In this randomized, placebo-controlled trial of 133 children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal ...antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn. Fourteen patients had serious adverse events, including seven patients with serious infections.
In children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn.
Juvenile rheumatoid arthritis is the most common rheumatic disease of childhood and is an important cause of disability among children.
1
Weekly methotrexate (oral or parenteral), at dosages of up to 15 mg per square meter of body-surface area per week for parenteral administration, has been established as an effective therapy in polyarticular juvenile rheumatoid arthritis.
2
,
3
During the past decade, the use of tumor necrosis factor (TNF) antagonists in adult rheumatoid arthritis has shifted the paradigm of care.
4
–
6
More recently, TNF blockade has been shown to be an efficacious treatment option for polyarticular juvenile rheumatoid arthritis.
7
Adalimumab (Humira, Abbott . . .
Background Recommendations for vaccination in juvenile idiopathic arthritis mirror recommendations for healthy children except that live attenuated vaccines are withheld from those children treated ...with most disease modifying anti-rheumatic drugs (DMARDs) and chronic steroids. A new type of vaccine composed of four “vaccine-like particles” (VLPs) was approved for marketing to induce protection against four serotypes of human papilloma virus (HPV) (Gardasil®) in females. For patients on immune suppressive medications, HPV infection may not resolve spontaneously as frequently as in normals, making vaccination in JIA even more important. Objectives The study was designed to determine the safety and efficacy of immunization with quadrivalent HPV vaccine (Gardasil®) in JIA females who were age 9-26 at study start. Response to vaccine was to be measured by geometric mean titers (GMTs) and compared to population controls. Bio-specimens were to be collected in order to perform future studies aimed at studying mechanism of vaccine response. Methods Female subjects age 9-26 were recruited according to disease category (polyarticular (poly or sJIA onset), oligo (pauci)-articular onset, and serongative-24 per group planned). ILAR criterion were recorded. Subjects with active systemic JIA (sJIA) (as evidenced by fever, rash and labs) were excluded but SJIA subjects lacking systemic features were permitted to enroll. GMTs were measured at 0, 7, 12 and, where possible 24 months. Blood was collected for post-hoc analyses to be performed if GMTs from patients are found to be lower than age and sex-matched population controls. Adverse events (AEs) and serious adverse events (SAEs) were collected and evaluated at follow up. Subjects with a known history of HPV were excluded. Results To date, 38 subjects are enrolled. One subject was excluded from GMT analysis because of baseline seropositivity. Of the 28 subjects with baseline and at least one measurement at 7 or 12 months, all but one subject had a rise in titers comparable to population controls in GMTs in response to the four HPV serotypes included in the vaccine. No SAEs were observed AEs observed to date include: URI/sinusitis (8), fever (2), nausea, emesis and/or diarrhea (5), injection site soreness (1), achiness/fatigue/flu (3), lightheadedness/dizziness (4), vasovagal syncope (1), healthy pregnancy >6 months post-last immunization (1), whiplash (1), herpes zoster (1), plantar warts (1), dry socket following wisdom tooth extraction (1), MVA (1), joint pain post-MVA (1), rash/urticaria (2), arthralgia/stiffness (4), arthritis flare (1), enthesitis flare (1), thrush (1), insomnia (1), shortness of breath (1), fatigue (2), strep throat (1), ecchymosis finger (1), otalgia (1). Conclusions Immunization with quadrivalent HPV vaccine with Gardasil® appears to be safe and induced comparable levels of anti-HPV anitbodies to those observed in control populations in all but one subject to date. Minor disease flare was observed in 2 out of 38 following immunization with Gardasil® but was transient and readily controlled in our study to date. Acknowledgements Funding for this study has been provided through an IIG from Merck to NGS. The trial is registered as NCT00573651 at Clinical Trials.gov. Merck provided support for GMT measurement that was performed by PPD. The authors thank D. Morus, M. Wallette, K. Krogstad, D. Latham, S. Milhalus, C. Mawhorter, B. Pulova and S. Dawson for study coordination and monitoring and Alfred Saah (Merck) for his support and helpful discussion. Disclosure of Interest N. Singer Grant/research support: Merck IIG, L. Wagner-Weiner: None declared, K. Nanda: None declared, A. Robinson: None declared, S. Spalding: None declared, H. Bükülmez: None declared DOI 10.1136/annrheumdis-2014-eular.3050
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.
In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus ...erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.
Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA).
...This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434.
Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 29% of 72 patients) than with placebo (37 53% of 70 patients; hazard ratio 0·46, 95% CI 0·27–0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study.
The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections.
Pfizer.
Objective
To prospectively validate the preliminary criteria for clinical inactive disease (CID) in patients with select categories of juvenile idiopathic arthritis (JIA).
