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RMD Open Dec 2023To identify the best evidence on the efficacy of pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases... (Meta-Analysis)
Meta-Analysis
Efficacy of pharmacological interventions: a systematic review informing the 2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.
OBJECTIVE
To identify the best evidence on the efficacy of pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and to summarise their safety in the identified studies to inform European Alliance of Associations for Rheumatology recommendations for the management of fatigue in people with I-RMDs.
METHODS
Systematic review of adults with I-RMDs conducted according to the Cochrane Handbook. Search strategy ran in Medline, Embase, Cochrane Library, CINAHL Complete, PEDro, OTseeker and PsycINFO. Only randomised controlled trials (RCTs) or controlled clinical trials were eligible. Assessment of risk of bias, data extraction and synthesis performed by two reviewers independently and in duplicate. Data pooled in statistical meta-analyses.
RESULTS
From 4151 records, 455 were selected for full-text review, 99 fulfilled the inclusion criteria and 19 RCTs were included in meta-analyses. Adalimumab was superior to placebo in reducing fatigue at 12 and 52 weeks in rheumatoid arthritis (RA) (n=3 and 2 RCTs; mean difference (MD)= -3.03, p<0.001; MD=-2.25, p=0.03, respectively). Golimumab (n=2 RCTs; 24 weeks: MD=-5.27, p<0.001), baricitinib (n=2 RCTs; 24 weeks: MD=-4.06, p<0.001), sarilumab (n=2 RCTs; 24 weeks: MD=-3.15, p<0.001), tocilizumab (n=3 RCTs; 24 weeks: MD=-3.69, p<0.001) and tofacitinib (n=3 RCTs; 12 weeks: MD=-4.44, p<0.001) were also superior to placebo in reducing fatigue in RA. A dose/effect relationship was observed for sarilumab, tocilizumab and tofacitinib. In spondyloarthritis (excluding psoriatic arthritis), secukinumab was superior to placebo in reducing fatigue at 16 weeks (n=2 RCTs; MD=-4.15, p<0.001), with a dose/effect relationship also observed. The narrative results of the RCTs not included in the meta-analysis indicated that several other pharmacological interventions were efficacious in reducing fatigue, with reassuring safety results.
CONCLUSIONS
Several pharmacological interventions are efficacious and generally safe for managing fatigue in people with I-RMDs.
Topics: Adult; Humans; Adalimumab; Arthritis, Rheumatoid; Fatigue
PubMed: 38056919
DOI: 10.1136/rmdopen-2023-003349 -
Clinical and Experimental Medicine Nov 2023Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for... (Meta-Analysis)
Meta-Analysis
Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases globally, leading to chronic disability and poor prognosis. One of the approaches for optimizing OA treatment is to find early effective diagnostic biomarkers. The contribution of microRNAs (miRNAs) in OA progression is now being increasingly recognized. This review provides a comprehensive summary on studies reporting the expression profiling of miRNAs in OA and associated signaling pathways. We performed a systematic search of the Embase, Web of Science, PubMed, and Cochrane library databases. This systematic review is reported according to the PRISMA checklist. Studies which identified miRNAs with aberrant expression compared to controls during OA progression were included, and a meta-analysis was performed. Results from the random effects model were provided as log10 odds ratios (logORs) and 95% confidence intervals. Sensitivity analysis was conducted to confirm the accuracy of the results. Subgroup analysis was conducted based on tissue source. The target genes of miRNAs identified in this study were extracted from the MiRWalk database, and these target genes were enriched in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. A total of 191 studies reporting 162 miRNAs were included in our meta-analysis. Among them, 36 miRNAs distributed across 96 studies were expressed in the same direction in at least two studies (13 up-regulated and 23 down-regulated). Subgroup analysis of tissue source revealed that the highest number of studies was conducted using articular cartilage, where the most up-regulated miRNAs were miR-146a-5p (logOR 7.355; P < 0.001) and miR-34a-5p (logOR 6.955; P < 0.001), and the most down-regulated miRNAs were miR-127-5p (logOR 6.586; P < 0.001) and miR-140-5p (logOR 6.373; P < 0.001). Enrichment analysis of 752 downstream target genes of all identified miRNAs was performed, and the regulatory relationships among them were displayed. Mesenchymal stem cells and transforming growth factor-β were found to be the most important downstream effectors regulated by miRNA in OA. This study highlighted the importance of miRNA signaling in OA progression and identified a number of prominent miRNAs including miR-146a-5p, miR-34a-5p, miR-127-5p, and miR-140-5p which might be considered as potential biomarkers for OA.
