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PharmacoEconomics Sep 2020The objectives of this systematic review were to identify health state utility values (HSUV) of children and adults with juvenile idiopathic arthritis in the literature... (Review)
Review
OBJECTIVES
The objectives of this systematic review were to identify health state utility values (HSUV) of children and adults with juvenile idiopathic arthritis in the literature and to assess whether HSUV were appropriately reported and could be used to inform parameter inputs for a model-based cost-utility analysis to inform decision making.
METHODS
MEDLINE, EMBASE, PsycINFO, EconLit and CINAHL databases were searched in July 2019. Inclusion criteria were studies using preference-based instruments, targeting children or adults with juvenile idiopathic arthritis, and in the English language. The quality of studies was assessed using a modified checklist that included relevant sources of bias and assessment of quality of HSUV valuation and measurement. A descriptive analysis was conducted, including assessment on reporting of population characteristics and stratification of HSUV by potential health states or population subgroup.
RESULTS
From 620 identified articles, ten reported HSUV. Seven studies reported HSUV of children with juvenile idiopathic arthritis, and three of adults with a history of juvenile idiopathic arthritis. Population disease activity status and drug treatment were reported in less than half of the studies. Six (out of ten) studies stratified HSUV results for at least one of the potential health state categories, but they represent very specific situations or interventions (e.g. patients receiving different types of physiotherapy or treated with etanercept over time).
CONCLUSIONS
We have identified critical gaps in the literature reporting HSUV in patients with juvenile idiopathic arthritis including a lack of HSUV measures for distinct health states, particularly in adults with a history of juvenile idiopathic arthritis. The current reported HSUV data in juvenile idiopathic arthritis are insufficient for a full cost-utility analysis with a short or lifetime horizon.
Topics: Arthritis, Juvenile; Child; Cost-Benefit Analysis; Etanercept; Humans; Research Design
PubMed: 32390065
DOI: 10.1007/s40273-020-00921-7 -
BMC Pediatrics Jan 2023The association between diet, symptoms and health related quality of life in children and young people with Juvenile idiopathic arthritis (JIA) is not clearly... (Meta-Analysis)
Meta-Analysis
An investigation into the relationship between nutritional status, dietary intake, symptoms and health-related quality of life in children and young people with juvenile idiopathic arthritis: a systematic review and meta-analysis.
BACKGROUND
The association between diet, symptoms and health related quality of life in children and young people with Juvenile idiopathic arthritis (JIA) is not clearly understood. The objectives of this systematic review and meta-analysis were to explore the evidence for a relationship between nutritional status, dietary intake, arthritis symptoms, disease activity and health-related quality of life in children and young people with JIA considering both observational and interventional studies separately.
METHOD
The databases PubMed, CINAHL, PsycINFO, Web of Science and Cochrane were searched in October 2019, updated in September 2020 and October 2021. Searches were restricted to English language, human and age (2-18 years old). Studies were included if they measured the effect of dietary supplements, vitamins or minerals, or diet in general, on quality of life and/ or arthritis symptom management. Two researchers independently screened titles and abstracts. Full texts were sourced for relevant articles. PRISMA guidelines were used for extracting data. For variables (vitamin D and disease activity), a random-effects meta-analysis model was performed. Two authors using a standardized data extraction form, extracted data independently.
RESULTS
11,793 papers were identified through database searching, 26 studies met our inclusion criteria with 1621 participants. Overall studies quality were fair to good. Results from controlled trial and case control studies with total 146 JIA patients, found that Ɯ-3 PUFA improved the mean active joint count (p < 0.001), Juvenile Arthritis Disease Activity Score (JADAS-27) (p < 0.001) and immune system (≤ 0.05). Furthermore, n-3 and n-6 PUFAs have a negative correlation with CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) (p < 0.05). Improvement in JIA symptoms were observed in one case, one pilot and one exploratory study with overall 9 JIA patients after receiving Exclusive Enteral Nutrition (EEN) which contains protein and what is required for a complete nutrition, A clinical trial study found Kre-Celazine nutrition (composed of a proprietary alkali buffered, creatine monohydrate and fatty acids mixture) in 16 JIA patients improved symptoms of JIA. No association was found between vitamin D and disease activity from three studies. Height and weight values in relation to healthy controls varied across studies (p = 0.029).
