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Pediatric Rheumatology Online Journal Mar 2021Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent...
Biologic disease modifying antirheumatic drugs and Janus kinase inhibitors in paediatric rheumatology - what we know and what we do not know from randomized controlled trials.
BACKGROUND
Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients.
METHODS
A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted.
RESULTS
Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.
CONCLUSION
Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.
Topics: Antirheumatic Agents; Child; Humans; Janus Kinase Inhibitors; Randomized Controlled Trials as Topic; Rheumatic Diseases
PubMed: 33766063
DOI: 10.1186/s12969-021-00514-4 -
Pediatric Rheumatology Online Journal Mar 2021Autoimmune rheumatic diseases (ARDs) are associated with a significant sex-bias, which becomes more evident post-puberty. This systematic review aims to elucidate the...
BACKGROUND
Autoimmune rheumatic diseases (ARDs) are associated with a significant sex-bias, which becomes more evident post-puberty. This systematic review aims to elucidate the bidirectional relationship between puberty and ARD-related outcomes.
METHODS
Studies published in English until October 2019 were identified using a systematic search of endocrinology and rheumatology literature. Information was extracted on study design, sample size, demographics, puberty outcome measures, disease outcome measures, and main findings. The methodological quality of the studies included was analysed using the Newcastle-Ottawa Scale (NOS).
RESULTS
Sixteen non-randomised studies reporting on the impact of puberty on ARD outcomes (n = 7), ARD impact on puberty-related outcomes (n = 8), or both (n = 1) have been identified. The impact of puberty on ARD outcomes were investigated in patients with juvenile idiopathic arthritis (JIA)-associated uveitis (n = 1), juvenile systemic lupus erythematosus (JSLE) (n = 5) or in healthy controls who developed adult-onset SLE (n = 1) or had non-specific symptoms (n = 1). The impact of ARD on puberty outcomes was explored in JIA (n = 4) and JSLE (n = 3). Quality assessment of studies showed a small to moderate risk of bias overall (NOS 4-9/9). Due to large heterogeneity of the studies it was not possible to perform a meta-analysis. Multiple studies reported on delayed puberty in patients with JIA/JSLE, menstrual and hormonal abnormalities, and lower height and weight than controls. Earlier (pre-pubertal) onset of JSLE was correlated with more severe disease and more need for systemic treatment.
CONCLUSION
A bidirectional relationship exists between puberty and ARDs; however, more and better research is required to elucidate the complexity of this relationship. We propose puberty-related clinical assessments in patients with ARDs, which can improve patient outcomes and facilitate future research.
Topics: Autoimmune Diseases; Humans; Puberty; Rheumatic Diseases
PubMed: 33781271
DOI: 10.1186/s12969-021-00528-y -
Annals of the Rheumatic Diseases Apr 2017To develop standards and recommendations for transitional care for young people (YP) with juvenile-onset rheumatic and musculoskeletal diseases (jRMD). The consensus...
To develop standards and recommendations for transitional care for young people (YP) with juvenile-onset rheumatic and musculoskeletal diseases (jRMD). The consensus process involved the following: (1) establishing an international expert panel to include patients and representatives from multidisciplinary teams in adult and paediatric rheumatology; (2) a systematic review of published models of transitional care in jRMDs, potential standards and recommendations, strategies for implementation and tools to evaluate services and outcomes; (3) setting the framework, developing the process map and generating a first draft of standards and recommendations; (4) further iteration of recommendations; (5) establishing consensus recommendations with Delphi methodology and (6) establishing standards and quality indicators. The final consensus derived 12 specific recommendations for YP with jRMD focused on transitional care. These included: high-quality, multidisciplinary care starting in early adolescence; the integral role of a transition co-ordinator; transition policies and protocols; efficient communications; transfer documentation; an open electronic-based platform to access resources; appropriate training for paediatric and adult healthcare teams; secure funding to continue treatments and services into adult rheumatology and the need for increased evidence to inform best practice. These consensus-based recommendations inform strategies to reach optimal outcomes in transitional care for YP with jRMD based on available evidence and expert opinion. They need to be implemented in the context of individual countries, healthcare systems and regulatory frameworks.
Topics: Adolescent; Adult; Child; Communication; Documentation; Humans; Musculoskeletal Diseases; Organizational Policy; Patient Care Team; Rheumatic Diseases; Time Factors; Transition to Adult Care; Young Adult
PubMed: 27802961
DOI: 10.1136/annrheumdis-2016-210112 -
Health Technology Assessment... Apr 2016Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to... (Review)
Review
The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation.