Topics: Humans; MicroRNAs; Osteoarthritis; Biomarkers
PubMed: 37027064
DOI: 10.1007/s10238-023-01063-8 -
Clinical Nutrition ESPEN Feb 2024Coenzyme Q10 (CoQ10) is a potent antioxidant and anti-inflammatory substance used to treat some rheumatic diseases. Our objective was to review the use of CoQ10 in... (Review)
Review
Coenzyme Q10 (CoQ10) is a potent antioxidant and anti-inflammatory substance used to treat some rheumatic diseases. Our objective was to review the use of CoQ10 in rheumatic diseases. PubMed/Medline, Embase, Scopus, and Web of Science databases were searched for articles on CoQ10 and rheumatic diseases between 1966 and April 2023. Twenty articles were found, including 483 patients. The investigated conditions were Fibromyalgia (FM) with 15 studies, Rheumatoid Arthritis (RA) with 3 studies, and Antiphospholipid Syndrome (APS) with 2 studies. After CoQ10 supplementation, RA patients observed improvements in disease activity index, inflammatory biomarkers (erythrocyte sedimentation rate), cytokine levels, and a decrease in malondialdehyde. In APS, CoQ10 improved endothelial function and decreased prothrombotic and proinflammatory mediators. Regarding FM, in most of the studies, the patients observed improvements in pain, fatigue, sleep, tender points count, mood disorders, and scores on the Fibromyalgia Impact Questionnaire (FIQ). The drug was well tolerated, with reports of minor side effects in two studies. CoQ10 supplementation seems to be efficacious as a complementary treatment for RA and FM. Upcoming studies with larger samples and including other rheumatic diseases are welcome.
Topics: Humans; Fibromyalgia; Ubiquinone; Antioxidants; Arthritis, Rheumatoid; Dietary Supplements
PubMed: 38220408
DOI: 10.1016/j.clnesp.2023.11.016 -
Clinical Therapeutics Sep 2023Psoriatic arthritis (PsA) is a multisystem inflammatory disorder associated with significant mortality and morbidity, including functional impairment and psychological... (Review)
Review
PURPOSE
Psoriatic arthritis (PsA) is a multisystem inflammatory disorder associated with significant mortality and morbidity, including functional impairment and psychological disability. Although evidence-based treatment recommendations are available for the use of drug treatments in PsA, there is little guidance for health professionals on nonpharmacologic and psychological interventions that may be useful in PsA. The objective of this systematic review (SR) was to identify how lifestyle modifications and the use of nonpharmacologic and psychological interventions may improve the outcomes of patients with PsA.
METHODS
Studies were included if they evaluated adults diagnosed with PsA and included exposure to nonpharmacologic interventions, psychological interventions, and lifestyle modifications. The outcomes used needed to have been validated in PsA. A systematic literature search was run on May 28, 2021, in the Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), EMBASE, Global Health, MEDLINE, and PsycINFO databases to identify articles related to lifestyle modifications and nonpharmacologic or psychological interventions for adults with PsA published between 2010 and 2021. Two review authors independently screened and selected full-text studies for inclusion in the SR. Risk of bias was assessed with either the Risk of Bias 2 (ie, RoB 2) tool or Critical Appraisal Skills Program checklist depending on the study type.
FINDINGS
The search strategy identified 26,132 references. Eight studies examining lifestyle modifications and the effect on PsA were eligible to be included in the SR. Three of the 8 studies were randomized controlled trials, and 5 were nonrandomized studies. Three studies assessed physical activity, 3 assessed diet, 1 study assessed smoking, and another study assessed mud bath therapy. There was large heterogeneity between studies, and the measures of disease activity, and psychological and functional outcomes varied widely between studies.
