitted. The 5 subjects with defined autoantibodies did not differ clinically from the remainder of the subjects with the exception of the late development of scleroderma features in 2. Fourteen other subjects with juvenile DM had unidentified bands on immunoprecipitation, which may represent as yet undiscovered myositis specific antibodies. No myositis specific antibodies were detected in any of the 7 subjects with other IIM syndromes. CONCLUSION: Based on our findings, we do not recommend routine clinical testing for these antibodies in children with typical juvenile DM. Further study of the unidentified bands seen in our subjects may lead to better understanding of the clinical groupings and etiopathogenesis of childhood myositis.

Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus.

This study was undertaken to determine the role of antibodies against both recombinant Ro (r-Ro) and La (r-La) proteins and polypeptides derived from the recombinant La protein in predicting fetal and neonatal outcome in children at risk to develop neonatal lupus erythematosus (NLE). All sera were obtained in the perinatal period and quantitative ELISA assays were used. We collected 41 maternal sera within 2 months of delivery of a child with NLE (21 with congenital heart disease block (CHB) and 20 with dermatologic NLE) and 19 sera from anti-Ro and/or anti-La antibody-positive mothers with systemic lupus erythematosus (SLE) who delivered a child without NLE. All sera were tested for anti-r-La and anti-r-Ro antibodies by ELISA, and most sera were tested for antibodies directed against La polypeptides by immunoblot. We found significantly higher anti-r-La antibody levels in the sera from mothers of children with NLE compared with sera from mothers of unaffected children (0.67 +/- 0.43 versus 0.14 +/- 0.30; P < 0.0001). There was a statistically significant difference in the mean anti-r-La levels between the sera of mothers of children with CHB compared with dermatologic NLE (0.51 +/- 0.45 versus 0.83 +/- 0.37 respectively; P = 0.0091). When we examined antibodies directed against the recombinant 52-kD Ro protein, there was a statistically significant elevation of titres in the sera of mothers of NLE children (0.77 +/- 0.35) compared with non-NLE mothers (0.29 +/- 0.39; P < 0.0001). There was no difference in the r-Ro levels between mothers of children with dermatologic NLE compared with CHB (0.82 +/- 0.37 versus 0.71 +/- 0.74; P = 0.32). When we examined polypeptides derived from the recombinant La protein, the mean number of polypeptides recognized by sera from mothers of children with NLE was significantly higher than the mean number of polypeptides recognized by sera from mothers of unaffected children (5.1 +/- 0.54 versus 2.3 +/- 0.54 respectively; P < 0.001). More importantly, when we examined the individual polypeptides, we found that only sera from mothers of children with NLE and not from mothers of unaffected children recognized a polypeptide designated DD (30% versus 0%, respectively). These studies indicate that the autoantibody response to the Ro/La particle can differentiate sera from mothers of children with NLE and sera from mothers of unaffected children. Furthermore, there was a difference in the anti-La autoantibody response between mothers of children with CHB and dermatologic NLE.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of the cytokine response in Kawasaki disease.

Intracellular cytokines interleukin 6, tumor necrosis factor (TNF) alpha and TNF-beta were studied in peripheral blood mononuclear cells of patients with Kawasaki disease during the acute, subacute and convalescent stages of the disease utilizing cytokine-specific monoclonal antibodies and indirect immunofluorescence. Intracellular cytokines TNF-alpha and -beta were present only during the acute stage before initiation of therapy and not in the subacute or convalescent phase. Intracellular interleukin 6 was seen in both the acute phase and, in small numbers of patients, in the subacute stage of the illness. Overall 15 of 25 (60%) patients produced at least one intracellular cytokine. In the acute stage both monocyte and lymphocyte cytokines were detected intracellularly, TNF-alpha and TNF-beta in 58% of patients whereas interleukin 6 was seen in only 16%. This study provides evidence to support the involvement of activated mononuclear cells, both T cells and monocytes and their secreted soluble products, cytokines, in the pathogenesis of Kawasaki disease.

Arthropathy in thalassaemia patients receiving deferiprone.

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Local synthesis of both macrophage and T cell cytokines by synovial fluid cells from children with juvenile rheumatoid arthritis.

The production of tumour necrosis factor-alpha (TNF-alpha), TNF-beta and IL-6 in synovial fluid was studied in 50 samples of synovial fluid from 44 children with juvenile rheumatoid arthritis (JRA) by identifying cytokine production at a single-cell level. Post Ficoll-separated synovial fluid mononuclear cells were permeabilized and then intracellular TNF-alpha, TNF-beta and IL-6 protein production was examined using indirect immunofluorescence and murine anti-cytokine MoAbs. All three cytokines were measured in 37 of the 50 samples. In 25 of the 37 samples there was complete concordance; all three cytokines were present in six and absent in 19 samples. At least one cytokine was present in 27/50 (54%) of synovial fluid samples. Overall, TNF-alpha was detected in 22/49 (45%) samples, TNF-beta in 15/41 (37%) and IL-6 in 16/45 (36%) samples. Five patients had serial arthrocentesis, and in these samples there were two patients who had initially positive cytokine production, which on subsequent measurement was negative; in the other three patients there was no change from the previous cytokine production. We provide evidence that synovial fluid mononuclear cells produce monocyte and T cell cytokines in JRA. These findings suggest a role for both T cell and macrophage products in the pathogenesis of JRA, and the potential for modulation of cytokine production as a target for therapeutic intervention.

Localized scleroderma in childhood: a report of 30 cases.

Localized scleroderma (LS), a rare disease that occurs primarily in the pediatric age group, differs from systemic sclerosis (SSc) in that it is usually limited to the skin and subcutaneous tissue and is only rarely associated with systemic manifestations. The authors' experience with pediatric LS seen in 30 patients at a tertiary care center was reviewed: 26 had linear scleroderma, 19 on an extremity and 7 on the face; 3 had morphea; and 1 had generalized morphea. Antinuclear antibodies were present in 76% and rheumatoid factor in 39%. Five of 19 patients with linear scleroderma that involved an extremity had growth failure in that limb, and 1 required surgery. Sclerodermatous involvement over a joint resulted in limited range of movement in 6 patients, and 1 required surgery. One of the 30 patients developed SSc and polymyositis. There was difficulty in evaluating disease activity and hence in evaluating treatment. This experience with a large patient population suggests that LS, although usually a self-limiting disease, can result in significant morbidity.

Localized scleroderma progressing to systemic disease. Case report and review of the literature.

We describe a 15-year-old girl with biopsy-proven morphea who developed progression to systemic disease 2 years after initial presentation. In contrast to other reported patients with localized scleroderma, some of whom have had mild, nonprogressive systemic involvement, this patient developed severe, debilitating disease, with skin tightness, sclerodactyly, esophageal involvement, restrictive pulmonary disease, and myopathy. From the time of her initial evaluation, the patient was positive for antinuclear antibodies (ANA), which were shown to be primarily directed against the Ku antigens. This observation suggests that ANA may be a prognostic indicator for progression to systemic disease.