BACKGROUND
Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated.
OBJECTIVE
To assess the clinical effectiveness and cost-effectiveness of four biologic DMARDs [etanercept (Enbrel(®), Pfizer), abatacept (Orencia(®), Bristol-Myers Squibb), adalimumab (Humira(®), AbbVie) and tocilizumab (RoActemra(®), Roche) - with or without methotrexate where indicated] for the treatment of JIA (systemic or oligoarticular JIA are excluded).
DATA SOURCES
Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and the Database of Abstracts of Reviews of Effects were searched for published studies from inception to May 2015 for English-language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence.
REVIEW METHODS
Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision-analytic model was developed to compare the estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base-case time horizon was 30 years and the model took a NHS perspective, with costs and benefits discounted at 3.5%.
RESULTS
Four placebo-controlled randomised controlled trials (RCTs) met the inclusion criteria for the clinical effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi)-30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar, with fewer disease flares and greater proportions of ACR Pedi-50 and -70 responses among participants randomised to continued biologic DMARDs. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that, generally, ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between the treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality-of-life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratios (ICERs) for adalimumab, etanercept and tocilizumab versus methotrexate were £38,127, £32,526 and £38,656 per quality-adjusted life year (QALY), respectively. The ICER for abatacept versus methotrexate as a second-line biologic was £39,536 per QALY.
LIMITATIONS
The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs, and clinical evidence for specific JIA subtypes is limited.
CONCLUSIONS
Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA who have had an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow-up are needed to establish comparative effectiveness. RCTs for JIA subtypes for which evidence is lacking are also required.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42015016459.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Abatacept; Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Juvenile; Cost-Benefit Analysis; Double-Blind Method; Etanercept; Humans; Methotrexate; Treatment Outcome
PubMed: 27135404
DOI: 10.3310/hta20340 -
Pediatric Rheumatology Online Journal Jun 2023Pain is one of the most frequently reported experiences amongst children with Juvenile Idiopathic Arthritis (JIA); however, the management of JIA pain remains...
BACKGROUND
Pain is one of the most frequently reported experiences amongst children with Juvenile Idiopathic Arthritis (JIA); however, the management of JIA pain remains challenging. As pain is a multidimensional experience that is influenced by biological, psychological, and social factors, the key to effective pain management lies in understanding these complex relationships. The objective of this study is to systematically review the literature on psychosocial factors of children with JIA and their caregivers 1) associated with and 2) predictive of later JIA pain intensity, frequency, and sensitivity in children 0-17 years of age.
METHODS
The Joanna Briggs Institute methodology for etiology and risk and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guided the conduct and reporting of this review. Terms related to pain and JIA were searched in English without date restrictions across various databases (PubMed, CINAHL, PsycINFO, Embase, Scopus, and the Cochrane Central Register of Controlled Trials) in September 2021. Two independent reviewers identified, extracted data from, and critically appraised the included studies. Conflicts were resolved via consensus.
RESULTS
Of the 9,929 unique studies identified, 61 were included in this review and reported on 516 associations. Results were heterogeneous, likely due to methodological differences and moderate study quality. Results identified predominantly significant associations between pain and primary and secondary appraisals (e.g., more child pain beliefs, lower parent/child self-efficacy, lower child social functioning), parent/child internalizing symptoms, and lower child well-being and health-related quality of life. Prognostically, studies had 1-to-60-month follow-up periods. Fewer beliefs of harm, disability, and no control were associated with lower pain at follow-up, whereas internalizing symptoms and lower well-being were predictive of higher pain at follow-up (bidirectional relationships were also identified).
CONCLUSIONS
Despite the heterogeneous results, this review highlights important associations between psychosocial factors and JIA pain. Clinically, this information supports an interdisciplinary approach to pain management, informs the role of psychosocial supports, and provides information to better optimize JIA pain assessments and interventions. It also identifies a need for high quality studies with larger samples and more complex and longitudinal analyses to understand factors that impact the pain experience in children with JIA.
TRIAL REGISTRATION
PROSPERO CRD42021266716.
Topics: Child; Humans; Arthritis, Juvenile; Quality of Life; Pain; Pain Management; Acetaminophen
PubMed: 37328738
DOI: 10.1186/s12969-023-00828-5 -
Paediatric Drugs Dec 2019Early diagnosis and treatment of juvenile idiopathic arthritis (JIA) with conventional and biologic disease-modifying anti-rheumatic drugs have vastly improved outcomes...