CONCLUSIONS
We were only able to include small studies, of lower design hierarchy, mainly pilot studies. We found some evidence of lower height and weight across studies in JIA, but were unable to confirm an association between diet, symptoms and health-related quality of life in children and young people with JIA. Well-designed, carefully measured and controlled interventional studies of dietary patterns in combination with important contributing factors such as medication and lifestyle behaviours, including physical activity, are required to determine the impact of diet in improving symptoms and growth patterns in children and young people with JIA, with an aim to improve the quality of their life.
TRIAL REGISTRATION
PROSPERO [CRD42019145587].
Topics: Child; Humans; Adolescent; Child, Preschool; Arthritis, Juvenile; Nutritional Status; Quality of Life; Vitamins; Vitamin D; Eating; Observational Studies as Topic
PubMed: 36593466
DOI: 10.1186/s12887-022-03810-4 -
The Cochrane Database of Systematic... Feb 2024Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used... (Review)
Review
BACKGROUND
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA.
OBJECTIVES
To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis.
SEARCH METHODS
The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023.
SELECTION CRITERIA
We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS
We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m/week to 15 mg/m/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease.
AUTHORS' CONCLUSIONS
Oral methotrexate (5 mg/m/week to 15 mg/m/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.
Topics: Child; Female; Humans; Adolescent; Aged; Child, Preschool; Male; Methotrexate; Arthritis, Juvenile; Leflunomide; Australia; Antirheumatic Agents; Glucocorticoids; Pain
PubMed: 38334147
DOI: 10.1002/14651858.CD003129.pub2 -
Archives of Dermatological Research Oct 2023Atopic dermatitis (AD) is a highly pruritic, inflammatory skin disease with a strong immune component. Rheumatoid arthritis (RA) is a systemic autoimmune disease that... (Meta-Analysis)
Meta-Analysis Review
Atopic dermatitis (AD) is a highly pruritic, inflammatory skin disease with a strong immune component. Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes synovitis and destruction of small joints. Researchers have attempted to quantify an association between both diseases with mixed conclusions. This systematic review and meta-analysis will study the association between AD and RA. Additionally, we conducted a systematic review between AD and other arthritic conditions including osteoarthritis (OA), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Medline, Web of Science, Cochrane, and EMBASE databases were searched for relevant studies from inception to March 2021. Observational studies examining relationships between AD and arthritic conditions were selected. 2539 studies were screened; nine were found suitable for quantitative analysis, all of which examined AD and RA. All studies had low risk of bias as determined by the Newcastle-Ottawa Scale. Patients with RA did not have significantly increased odds of comorbid AD. These findings were consistent across multiple study designs. However, patients with AD had significantly increased odds of comorbid RA. There were not enough studies identified to perform quantitative analysis between AD and other arthritic conditions. Two studies, one on JIA and one PsA, found no association with AD. Two studies on AD and OA had conflicting results. The present study provides definitive evidence of increased odds of comorbid RA in AD patients. There were no such increased odds of comorbid AD in RA patients. No such association was found between AD and PsA, OA or JIA.
Topics: Humans; Dermatitis, Atopic; Arthritis, Psoriatic; Arthritis, Rheumatoid; Risk; Databases, Factual
PubMed: 37043009
DOI: 10.1007/s00403-023-02619-0 -
Rheumatology International May 2020Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile... (Review)
Review
Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile dermatomyositis (JDM). Indeed, MAS is not considered as a frequent complication of JDM, but its occurrence could be under-estimated. In order to address this issue, we performed a revision of the available medical literature, describing and assessing patients with both MAS and JDM. After retrieving 253 records initially, 11 papers were selected as appropriate for our research objective, which provided a total of 12 patients affected with both MAS and JDM. Our pooled case series suggested that MAS in JDM may not be very rare, even though no final conclusion about its incidence and mortality rate can be made. However, JDM-related MAS seems to be difficult to treat, since methylprednisolone pulse therapy alone was not sufficient in most cases. Moreover, MAS in JDM patients often occurred at the onset of the rheumatic disease, before the final diagnosis of JDM could be established. Finally, MAS criteria validated for systemic Juvenile Idiopathic Arthritis (sJIA) resulted to be a very useful guidance to diagnose MAS in JDM patients as well, but their reliability may not be absolute. Therefore, cohort and multicenter studies are needed to assess the incidence and improve the diagnostic criteria for MAS in JDM patients.
Topics: Adolescent; Child; Child, Preschool; Dermatomyositis; Female; Humans; Macrophage Activation Syndrome; Male
PubMed: 31529231
DOI: 10.1007/s00296-019-04442-1 -
Pediatric Health, Medicine and... 2022Children with juvenile arthritis (JA) experience pain, stiffness, fatigue, and decreased motion leading to difficulties with daily activities and low physical activity... (Review)
Review
INTRODUCTION
Children with juvenile arthritis (JA) experience pain, stiffness, fatigue, and decreased motion leading to difficulties with daily activities and low physical activity (PA). PA is critical to improve health and function and mitigate JA-associated symptoms. This study evaluated the evidence for PA interventions in children with JA.