Methods
We used the process ...for development of classification and response criteria recommended by the American College of Rheumatology Quality of Care Committee. Patient‐visit profiles were extracted from the phase III randomized controlled trial of infliximab in polyarticular‐course JIA (i.e., patients considered to resemble those with select categories of JIA) and sent to an international group of expert physician raters. Using the physician ratings as the gold standard, the sensitivity and specificity were calculated using the preliminary criteria. Modifications to the criteria were made, and these were sent to a larger group of pediatric rheumatologists to determine quantitative, face, and content validity.
Results
Variables weighted heaviest by physicians when making their judgment were the number of joints with active arthritis, erythrocyte sedimentation rate (ESR), physician's global assessment, and duration of morning stiffness. Three modifications were made: the definition of uveitis, the definition of abnormal ESR, and the addition of morning stiffness. These changes did not alter the accuracy of the preliminary set.
Conclusion
The modified criteria, termed the “criteria for CID in select categories of JIA,” have excellent feasibility and face, content, criterion, and discriminant validity to detect CID in select categories of JIA. The small changes made to the preliminary criteria set did not alter the area under the receiver operating characteristic curve (0.954) or accuracy (91%), but have increased face and content validity.
Background
For children with polyarticular juvenile idiopathic arthritis (pJIA) and inadequate response or intolerance to initial treatment with MTX, treatment options include abatacept.
1
Abatacept, ...a selective T-cell co-stimulation modulator, has a distinct mechanism of action from other current treatments for rheumatic diseases,
2
and factors predicting clinical response can help determine optimal treatment strategy. Two phase 3 studies demonstrated the efficacy and safety of IV and SC abatacept in patients with pJIA and an inadequate response to other DMARDs.
2,3
Objectives
To determine baseline and post-baseline factors that may predict a clinical response in children and adolescents with pJIA treated with abatacept for 2 years.
Methods
Baseline demographic and disease characteristics and post-baseline factors (50% and 70% improvement in ACR criteria ACR50, ACR70 at days 57 and 85) were analyzed using data from 2 phase 3 studies of abatacept in patients with JIA aged 2–17 years (SC administration) and 6–17 years (IV administration). Efficacy endpoints were Juvenile Arthritis Disease Activity Score in 10 joints based on CRP (JADAS10-CRP) inactive disease (ID; score of ≤ 2.7),
4
and remission, defined as 6 consecutive months of post-baseline JADAS10-CRP ID. Data were analyzed over the entire 2-year study period. The earliest time point at which patients achieved these outcomes was reported. The aforementioned study factors were subjected to a time-to-event analysis, including Cox proportional hazards univariate regression analysis and Cox proportional hazards multivariate regression analysis using stepwise regression; results of the multivariate analysis are reported. Kaplan–Meier analysis was used to estimate time to achieve clinical response. Receiver operating characteristic curves were used to determine threshold values for continuous variables.
Results
Overall, 347 patients were included in the analysis (SC, n = 219; IV, n = 128; 73.8% female; mean SD age, 11.3 4.0 years). Following abatacept treatment, both time to JADAS10-CRP ID and time to JADAS10-CRP remission were predicted (nominal
P
≤ 0.05) by age (≤ 11 years: hazard ratio HR, 1.52 95% CI, 1.14–2.02 and ≤ 10 years: HR, 1.73 95% CI, 1.20–2.48, respectively), high-sensitivity CRP (hsCRP; ≤ 0.6 mg/dL: HR, 1.67 95% CI, 1.22–2.28 and ≤ 0.21 mg/dL: HR, 1.67 95% CI, 1.15–2.42, respectively), Parent/Patient Global Assessment of well-being (≤ 35.86: HR, 1.88 95% CI, 1.41–2.51 and ≤ 43.16: HR, 2.05 95% CI, 1.35–3.10, respectively), and Childhood HAQ-DI (CHAQ-DI; ≤ 1.63: HR, 2.23 95% CI, 1.47–3.39 and ≤ 0.75: HR, 1.84 95% CI, 1.24–2.73, respectively) (remission data shown in Figure 1). Disease duration ≤ 2 years from baseline (HR, 1.66 95% CI, 1.25–2.21) and SC route of administration (HR, 2.05 95% CI, 1.45–2.91) also predicted ID. Among the post-baseline factors, ACR50 at days 57 and 85 predicted both ID (HR, 1.57 95% CI, 1.04–2.36 and HR, 1.88 95% CI, 1.41–2.51, respectively) and remission (HR, 1.96 95% CI, 1.11–3.45 and HR, 3.05 95% CI, 1.47–6.34, respectively); ACR70 at day 57 also predicted ID (data not shown). Patients with predictive factors for age, hsCRP, Parent/Patient Global Assessment of well-being, and CHAQ-DI, and with lower disease activity achieved ID and/or remission earlier than patients with high disease activity.