IMPLICATIONS
Although this SR identified 8 relevant studies, these studies did not provide high-quality evidence to guide patients for non-drug treatments of PsA. The effectiveness of these interventions has therefore not been established. We found that physical activity seems to have a positive impact on disease activity and psychological well-being. Further well-designed research studies are needed to develop treatment recommendations. PROSPERO identifier: CRD42021257404.
Topics: Adult; Humans; Arthritis, Psoriatic; Behavior Therapy; Life Style
PubMed: 37541907
DOI: 10.1016/j.clinthera.2023.05.009 -
Annals of Physical and Rehabilitation... Feb 2024Internet-based telerehabilitation could be a valuable option for the treatment of musculoskeletal disorders, with the advantage of providing rehabilitation from... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Internet-based telerehabilitation could be a valuable option for the treatment of musculoskeletal disorders, with the advantage of providing rehabilitation from anywhere. However, there is no solid and updated evidence demonstrating its effectiveness on relevant clinical and cost outcomes.
OBJECTIVE
This systematic review aims to determine the clinical and cost-effectiveness of internet-based telerehabilitation during the recovery of musculoskeletal disorders.
METHODS
Medline, Web of Science, Scopus and Cochrane databases were systematically searched from inception to June 2023. Trials investigating the effects of internet-based telerehabilitation in any musculoskeletal disorder were selected. Nonoriginal articles and grey literature were excluded. Two independent reviewers conducted the study selection and data extraction. Random effect meta-analyses (standardized mean difference) and further sensitivity analyses were performed.
RESULTS
We selected 37 clinical trials (33 randomized and 4 non-randomized) and 5 health economics studies, which included a total of 4,288 participants. Telerehabilitation was more favourable than control treatments in improving all studied clinical outcomes, although the effectiveness varied depending on the type of musculoskeletal disorder. The standard mean differences (SMD) ranged from 0.24 to 0.91. For physical function, the primary outcome, superior effectiveness was found only in people with hip fractures (SMD, 0.87; 95 % CI, 0.34 to 1.41). The effects for joint replacement, osteoarthritis, and spine pain were similar to those of control treatments. However, the favourable outcomes for telerehabilitation became insignificant when compared specifically to face-to-face rehabilitation. Some results displayed publication bias and a lack of robustness, necessitating cautious interpretation. In terms of health economics studies, telerehabilitation was 89.55$ (95 % CI 4.6 to 174.5) cheaper per individual than conventional treatments.
CONCLUSIONS
Telerehabilitation should be considered in the recovery process of musculoskeletal disorders when optimal face-to-face rehabilitation is not feasible. Moreover, telerehabilitation reduces costs and time.
PROSPERO NUMBER
CRD42022322425.
Topics: Humans; Telerehabilitation; Cost-Benefit Analysis; Osteoarthritis; Musculoskeletal Pain
PubMed: 38128150
DOI: 10.1016/j.rehab.2023.101791 -
Journal of Orthopaedic Surgery and... Jul 2023The objective of the study was to evaluate the effectiveness of home-based exercise interventions on pain, physical function and quality of life in individuals with knee... (Meta-Analysis)
Meta-Analysis
Effectiveness of home-based exercise interventions on pain, physical function and quality of life in individuals with knee osteoarthritis: a systematic review and meta-analysis.
OBJECTIVE
The objective of the study was to evaluate the effectiveness of home-based exercise interventions on pain, physical function and quality of life in individuals with knee osteoarthritis (KOA).
METHODS
Five databases (PubMed, Embase, Cochrane Library, CINAHL, Web of Science Core Collection) were searched for relevant randomized controlled trials (RCTs) published from database inception to 2 August 2022. The Cochrane Collaboration's standards were followed for study selection, eligibility criteria, data extraction and statistics, using the Cochrane Collaboration Risk of Bias Tool and PEDro for quality assessment. A meta-analysis and subgroup analyses, stratified by control condition and intervention duration, were conducted using RevMan 5.4. The study was reported in compliance with the PRISMA statement.