BACKGROUND
Early diagnosis and treatment of juvenile idiopathic arthritis (JIA) with conventional and biologic disease-modifying anti-rheumatic drugs have vastly improved outcomes for children with these diseases. Currently, a large proportion of children with JIA are able to achieve clinical inactive disease and remission. With this success, important questions have arisen about when medications can be stopped and how to balance the risks and benefits of continuing medications versus the potential for flare after stopping.
AIM
The aim was to conduct a systematic review of the available literature to summarize current evidence about medication withdrawal for JIA in remission.
METHODS
We conducted a systematic literature search in PubMed and Embase from 1990 to 2019. References were first screened by title and then independently screened by title and abstract by two authors. A total of 77 original papers were selected for full-text review. Data were extracted from 30 papers on JIA and JIA-associated uveitis, and the quality of the evidence was evaluated using National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) tools. Studies on biochemical and radiologic biomarkers were also reviewed and summarized.
RESULTS
Most studies investigating treatment withdrawal in JIA have been observational and of poor or fair quality; interpretations of these studies have been limited by differences in study populations, disease and remission durations, the medications withdrawn, approaches to withdrawal, and definitions of disease outcomes. Overall the data suggest that flares are common after stopping JIA medications, particularly biologic medications. Clinical characteristics associated with increased risks of flare have not been consistently identified. Biochemical biomarkers and ultrasound findings have been shown to predict outcomes after stopping medications, but to date, no such predictor has been consistently validated across JIA populations. Studies have also not identified optimal strategies for withdrawing medication for well-controlled JIA. Promising withdrawal strategies include discontinuing methotrexate before biologic medications in children receiving combination therapy, dose reduction for children on biologics, and treat-to-target approaches to withdrawal. These and other strategies require further investigation in larger, high-quality studies.
CONCLUSIONS
The published literature on treatment withdrawal in JIA has varied in design and quality, yielding little conclusive evidence thus far on the management of JIA in remission. Given the importance of this question, international collaborative efforts are underway to study clinical and biologic predictors of successful medication withdrawal in JIA. These efforts may ultimately support the development of personalized approaches to withdrawing medication in children with JIA in remission.
Topics: Antirheumatic Agents; Arthritis, Juvenile; Biological Products; Child; Humans; Methotrexate; Remission Induction; Withholding Treatment
PubMed: 31673960
DOI: 10.1007/s40272-019-00362-6 -
Arthritis Care & Research May 2015To critically evaluate studies purporting to measure quality of life (QOL) or health-related QOL (HRQOL) in juvenile idiopathic arthritis (JIA) by assessing the face... (Review)
Review
OBJECTIVE
To critically evaluate studies purporting to measure quality of life (QOL) or health-related QOL (HRQOL) in juvenile idiopathic arthritis (JIA) by assessing the face validity of studies via a predefined set of criteria based on Gill and Feinstein (1994).
METHODS
Systematic review was conducted of studies in Medline, Embase, and PsycInfo purporting to measure QOL or HRQOL in JIA. Studies were evaluated based on a set of 8 yes/no criteria set forth by Gill and Feinstein in 1994.
RESULTS
Thirty-four of 50 studies (68%) purported to measure HRQOL, 13 of 50 (26%) measured QOL, and 3 of 50 (6%) measured both QOL and HRQOL. The descriptive analysis of studies is as follows: 22 of 50 studies (44%) explained and defined the authors' meaning of QOL or HRQOL, 42 of 50 studies (84%) stated and explained the domains of the instruments used to measure QOL and HRQOL, authors gave reasons for using a particular instrument in 25 of 50 studies (50%), 14 of 50 studies (28%) asked the patients to give their own global rating, 4 of 50 study authors (8%) tried to differentiate QOL from HRQOL, 5 of 50 authors (10%) provided an opportunity for patients to add items to an instrument, 30 of 50 study authors (60%) reported providing the patients with an opportunity to rate items of importance, and 18 of 50 studies (36%) reported an overall composite score for QOL or HRQOL.
CONCLUSION
Our results show that the face validity of studies measuring QOL in JIA is not up to the standards and recommendations set forth by Gill and Feinstein in 1994.