Conclusion
We identified baseline and post-baseline factors that predicted JADAS10-CRP ID and remission in patients with pJIA treated with abatacept for 2 years. Screening of abatacept-treated patients with pJIA for such factors may help predict earlier achievement of ID and/or remission.
References
1Ringold S, et al.
Arthritis Rheumatol
2019;71:846–63.
2Brunner HI, et al.
Arthritis Rheumatol
2018;70:1144–54.
3Ruperto N, et al.
Lancet
2008;372:383–91.
4Trincianti C, et al.
Arthritis Rheumatol
2021;73:1966–75.
Acknowledgements
This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance were provided by Candice Judith Dcosta, MSc, of Caudex, funded by Bristol Myers Squibb. We would like to acknowledge Mara Becker, Duke Clinical Research Institute, Durham, NC, USA, for her contribution to the study analysis.
Disclosure of Interests
Nicolino Ruperto Speakers bureau: Honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers Squibb, Cambridge Healthcare Research, Celgene, Domain Therapeutic, Eli Lilly, EMD Serono, GlaxoSmithKline, Idorsia, inMed, Janssen, Novartis, Pfizer, Sobi, UCB, Consultant of: Honoraria for consultancies or speaker bureaus from the following pharmaceutical companies in the past 3 years: 2 Bridge, Amgen, AstraZeneca, Aurinia, Bayer, Brystol Myers Squibb, Cambridge Healthcare Research, Celgene, Domain Therapeutic, Eli Lilly, EMD Serono, GlaxoSmithKline, Idorsia, inMed, Janssen, Novartis, Pfizer, Sobi, UCB, Hermine Brunner Speakers bureau: GlaxoSmithKline, Novartis, Pfizer, Consultant of: AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Cerocor, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GlaxoSmithKline, Idorsia, Janssen, Merck, Novartis, R-Pharm, Sanofi, Grant/research support from: The Cincinnati Children’s Hospital, where HIB works as a full-time public employee, has received contributions from the following industries in the past 3 years: Bristol Myers Squibb, F. Hoffmann-La Roche, Janssen, Novartis, and Pfizer. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment to third parties, Alberto Berman Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, Francisco Avila Zapata: None declared, Gerd Horneff Speakers bureau: AbbVie, Chugai, Janssen, Novartis, Pfizer, Grant/research support from: AbbVie, Chugai, MSD, Novartis, Pfizer, Roche, Linda Wagner-Weiner Grant/research support from: Abbott, Bristol Myers Squibb, Merck, Pfizer, UCB, Alexander Belot Speakers bureau: Chugai, GlaxoSmithKline, Novartis, Roche (punctual scientific intervention), Grant/research support from: Boehringer Ingelheim, Merck (joint research project), Ruben Burgos-Vargas: None declared, Maria Luz Gámir Gámir: None declared, Claudia Goldenstein-Schainberg Speakers bureau: AbbVie, Janssen, Novartis, Consultant of: AbbVie, Janssen, Novartis, Maria T. Terreri: None declared, Margarita Askelson Consultant of: Acerta Pharma, Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Robert Wong Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Alberto Martini Consultant of: AbbVie, Eli Lilly, EMD Serono, Idorsia, Janssen, Novartis, Pfizer, Daniel J Lovell Consultant of: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman LaRoche, Novartis, UBC (all contracts with employer, CCHMC), Grant/research support from: Bristol Myers Squibb, Janssen, Pfizer, Roche (all contracts with employer, CCHMC); NIH grants: NIAMS, NICHD
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.
To describe the health and functional status of children with juvenile rheumatoid arthritis (JRA) diagnosed in the early 1990s.
Patients were obtained from the Pediatric Rheumatology Disease ...Registry, a database of patients seen in pediatric rheumatology centers across the United States. Questionnaires designed to be filled out after retrospective chart review were sent to pediatric rheumatologists caring for children diagnosed with JRA between 1992 and 1997.
We studied 703 patients -- 376 with pauciarticular onset (pauci), 232 with polyarticular onset (poly), and 95 with systemic onset JRA (systemic). At 1 year after diagnosis, half of the pauci and systemic patients no longer required medication, compared to 78% of the poly patients; 98% of the patients functioned in Steinbrocker classes I and II. Six percent of pauci, 27% of poly, and 11% of systemic patients had limitations in school function. Nearly 1/3 of poly patients already had joint space narrowing on radiograph. By 5 years after diagnosis, all pauci, 88% of poly, and 70% of systemic patients were in Steinbrocker classes I and II; but 6% of pauci, 28% of poly, and 44% of systemic patients had limitations in school function. Nearly 2/3 of poly and systemic patients had joint space narrowing.
In these children treated prior to the era of biologic therapy, at 5 years after onset, > 25% of poly and nearly half of systemic patients had functional limitations that required modifications in their school schedule. Radiographically evident joint space damage was seen within a year of onset in poly patients, and by 5 years 2/3 of poly and systemic patients had damage.
PDF
