Lisa Imundo

Long-Term Efficacy and Safety of Infliximab plus Methotrexate for The Treatment of Polyarticular Course Juvenile Rheumatoid Arthritis: Findings from an Open-Label Treatment Extension

Objective To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). Methods Patients eligible for the open-label extension (OLE, weeks 52–204) received infliximab 3–6 mg/kg every 8 weeks plus methotrexate. Results Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. Conclusions In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate. Clinical trials registration number NCT00036374.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM. Abbreviations: CI = confidence interval, CT = computerized tomography, dlk = delta-like, DM= dermatomyositis, DXA = dual-energy X-ray absorptiometry, HDL = high-density lipoprotein, HIV = human immunodeficiency virus, HOMA-IR = homeostasis model assessment of insulin resistance, IL = interleukin, IR = insulin resistance, JDM = juvenile dermatomyositis, LA = lipoatrophy, LD = lipodystrophy, LDL = low-density lipoprotein, LMNA= lamin A, MRI = magnetic resonance imaging, NASH = nonalcoholic steatohepatitis, NIH = National Institutes of Health, OGTT = oral glucose tolerance test, OR = odds ratio, PCR = polymerase chain reaction, TNF = tumor necrosis factor, TTP = tristetraprolin.

Use of Atorvastatin in Systemic Lupus Erythematosus in Children and Adolescents

OBJECTIVE Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis

To assess the efficacy and safety of rilonacept, an interleukin‐1 inhibitor, in a randomized, double‐blind, placebo‐controlled trial.

Safety and Efficacy of Belimumab to Treat Systemic Lupus Erythematosus in Academic Clinical Practices.

Objective. To evaluate the use and efficacy of belimumab in academic practices. Belimumab is a human monoclonal antibody that inhibits soluble B lymphocyte stimulator and has been approved for the treatment of adults with systemic lupus erythematosus (SLE). Methods. Invitations to participate and complete a 1-page questionnaire for each patient prescribed belimumab were sent to 16 physicians experienced in SLE phase III clinical trials. The outcome was defined as the physician’s impression of improvement in the initial manifestation(s) being treated without worsening in other organ systems. Results. Of 195 patients treated with belimumab at 10 academic centers, 96% were taking background medications for SLE at initiation of belimumab, with 74% taking corticosteroids. The main indications for initiation of belimumab were arthritis, rash, and/or worsening serologic activity, with 30% of patients unable to taper corticosteroids. Of the 120 patients taking belimumab for at least 6 months, 51% responded clinically and 67% had ≥ 25% improvement in laboratory values. While numbers are limited, black patients showed improvement at 6 months. In a subset of 39 patients with childhood-onset SLE, 65% responded favorably at 6 months, and 35% discontinued corticosteroids. Conclusion. Our data demonstrate favorable clinical and laboratory outcomes in patients with SLE at 6 months across all racial and ethnic groups, with similar improvement seen among patients with childhood-onset SLE.

Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein

Objective Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. Methods Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. Results Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. Conclusions Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. ClinicalTrials.gov identifier: NCT00065806.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R2 for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Increased sensitivity of the European medicines agency algorithm for classification of childhood granulomatosis with polyangiitis.

Objective. Granulomatosis with polyangiitis (Wegener’s; GPA) and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare in childhood and are sometimes difficult to discriminate. We compared use of adult-derived classification schemes for GPA against validated pediatric criteria in the ARChiVe (A Registry for Childhood Vasculitis e-entry) cohort, a Childhood Arthritis and Rheumatology Research Alliance initiative. Methods. Time-of-diagnosis data for children with physician (MD) diagnosis of AAV and unclassified vasculitis (UCV) from 33 US/Canadian centers were analyzed. The European Medicines Agency (EMA) classification algorithm and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) and American College of Rheumatology (ACR) criteria for GPA were applied to all patients. Sensitivity and specificity were calculated (MD-diagnosis as reference). Results. MD-diagnoses for 155 children were 100 GPA, 25 microscopic polyangiitis (MPA), 6 ANCA-positive pauciimmune glomerulonephritis, 3 Churg-Strauss syndrome, and 21 UCV. Of these, 114 had GPA as defined by EMA, 98 by EULAR/PRINTO/PRES, and 87 by ACR. Fourteen patients were identified as GPA by EULAR/PRINTO/PRES but not by ACR; 3 were identified as GPA by ACR but not EULAR/PRINTO/PRES. Using the EMA algorithm, 135 (87%) children were classifiable. The sensitivity of the EMA algorithm, the EULAR/PRINTO/PRES, and ACR criteria for classifying GPA was 90%, 77%, and 69%, respectively, with specificities of 56%, 62%, and 67%. The relatively poor sensitivity of the 2 criteria related to their inability to discriminate patients with MPA. Conclusion. EULAR/PRINTO/PRES was more sensitive than ACR criteria in classifying pediatric GPA. Neither classification system has criteria for MPA; therefore usefulness in discriminating patients in ARChiVe was limited. Even when using the most sensitive EMA algorithm, many children remained unclassified.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults

Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity.

Inactive Disease and Remission in Childhood-onset Systemic Lupus Erythematosus

To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood‐onset systemic lupus erythematosus (cSLE).