Topics: Arthritis, Juvenile; Disability Evaluation; Humans; Pain Measurement; Predictive Value of Tests; Quality of Life; Reproducibility of Results; Surveys and Questionnaires
PubMed: 25384887
DOI: 10.1002/acr.22514 -
Orphanet Journal of Rare Diseases Feb 2020Despite the low prevalence of uveitis in pediatric rheumatic diseases, potential problems as well as high disease burden can complicate its management. In this review,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the low prevalence of uveitis in pediatric rheumatic diseases, potential problems as well as high disease burden can complicate its management. In this review, we systematically assessed the epidemiological, etiological, and managerial aspects of uveitis in pediatric rheumatic diseases.
METHODS
This current study was conducted in accordance with the established methods and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). We searched the manuscript databases, including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane for all eligible studies in line with the considered keywords. We also conducted the statistical analysis using the Stata software.
RESULTS
Considering studies focusing on uveitis in Juvenile Idiopathic Arthritis (JIA) yielded a pooled prevalence of 11.8% (95%CI: 11.2 to 12.4%) for uveitis following JIA. In this regard, the prevalence rate of uveitis related to Behçets disease and Systemic Lupus Erythematosus (SLE( was estimated to be 15.0 and 0.8%, respectively. The pooled response rate to Adalimumab and Infliximab was estimated to be 68.0% (95%CI: 65.4 to 70.6%), 64.7% (95%CI: 59.8 to 69.3%), respectively. The documents for the systematical assessment of other biological medications (e.g. Tocilizumab, Daclizumab and Rituximab) were inadequate; however, the mean response rate for these drugs was 59, 75 and 80%, respectively. Our meta-analysis showed a pooled response rate of 40.0% (95%CI, 36.0% to 44.2) to Methotrexate. Significant heterogeneity and significant diffusion bias were demonstrated by reviewing studies.
CONCLUSIONS
The pooled prevalence of uveitis in pediatric rheumatic diseases widely varied based on the underlying disease requiring more investigations in different subtypes of rheumatic diseases. The biologic medications, especially Adalimumab are the most effective treatments for uveitis in pediatric rheumatic diseases; however, a combination of the safe, available alternatives is preferred to achieve the most desirable treatment response.
Topics: Adalimumab; Antirheumatic Agents; Arthritis, Juvenile; Child; Humans; Methotrexate; Uveitis
PubMed: 32019589
DOI: 10.1186/s13023-020-1324-x -
Rheumatology (Oxford, England) Apr 2016To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT).
METHODS
Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.
RESULTS
From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo.
CONCLUSION
Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Juvenile; Biological Products; Humans; Interleukin 1 Receptor Antagonist Protein; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins
PubMed: 26628580
DOI: 10.1093/rheumatology/kev382 -
European Journal of Paediatric Dentistry Sep 2020Asymptomatic TMJ arthritis in juvenile idiopathic arthritis (JIA) patients may cause damage and deformity of the joint. The clinical manifestation of early-stage TMJ...
AIM
Asymptomatic TMJ arthritis in juvenile idiopathic arthritis (JIA) patients may cause damage and deformity of the joint. The clinical manifestation of early-stage TMJ arthritis is not characteristic. Clinical findings commonly appear in a late stage of TMJ involvement, but they can also be masked by antirheumatic therapy. The absence of clinical symptoms, and the lack or insufficient clinical signs do not provide reliable information about the TMJ involvement. The aim of the study was to conduct a systematic review of the evidence for clinical symptoms and signs of early-stage TMJ arthritis, as well as for correlation between clinical parameters and TMJ abnormalities imaging in JIA patients.
METHODS
Study design: A systematic review of papers published from 1998 to 2019 regarding early clinical and imaging findings of TMJ arthritis in JIA patients.
RESULTS
The search resulted in 292 studies. Eleven publications were included in the review.
CONCLUSION
Clinical signs and symptoms do not allow to detect the early stage of TMJ arthritis in JIA patients. To monitor individual orofacial development, periodic TMJ clinical examination should be a part of an evaluation of JIA children's growth. There is a need to develop clinical management guidelines, as well as diagnosis standards of clinical and imaging TMJ examination for JIA children, considering their developmental age.
Topics: Arthritis, Juvenile; Child; Early Diagnosis; Humans; Magnetic Resonance Imaging; Temporomandibular Joint; Temporomandibular Joint Disorders
PubMed: 32893656
DOI: 10.23804/ejpd.2020.21.03.12