MATERIALS AND METHODS
A systematic review of randomized controlled trials (RCTs) of PA interventions in children with JA was conducted. Ovid (Medline), Cochrane Library, EMBASE, and CINAHL databases were searched for papers published in English between 1/1/1946 and 9/1/2021. Studies which concurrently assessed medical interventions were excluded. Participant and intervention characteristics and outcomes were extracted. Study internal validity and intervention attributes were assessed.
RESULTS
A total of 555 studies were identified, with 13 studies from 10 countries included. Data from 672 children diagnosed with juvenile idiopathic arthritis (JIA) (range of mean ages, 8.7 to 16.1 years) were analyzed. Fifty-two percent of intervention arms incorporated strengthening exercise alone or combined with other exercise, with 61.9% performed 3x/week. About 43.5% of sessions lasted >45 to ≤60 minutes and 65.2% of programs were ≥12 to <28 weeks. PA interventions improved function and symptoms without adverse events. Intervention details were missing especially regarding PA intensity, reasons for dropouts, and adherence. Only two studies incorporated strategies to promote adherence.
DISCUSSION
RCTs of PA interventions in JA only include JIA. Available RCTs used mixed modes of interventions. Reporting of PA interventions lacks sufficient detail to discern the dose-response relationship. Strategies to motivate engagement in PA and to support families to promote PA are lacking, as are studies of long-term outcomes.
CONCLUSION
There are limited RCTs of PA interventions in JIA. Adherence was better with low intensity programs. PA interventions for JIA yield positive health benefits but better reporting of PA intervention details is needed to generate more high-quality evidence and inform clinical practice.
PROSPERO REGISTRATION
Maura Iversen, Johan von Heideken, Marie Andre. Physical Activity in Children with Rheumatic Diseases: a systematic review. PROSPERO 2021 CRD42021274634 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021274634.
PubMed: 35444485
DOI: 10.2147/PHMT.S282611 -
European Journal of Pediatrics Jul 2023Musculoskeletal ultrasound (MSUS) is an important measurement tool in pediatric rheumatology as it detects subclinical disease activity and enables clinicians to treat... (Review)
Review
Musculoskeletal ultrasound (MSUS) is an important measurement tool in pediatric rheumatology as it detects subclinical disease activity and enables clinicians to treat patients during "the window of opportunity". However, the role of MSUS in assessing remission in JIA patients is not well-defined. This systematic review aimed to provide the most up-to-date published literature regarding the added value of MSUS in JIA patients in remission. This systematic review followed the preferred reporting items for systematic reviews guidelines. Original articles from PubMed and Scopus, published until February 7th 2022, and tackling the role of MSUS in JIA patients in remission were included. Eight studies met the inclusion criteria. They were published between 2011 and 2019 and included 356 children with JIA. Remission criteria were unanimous and relied on the Wallace criteria. Subclinical synovitis and Power Doppler signal (PD) were found in up to 84% and 33% of patients in remission, respectively. In most of the studies, predictors of future flares were abnormal MSUS findings at baseline particularly the presence of PD signal and patients without medication. Conclusion: Published data indicate that JIA children in remission may have abnormal MSUS findings including PD signal. The application of a specific scoring system for the pediatric joint may be helpful in homogenizing outcomes in future trials. Further studies on this matter are needed to ascertain the specific implication for each subset for a better holistic approach. What is Known: • In these recent years, significant progress has been made on building the evidence base for MSUS in pediatric rheumatology, particularly in juvenile idiopathic arthritis (JIA). • In the frame of the OMERACT ultrasound pediatric subtask force, standardized musculoskeletal US examination for the pediatric population was established. What is New: • Published data indicate that JIA children in remission may have abnormal MSUS findings including PD signal. The role of MSUS in assessing remission in JIA is still not well-defined. • The application of a specific scoring system for the pediatric joint may be helpful in homogenizing outcomes and comparing results.
