Rik Joos

Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA). METHODS This phase II, multicenter, randomized, double-blind, placebo-controlled study included the following: a 12-week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12-week treatment-extension phase, with patients in the placebo group re-randomized to receive apremilast; and a 4-week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms. RESULTS Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment-extension phase (68.3%) reported ≥ 1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported. CONCLUSION Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus

Objective: To investigate differences in clinical signs and symptoms, and in antinuclear antibodies (ANA), between patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). Methods: Clinical and serological data of 56 patients with juvenile-onset SLE were compared with data of 194 patients with adult-onset SLE. ANA were determined by line immunoassay and by indirect immunofluorescence on Crithidia luciliae. Results: Renal involvement, encephalopathy and haemolytic anaemia were seen, and anti-dsDNA, anti-ribosomal P and antihistone antibodies found, significantly more often in juvenile-onset SLE. Anti-dsDNA antibodies were directly associated, and anti-ribosomal P antibodies inversely associated, with renal involvement in juvenile-onset SLE. In juvenile patients with SLE and anti-dsDNA and without anti-ribosomal P antibodies the odds ratio for glomerulonephritis was 9.00; no patients with anti-ribosomal P but without anti-dsDNA had renal involvement. Conclusion: Patients with juvenile-onset SLE more often have renal involvement and encephalopathy than patients with adult-onset SLE. Anti-ribosomal P, anti-dsDNA and antihistone antibodies are more often found in patients with juvenile-onset SLE.

Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis : a randomised trial

BACKGROUND Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedmans test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

Expressive dimensions of pain catastrophizing: a comparative analysis of school children and children with clinical pain

&NA; We investigated the role of the child’s pain catastrophizing in explaining (1) children’s self‐reported tendency to verbally share their pain experience with others and (2) different dimensions of pain expression, as described by the mother and the father, including non‐verbal and verbal communicative pain behaviour and protective pain behaviour. Participants were school children, children with chronic or recurrent pain, and their parents. The results showed that: (1) Pain catastrophizing was associated with children’s greater self‐acknowledged tendency to verbally share their pain experience with others. (2) Mothers and fathers perceived highly catastrophizing children to be more communicative about their pain. (3) The role of pain catastrophizing in the child’s verbal sharing of pain experiences and in explaining expressive behaviour as rated by parents did not differ between the school children and children with recurrent and chronic pain. (4) Nevertheless, findings indicated marked differences between school children and the clinical sample. Children of the clinical sample experienced more severe pain, more pain catastrophizing, more protective pain behaviour, but less verbal communications about their pain. These results further corroborate the position that catastrophic thoughts about pain have interpersonal consequences. Findings are discussed in terms of the possible functions and effects upon others of pain catastrophizing and associated categories of pain behaviour.

Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial

Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial. Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered. Results Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, therapy-related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006). Conclusions For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile. EudraCT number: 2008-007225-39.

Health‐related quality of life of patients with juvenile dermatomyositis: Results from the paediatric rheumatology international trials organisation multinational quality of life cohort study

OBJECTIVE To investigate the health-related quality of life (HRQOL) change over time, as measured by the Child Health Questionnaire (CHQ), and its determinants in patients with active juvenile dermatomyositis (DM). METHODS We assessed patients with juvenile DM at both baseline and 6 months of followup, and healthy children age < or =18 years. Potential determinants of poor HRQOL included demographic data, physicians and parents global assessments, muscle strength, functional ability as measured by the Childhood Health Assessment Questionnaire (C-HAQ), global disease activity assessments, and laboratory markers. RESULTS A total of 272 children with juvenile DM and 2,288 healthy children were enrolled from 37 countries. The mean +/- SD CHQ physical and psychosocial summary scores were significantly lower in children with juvenile DM (33.7 +/- 11.7 versus 54.6 +/- 4.1) than in healthy children (45.1 +/- 9.0 versus 52 +/- 7.2), with physical well-being domains being the most impaired. HRQOL improved over time in responders to treatment and remained unchanged or worsened in nonresponders. Both physical and psychosocial summary scores decreased with increasing levels of disease activity, muscle strength, and parents evaluation of the childs overall well-being. A C-HAQ score >1.6 (odds ratio [OR] 5.06, 95% confidence interval [95% CI] 2.03-12.59), childs overall well-being score >6.2 (OR 5.24, 95% CI 2.27-12.10), and to a lesser extent muscle strength and alanine aminotransferase level were the strongest determinants of poor physical well-being at baseline. Baseline disability and longer disease duration were the major determinants for poor physical well-being at followup. CONCLUSION We found that patients with juvenile DM have a significant impairment in their HRQOL compared with healthy peers, particularly in the physical domain. Physical well-being was mostly affected by the level of functional impairment.

Efficacy and safety of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (SJIA): tender 52-week data

Purpose Treatment options for sJIA are limited. Excessive IL-6 production has been implicated in several manifestations of this disease. In a previous Japanese study, TCZ, an IL-6 receptor inhibitor, improved arthritis and systemic features of patients with refractory sJIA. We present efficacy and safety of TCZ in patients with active sJIA who were treated for ≥52 wks in the global, 3-part, 5-yr, phase 3, multicenter TENDER study. Methods

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.

Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial

Objectives Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. Methods The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). Results 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. Conclusions MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. Trial registration numbers EudraCT-number 2008-007225-39 and NCT01172639; Results.

Diagnostic value of MRI features of sacroiliitis in juvenile spondyloarthritis.

AIM To determine the diagnostic utility of magnetic resonance imaging (MRI) features of sacroiliitis in juvenile spondyloarthritis (JSpA). MATERIALS AND METHODS This was a prospective study of 80 paediatric patients who underwent MRI of the sacroiliac joints that were clinically suspected to have sacroiliitis. The prevalence of MRI features of active and structural lesions of sacroiliitis was recorded. Patients were classified according to the International League of Association for Rheumatology criteria. The MRI findings were compared to the final clinical diagnosis. RESULTS Sacroiliitis was seen in 25/80 (31%) patients. MRI showed active inflammation in 23 patients (29%): synovial enhancement (28%), high short tau inversion recovery (STIR)-signal in the joint space (29%), bone marrow oedema (BMO; 20%), and capsulitis (8%). Structural changes were present in 14 patients (18%): erosion (14%), fat infiltration (13%), sclerosis (8%), and ankylosis (1%). Of all MRI features, ankylosis (100%), capsulitis (98%), BMO (96%), and erosion (96%) had the highest specificity for JSpA; global diagnostic impression (55%) and synovial enhancement (52%) were the MRI features with the highest sensitivity. The likelihood ratios (LR+) for diagnosis of JSpA were high for BMO (10.5), capsulitis (7.5), global diagnostic impression (6.9), and erosions (6.75), but greater for BMO concomitant with synovial enhancement (LR+ 19.5) and for erosion concomitant with BMO (LR+ 12) or synovial enhancement (LR+ 13.5). CONCLUSION There are multiple features of active inflammation and structural damage visible at MRI of the sacroiliac joints that can provide a specific diagnosis of JSpA when present in children with suspected sacroiliitis. Synovial enhancement is the MRI feature with the highest sensitivity for JSpA. If BMO is seen concomitant with synovial enhancement or erosion, the diagnosis of JSpA is very likely. Ankylosis, capsulitis, bone marrow oedema, and erosion all have a high specificity for JSpA. Absence of MRI findings of sacroiliitis does not exclude the diagnosis of JSpA.