Vyacheslav Chasnyk

EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria

Objectives To validate the previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial

Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). Methods This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. Results In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: −0.21; 95% CI −0.35 to −0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). Conclusions Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. Trial registration number: NCT00988221.

Clinical Features, Treatment, and Outcome of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A Multinational, Multicenter Study of 362 Patients

To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA).

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study

Objective To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Methods CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2–17 years), ERA (12–17 years), or PsA (12–17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. Results 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. Conclusions ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial

Objective This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). Methods In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0–16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16–48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. Results Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. Conclusion Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. Clinical Trial Registration NCT01230827; Results.

Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis

The case of a 10-year-old boy with Farber lipogranulomatosis with predominant joint involvement, subacute, laryngeal and tongue granulomas, microcytic anemia, elevated ESR and CRP, is presented. The boy had no signs of CNS and internal organ involvement. The disease manifested at 6 months; at 11 months the boy had widespread granulomatous polyarthritis with contractures, and juvenile idiopathic arthritis (JIA) was suggested. All antirheumatic therapies failed. Immunologic assessment revealed elevated serum interleukin-1β, increased T-helper, NK and CD25-positive cells, and circulating immune complexes. Our case with predominant rheumatologic manifestations illustrates a differential diagnosis of JIA.

A128: Hierarchical Clustering Methodology for Exploration of Proteomic Profile in Tears: Seeking for Markers of Uveitis Associated With Juvenile Idiopathic Arthritis

Uveitis often is the only initial clinical manifestation of JIA for years. There are no reliable markers of JIA‐associated uveitis and impossibility to overcome ocular barriers impede diagnosis and treatment leading to blindness. During the last years the number of proteins identified in tears increased from 200 (Herber et al., 2001) of only 17 (Zhou et al., 2003) different molecular weights (MW) to 491 (de Souza et al., 2006) with 80 chemokines, cytokines, and growth factors (Sack et al., 2005). Objective of the study is to reveal protein markers of JIA‐associated uveitis in tears using high‐resolution mass‐spectrometry and hierarchical clustering methodology.

Higher-dose canakinumab therapy for refractory macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: two case reports

Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) appears in non-remitted fever, cytopenia, coagulopathy, liver and CNS dysfunctions. Triggers of MAS could be disease activity, infections and medications. Known IL-1 is the key cytokine in pathogenesis of MAS and SJIA, and disease flare associated with increased amounts of different cytokines, especially IL-1β. Many cases of MAS are medically-refractory to traditional doses of cytokine inhibition and may require increased dosing of biologic cytokine blockade. Interleukin-1 (IL-1) is typically a key cytokine in the pathogenesis of sJIA and associated MAS. When MAS occurs in the setting of sJIA treated with IL-1 inhibitors, then increased dosing of IL-1 blockers may be beneficial. This has been shown for anakinra, an IL-1 receptor antagonist, but this drug is currently not available worldwide. Another IL-1 blocker, canakinumbab (CKB), is a monoclonal antibody that blocks IL-1β, but does not also block IL-1α like anakinra. Herein, we describe 2 sJIA patients who developed MAS on standard doses of CKB (4 mg/kg). Both patients received an increased dose of CKB: 150 mg (7.5 and 12.5 mg/kg, respectively) with rapid and complete resolution of MAS. Later the CKB doses was tapered to normal regimen. No side effects or adverse events were noticed during usage of increased CKB doses. Increased dosing of CKB should be considered for CKB-treated sJIA patients who develop MAS on standard dosing.

Identification of the best cut-off points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) – is a severe life-threatening hematological condition, mostly complicated systemic juvenile idiopathic arthritis (SJIA). Early detection of MAS can lead to appropriate therapeutic interventions and change the outcomes. There are no strict criteria for early MAS detection in SJIA. Currently applied HLH criteria can determinate only advanced stage of MAS, which lead to delay diagnosis, late start of specific treatment and associated with poor outcomes. There are several sets of preliminary criteria of MAS in SJIA.

A130: Is the CCR5‐delta32 Mutation Protective Against Systemic‐Onset Juvenile Idiopathic Arthritis?

The CCR5 protein is a chemokine receptor, and is known to be expressed on T cells, macrophages, dendritic and microglia cells. It is believed that different prevalence of HLA and CCR5‐ delta32—a 32 base pair deletion in the coding region—in various ethnic groups is associated with the severity and prevalence of chemokine‐mediated autoimmune diseases, systemic‐onset Juvenile Idiopathic Arthritis (soJIA) being among them (Del Rincon et al., 2003). Since the end of the last century the protective role of the CCR5‐delta32 mutation against JIA is discussed (Hinks et al., 2010), though it seems the role of this mutation is less simple than was hitherto thought. The purposes of the study was to compare the prevalence of the CCR5‐delta32 mutation in children with and without soJIA, to assess the association of this mutation with the severity of the disease and thus to evaluate its protective role.