Prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

BACKGROUND: Antibodies against cyclic citrullinated peptide (anti-CCP) are considered to be specific for rheumatoid arthritis (RA). OBJECTIVE: To assess the clinical significance of anti-CCP in a cohort of patients with juvenile idiopathic arthritis (JIA). METHODS: Anti-CCP were tested by an enzyme linked immunosorbent assay (ELISA) in serum samples from 109 patients with JIA (30 boys, 79 girls), with a mean age of 8.7 years (range 0.6-20.3) and mean disease duration of 3.6 years (range 3 months to 15.6 years). As control groups, anti-CCP were also tested in sera of 30 healthy children, 25 patients with juvenile onset systemic lupus erythematosus (SLE), and 50 adult patients (30 with RA, 20 with SLE). RESULTS: Positive anti-CCP values were found in sera of two patients with JIA (2%), one with polyarthritis, and one with oligoarthritis. Statistical analysis showed that anti-CCP were not associated with the presence of antinuclear antibodies, raised erythrocyte sedimentation rate, or erosions. In the control groups, none of the patients with juvenile onset SLE and only one of 20 adults with SLE were positive for anti-CCP, but 19/30 (63%) adults with RA showed anti-CCP positivity. CONCLUSIONS: Anti-CCP can be detected in children with JIA, but are less frequently present than in adults with RA.     

Does switching anti-TNFα biologic agents represent an effective option in childhood chronic uveitis: The evidence from a systematic review and meta-analysis approach

Objective

To summarize the evidence regarding the effectiveness of switching to a second anti-TNFα treatment in children with autoimmune chronic uveitis (ACU), refractory to the first course of anti-TNFα treatment.

Methods

We conducted a systematic literature review between January 2000 and May 2013 to investigate the efficacy of a second anti-TNFα agent in the treatment of ACU in children (≤16 years) refractory to a first course of a single anti-TNFα treatment, topical and/or systemic steroid therapy and at least one DMARD. The primary outcome measure was the improvement of intraocular inflammation, as defined by the SUN working group criteria, at 6 (±2) months of treatment.

Results

Among 1086 identified articles, 128 were scrutinized: 10 observational studies, 6 on adalimumab (ADA), 3 on infliximab (INF), and 1 on both, were deemed eligible. Study cohort included 40 children (ADA = 34 and INF = 6), median age 8 years (range 3–16). Nine were males, 28 females (gender not reported in 3), 39/40 were affected by JIA. Seventeen children received etanercept: 11 were switched to ADA, the remaining 6 to INF. All 23 children who previously received INF were switched to ADA. Altogether, 30 children (24 on ADA, 6 on INF) of 40 responded to treatment: 0.75 (95% CI: 0.51–100) was the combined estimate of the proportion of subjects improving.

Conclusions

Despite the fact that no RCT is available and the number of cases is small, this review provides evidence that switching to a second anti-TNFα agent results in improvement of ocular activity for the 75% treated children     

The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up

Objective

To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.

Methods

We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed.

Results

Individuals with low-penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-penetrance variants ultimately require these therapies.

Conclusions

Our study confirms that low-penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.     

Typical and severe tumor necrosis factor receptor–associated periodic syndrome in the absence of mutations in the TNFRSF1A gene: a case series

Tumor necrosis factor receptor-1?Cassociated periodic syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-??. TRAPS is characterized by recurrent attacks of fever, typically lasting from 1 to 3?weeks. In addition to fever, common clinical features include periorbital edema, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthralgia or arthritis. Serosal membrane inflammation is also a common feature, usually in the form of polyserositis. To date, at least 40 different TNFRSF1A mutations have been identified, but few patients with symptoms highly suggestive of TRAPS with no mutations in the TNFRSF1A gene have recently been described, thus suggesting that not all mutations are yet known or that alternative mechanisms might be involved in the pathogenesis of the disease. We report on three such patients here.     

Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the <Emphasis Type="Italic">MEFV</Emphasis> gene

Systemic juvenile idiopathic arthritis (SJIA) is a disorder characterized by arthritis in children starting before 16 years of age associated with daily high fever, persisting for more than 2 weeks, and at least one of the following clinical features: evanescent cutaneous rash, lymphadenopathy, serositis or hepatosplenomegaly. SJIA patients carry a significantly higher frequency of MEFV mutations, the gene responsible for familial Mediterranean fever, and may be characterized by a more aggressive disease. In this line, we describe a 9-year-old girl affected with SJIA who carried a heterozygous G196W mutation in MEFV. Our patient was characterized by an aggressive disease course, resistance to conventional immunosuppressive agents and developed renal amyloidosis just 2 years after the disease onset.     

What Do Cytokine Profiles Tell Us About Subsets of Juvenile Idiopathic Arthritis?

Classification of juvenile idiopathic arthritis is an ongoing process and up to now has been predominantly based on clinical manifestations—mainly number of joints at onset of disease. In the meantime, basic studies have advanced our knowledge regarding the disease pathogenesis. Unfortunately, studies of cytokines and cytokine polymorphisms have not followed the predominantly clinical International League of Associations for Rheumatology classification in that no significant biological differences among the different disease categories have been demonstrated with robust associations. Only systemic-onset disease seems to be quite different from other disease categories with regard to biologic mechanisms; indeed, it now seems closer to autoinflammatory than to classic autoimmune diseases. New players in the immunologic basis of juvenile idiopathic arthritis (eg, interleukin-17 and regulatory T cells) are also discussed in this review.     

Nonsteroidal antiinflammatory drug-induced gastroduodenal injury in children

Objective. To determine the incidence of abdominal pain and gastroduodenal injury in children with arthritis taking nonsteroidal antiinflammatory drugs (NSAIDs). Methods. A retrospective review of the records of all children (570 patients) receiving followup care in an academic rheumatology clinic between 1991 and 1993 was performed. Results. There were 344 patients who used NSAIDs during the study period. Abdominal pain was recorded in 27.9% of patients taking NSAIDs and 14.6% of patients not taking NSAIDs. Abdominal pain in 47 patients (49%) taking NSAIDs and 14 patients (42%) not taking NSAIDs was evaluated radiographically and/or endoscopically. Among those patients evaluated, gastric or duodenal injury was found in 16 (34.0%) who were taking NSAIDs and 1 (7.1%) who were not. This represented a relative risk for gastroduodenal injury of 4.8 for patients taking NSAIDs (P = 0.09). The incidence of injury did not change when analyses were controlled for prednisone or slow-acting antirheumatic drug use. None of the children were hospitalized or died as a result of gastroduodenal injury during the 3-year period. Conclusion. We conclude that NSAID use in children with arthritis frequently leads to gastroduodenal injury, with an estimated incidence and relative risk that are comparable to the rates found in adults with arthritis taking NSAIDs, but that hospitalization or death as a result of this injury is uncommon.     

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo “inverse wrap” model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.