Topics: Humans; Child; Arthritis, Juvenile; Ultrasonography; Ultrasonography, Doppler; Synovitis; Forecasting
PubMed: 37117764
DOI: 10.1007/s00431-023-04956-8 -
Children (Basel, Switzerland) Aug 2022Juvenile idiopathic arthritis (JIA) is childhood's most frequent chronic rheumatic disease. JIA is a broad term that includes all arthritides starting before 16 years,... (Review)
Review
Juvenile idiopathic arthritis (JIA) is childhood's most frequent chronic rheumatic disease. JIA is a broad term that includes all arthritides starting before 16 years, lasting at least six weeks, and of unknown cause. The temporomandibular joint (TMJ) could be involved in JIA both at onset and during the disease course. The presence of TMJ synovitis might severely impair dentofacial maturation in pediatric patients. The ultrasound (US) application to detect early signs of TMJ synovitis in children with JIA has provided contradictory results. We sought to assess the current role of TMJ US in JIA through a systematic literature review. The systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). The literature search found 345 records. After duplicates removal, 253 records were screened, 20 full-text articles were reviewed to assess their eligibility, and 7 of them were included in the qualitative analysis. Joint effusion was the most recorded parameter, followed by bony condylar abnormalities. Compared to contrast enhancement MRI, the capability to detect signs of active synovitis of TMJ by US is low, especially at the early stages. Understanding how US may help diagnose and manage children with JIA is advisable for several reasons. MRI cannot be frequently repeated, may need sedation, and is expensive. The constant technical improvement of US will undoubtedly allow for better evaluation of what, in the past, was not clear or not even captured by sonography. So far, the role of US in the assessment of TMJ involvement in JIA is indubitably secondary to the MRI. Even so, we think that a baseline MRI of TMJ and the repetition of the sonography over time might both help the interpretation of US images and intercept significative changes.
PubMed: 36010144
DOI: 10.3390/children9081254 -
Sleep Feb 2022Juvenile idiopathic arthritis (JIA) is one of the most common pediatric rheumatic disease. However, sleep alteration associated with this autoimmune disease remain... (Meta-Analysis)
Meta-Analysis
STUDY OBJECTIVES
Juvenile idiopathic arthritis (JIA) is one of the most common pediatric rheumatic disease. However, sleep alteration associated with this autoimmune disease remain unclear. We aimed in this systematic review and meta-analysis to compare sleep duration, quality, and architecture in JIA subjects with those in their healthy peers.
METHODS
Systematic search performed in PubMed, EMBase, Cochrane, and PsycINFO databases included 19 studies in the qualitative synthesis of which 10 met the inclusion criteria for the meta-analysis.
RESULTS
Pooled results from subjective methods indicated pronounced sleep disturbances and complaints in youth with JIA compared with their healthy counterparts. This was further confirmed by increased difficulty maintaining sleep (wake after sleep onset [WASO]; standardized mean differences [SMD]: -0.69; CI: -1.29 to -0.09, p = .02) and a tendency to increased difficulty initiating sleep (sleep onset latency [SOL]; SMD: -0.29; CI: -0.60 to 0.03, p = .07). There were no remarkable differences in sleep duration or sleep architecture between JIA patients and healthy controls. High heterogeneity was found for several outcomes. This could be explained by the different methods used as well as associated sleep disorders, medication, and comorbidities.
CONCLUSIONS
Although included studies were methodologically diverse, the summarized results of our review and meta-analysis bring evidence that children with JIA present more fragmented sleep compared to healthy peers. Thereby, the implementation of strategies to manage and improve sleep in this population are needed and might have a beneficial effect on the symptoms and functions of JIA.
STATEMENT OF SIGNIFICANCE
We observed that youth with Juvenile idiopathic arthritis (JIA) present pronounced sleep disturbances compared to their healthy counterparts: Meta-analysis found more difficulty maintaining sleep and a tendency to increased sleep latency in youth with JIA. However, results show discrepancies due to the different materials and methods used. Larger sample and further disentanglement of sample composition, considering associated sleep disorders, medication and comorbidities should be addressed in future studies.
Topics: Adolescent; Arthritis, Juvenile; Case-Control Studies; Child; Humans; Polysomnography; Sleep; Sleep Wake Disorders
PubMed: 34525202
DOI: 10.1093/sleep/zsab233 -
Rheumatology (Oxford, England) Oct 2019The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation.
METHODS
PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed.
RESULTS
A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52).
CONCLUSION
The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.
Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Antibody Formation; Antirheumatic Agents; Arthritis, Juvenile; Biological Factors; Child; Clinical Trials as Topic; Humans; Infliximab; Interleukin 1 Receptor Antagonist Protein; Methotrexate; Observational Studies as Topic
PubMed: 30809664
DOI: 10.1093/rheumatology/kez030