Jelena Vojinovic

Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial.

CONTEXT Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions. OBJECTIVES To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares. DESIGN, SETTING, AND PATIENTS Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined. INTERVENTION Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission. MAIN OUTCOME MEASURES Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed. RESULTS Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90). CONCLUSIONS In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN18186313.

Safety and Efficacy of an Oral Histone Deacetylase Inhibitor in Systemic-Onset Juvenile Idiopathic Arthritis

OBJECTIVE The current treatment options for systemic-onset juvenile idiopathic arthritis (JIA) are methotrexate, steroids, and biologic agents. This study was undertaken to evaluate the safety of the orally active histone deacetylase inhibitor givinostat (ITF2357) and its ability to affect the disease. METHODS Givinostat was administered orally, for up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17 patients with systemic-onset JIA who had had active disease for ≥1 month. Disease activity was clinically assessed using the American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi 70 criteria for improvement and a systemic feature score. The primary goal was safety and the primary efficacy end point was the number of patients completing 12 weeks of treatment who were responders. RESULTS Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self-limited. The 17 patients from the intent-to-treat population reported a total of 44 AEs, and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea, vomiting, and fatigue) were related to the study drug, but each resolved spontaneously and no patient was withdrawn from the study due to drug-related AEs. In the per-protocol population at week 4, the improvement as measured by the ACR Pedi 30, ACR Pedi 50, and ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%, and this increased further to 77.8%, 77.8%, and 66.7% at week 12. The most consistent finding was the reduction in the number of joints with active disease or with limited range of motion. CONCLUSION After 12 weeks, givinostat exhibited significant therapeutic benefit in patients with systemic-onset JIA, particularly with regard to the arthritic component of the disease, and showed an excellent safety profile.

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.

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are heterogeneous autoimmune diseases characterized by chronic joint inflammation. Methotrexate is used as the gold standard to treat rheumatoid arthritis, yet there are many patients in whom the disease cannot be controlled or who experience unacceptable intolerance. Most of the biologics currently used are effective, but mostly if combined with methotrexate. Long-term possible side effects, such as impaired host defense mechanisms against infection and lymphoma, are distinct disadvantages and a major concern of anticytokine therapies. Parenteral administration is a problem, particularly in children. Thus, there is a need to explore new treatment options. Here we review the properties of histone deacetylase inhibitors (HDACi) as they apply to rheumatoid arthritis by looking at effects on cytokine production, T-cell differentiation and the function of macrophages, dendritic cells, osteoblasts, osteoclasts and synovial fibroblasts. We also review the safety and efficacy of givinostat (ITF 2357) in the treatment of systemic onset juvenile idiopathic arthritis (SOJIA) and its influence on the cytokine networks in SOJIA. Givinostat is an orally active HDACi which was given to children with SOJIA. After 12 wk of treatment, there were significant benefits, particularly in reducing the pain and arthritic component of the disease and decreasing the neutrophilia. CD40L, IL-1α and IFNγ in whole blood lysates decreased at wks 2 and 4 compared with baseline levels The clinical data are consistent with those from animal models of rheumatoid arthritis and suggest that trials with HDACi are promising as a safe oral alternative to anticytokines and methotrexate.

Access to biologic treatment for rheumatoid arthritis in Central and Eastern European (CEE) countries

Summary Background The aim of this study was to assess and compare patients’ access to biologic anti-RA drugs in selected Central and Eastern European (CEE) countries and to analyze the determinants of differences between countries. Material/Methods This is a multi-country survey study, based on a combination of desk research and direct contact with national RA stakeholders. Data was collected using a pre-defined questionnaire. Affordability was measured using an affordability index, calculated comparing the index of health care expenditures to the price index, using Poland as an index of 1. Results The percentage of patients on biologic treatment in 2009 was highest in Hungary (5% RA patients on biologic treatment), followed by Slovenia (4.5%), Slovakia (3.5%), Czech Republic (2.92%), Romania (2.2%), Estonia (1.8%), and Croatia, Serbia, Poland (below 1.5%). Infliximab, etanercept, adalimumab and rituximab were included in the reimbursement system in all countries, but abatacept and tocilizumab were included only in Slovakia. In Slovenia, public payer covered 75% of the price, and 25% is covered by supplementary health insurance; in Bulgaria public payer covered 50% of etanercept and adalimumab costs, and 75% of rituximab cost. In other countries, biologic drugs are reimbursed at 100%. Affordability index for biologic drugs was the lowest in Slovenia (0.4). In each country national guidelines define which patients are eligible for biologic treatment. Disease Activity Score (DAS28) of over 5.1 and failure of 2 or more disease-modifying anti-RA drugs, including methotrexate, are commonly used criteria. Conclusions The most important factors limiting access to biologic anti-RA treatment in the CEE region are macroeconomic conditions and restrictive treatment guidelines.

Toward standardized musculoskeletal ultrasound in pediatric rheumatology: Normal age related ultrasound findings

The Outcome Measures in Rheumatology Ultrasound Task Force has recently started to work on the validation and standardization of musculoskeletal ultrasound (MSUS) examination in children in order to improve its applicability to joint examination.

Vitamin D receptor agonists' anti-inflammatory properties.

One century after its discovery, vitamin D has been shown to be, in fact, a pleiotropic steroid hormone, which, besides regulation of calcium homeostasis and bone turnover, has antiproliferative, prodifferentiation, antibacterial, immunomodulatory, and anti‐inflammatory properties in various cells and tissues. D hormone (1α,25(OH)2D), regulated in an endocrine, autocrine, and paracrine manner, must be bound to the specific nuclear vitamin D receptor (VDR) to exert epigenetic and genetic effects, acting as a connection between extracellular stimuli and genomic responses of the cells. Since only high doses of hormone, provoking hypercalcemia, can achieve immunomodulatory effects, more than 3000 VDR agonists have been synthesized. Numerous experimental trials have been performed in animal models, evidencing the preventive and therapeutic potential of VDR agonists for chronic inflammatory diseases and cancer. Considering the selective anti‐inflammatory effects of VDR agonists compared to glucocorticoids, sparing microbicidal functions, the fear of hypercalcemia as their only frequent side effect becomes a questionable reason for the lack of clinical studies.

Preliminary definitions for the sonographic features of synovitis in children

Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process.

Vitamin D—update for the pediatric rheumatologists

Vitamin D, upon its discovery one century ago, was classified as a vitamin. This classification still greatly affects our perception about its biological role. 1,25(OH)2D (now known as the D hormone) is a pleiotropic steroid hormone that has multiple biologic effects. It is integral to the regulation of calcium homeostasis and bone turnover as well as having anti-proliferative, pro-differentiation, anti-bacterial, immunomodulatory and anti-inflammatory properties within the body in various cells and tissues. Vitamin D (cholecalciferol) should be considered a nutritional substrate that must be ingested or synthesized in sufficient amounts for the further synthesis of the very important regulatory steroid hormone (D hormone), especially in patients with pediatric rheumatic diseases (PRD).Vitamin D insufficiency or deficiency was shown to be pandemic and associated with numerous chronic inflammatory and malignant diseases and even with increased risk of mortality. Several studies have demonstrated that a high percentage of children with pediatric rheumatic diseases (PRD-e.g., JIA, jSLE) have a vitamin D deficiency or insufficiency which might correlate with disease outcome and flares. Glucocorticoids used to treat disease may have a regulatory effect on vitamin D metabolism which can additionally aggravate bone turnover in PRD. An effort to define the optimal serum 25(OH)D concentrations for healthy children and adults was launched in 2010 but as of now there are no guidelines about supplementation in PRD.In this review we have tried to summarize the strong evidence now suggesting that as the knowledge of the optimal approach to diagnosis and treatment PRD has evolved, there is also an emerging need for vitamin D supplementation as an adjunct to regular disease treatment. So in accordance with new vitamin D recommendations, we recommend that a child with rheumatic disease, especially if treated with steroids, needs at least 2-3 time higher doses of vitamin D than the dose recommended for age (approximately 2000 UI/day). Vitamin D supplementation has become an appealing and important adjunct treatment option in PRD.

European multicentre pilot survey to assess vitamin D status in rheumatoid arthritis patients and early development of a new Patient Reported Outcome questionnaire (D-PRO)

OBJECTIVE To collect data on vitamin D (25(OH)D) serum levels in a large number of rheumatoid arthritis (RA) patients from different European countries, to investigate their relation with disease activity, disability, quality of life, and possibly to construct a new Patient Reported Outcome (PRO) questionnaire in order to self-estimate if they are at risk for vitamin D insufficiency/deficiency-related clinical implications (D-PRO). METHODS This was a European League Against Rheumatism (EULAR) supported cross-sectional study (project No CLI064) which involved 625 RA patients (mean age 55±11years, mean disease duration 11±9years), 276 age and sex matched healthy subjects, and rheumatologists working in academic institutions or hospital centres, as well as PARE organizations (patient representatives) from 13 European countries. Serum samples for 25(OH)D level measurement were collected during winter time and analyzed in a central laboratory using chemiluminescence immunoassay (DiaSorin). Patient past medical history was recorded. RA patients were provided with three questionnaires: the Rheumatoid Arthritis Impact Diseases score (RAID), the Health Assessment Questionnaire (HAQ), and the new D-PRO questionnaire at the time of 25(OH)D serum sampling. D-PRO questionnaire consisted of three domains, Symptom Risk Score (SRS), Habitus Risk Score (HRS) and Global Risk Score (SRS+HRS=GRS), constructed with items possibly related to vitamin D deficiency. D-PRO was correlated with both clinical and PRO scores. DAS28-CRP was also evaluated. Statistical analysis was performed by non parametric tests. RESULTS Mean serum concentration of 25(OH)D in RA patients (17.62±9.76ng/ml) was found significantly lower if compared to the levels obtained in matched controls (18.95±9.45ng/ml) (p=0.01), with statistically significant differences among several European countries. Negative correlations were found between 25(OH)D serum levels and DAS28-CRP (p<0.001), RAID (p=0.05) and HAQ (p=0.04) scores in the RA patients group. Negative correlations were also found in the cohort of enrolled RA patients between 25(OH)D serum concentrations and SRS (p=0.04), HRS (p=0.02) and GRS (p=0.02) domains of the D-PRO questionnaire. CONCLUSIONS This first multicentre European survey add new evidences that vitamin D insufficiency/deficiency is frequent in RA patients with statistically significant differences among several countries. Vitamin D serum concentrations seem to correlate negatively and significantly with the D-PRO Global Risk Score, clinimetric indexes for quality of life, disease activity and disability in present cohort of RA European patients.