RESULTS
A total of 12 independent RCTs with 1442 participants were included. The meta-analysis showed that the home-based exercise interventions significantly reduced pain in individuals with KOA (SMD = - 0.32, 95% CI [- 0.41, - 0.22], p < .01) and improved physical function (SMD = - 0.25, 95% CI [- 0.47, - 0.02], p = .03) and quality of life (SMD = 0.63, 95% CI [0.41, 0.85], p < .001). Subgroup analysis revealed that home-based exercise interventions were superior to health education and no treatment, in terms of pain and physical function, and similar to clinic-based exercise and pharmacologic treatment.
CONCLUSIONS
The effect of home-based exercise intervention is significantly better than health education and no treatment for reducing knee pain and improving physical function, and was able to achieve the effects of clinic-based exercise treatment and pharmacologic treatment. With regard to quality of life, the unsupervised home strength exercise intervention showed a significant effect compared with the health education control and combined with cognitive behavioural therapies may produce better results. Although home-based intervention provides effective treatment options for individuals with clinical treatment limitations, individual disease complications and the dosimetry of exercise need to be considered in practice. Furthermore, growing evidence supports the effectiveness of Tai Chi in the rehabilitation of KOA.
Topics: Humans; Exercise Therapy; Osteoarthritis, Knee; Quality of Life; Exercise; Pain
PubMed: 37461112
DOI: 10.1186/s13018-023-04004-z -
Arthritis Research & Therapy Nov 2023To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor...
Prevalence and predictors of sustained remission/low disease activity after discontinuation of induction or maintenance treatment with tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic and scoping review.
BACKGROUND
To determine the prevalence of sustained remission/low disease activity (LDA) in patients with rheumatoid arthritis (RA) after discontinuation of tumor necrosis factor inhibitors (TNFi), separately in induction treatment and maintenance treatment studies, and to identify predictors of successful discontinuation.
METHODS
We performed a systematic literature review of studies published from 2005 to May 2022 that reported outcomes after TNFi discontinuation among patients in remission/LDA. We computed prevalences of successful discontinuation by induction or maintenance treatment, remission criterion, and follow-up time. We performed a scoping review of predictors of successful discontinuation.
RESULTS
Twenty-two induction-withdrawal studies were identified. In pooled analyses, 58% (95% confidence interval (CI) 45, 70) had DAS28 < 3.2 (9 studies), 52% (95% CI 35, 69) had DAS28 < 2.6 (9 studies), and 40% (95% CI 18, 64) had SDAI ≤ 3.3 (4 studies) at 37-52 weeks after discontinuation. Among patients who continued TNFi, 62 to 85% maintained remission. Twenty-two studies of maintenance treatment discontinuation were also identified. At 37-52 weeks after TNFi discontinuation, 48% (95% CI 38, 59) had DAS28 < 3.2 (10 studies), and 47% (95% CI 33, 62) had DAS28 < 2.6 (6 studies). Heterogeneity among studies was high. Data on predictors in induction-withdrawal studies were limited. In both treatment scenarios, longer duration of RA was most consistently associated with less successful discontinuation.
CONCLUSIONS
Approximately one-half of patients with RA remain in remission/LDA for up to 1 year after TNFi discontinuation, with slightly higher proportions in induction-withdrawal settings than with maintenance treatment discontinuation.
Topics: Humans; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Prevalence; Tumor Necrosis Factor-alpha; Remission Induction; Arthritis, Rheumatoid; Treatment Outcome
PubMed: 37986101
DOI: 10.1186/s13075-023-03199-0 -
Journal of Orthopaedic Surgery and... Dec 2023To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis (KOA) individuals.
DATA SOURCES
PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, Technology Periodical Database and China Biology Medicine were searched from their inceptions to April 5, 2023.
REVIEW METHODS
We analyzed trials of acupuncture combined with active exercise training for KOA. The included studies were of high quality (Jadad ≥ 4) and RCTs. Study selection, data extraction, risk of bias and quality assessment were independently performed by two reviewers. We performed systematic analyses based on different outcome measures, including total efficiency rate, visual analogue scale (VAS), the Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC), the Lysholm Knee Scale (LKS) and range of motion (ROM). We used Review Manager 5.3 and Stata/MP 14.0 to analyze the data. And it was verified by trial sequence analysis (TSA). If I > 50% and p < 0.05, we performed sensitivity analysis and subgroup analysis to find the source of heterogeneity. Publication bias was studied by funnel plot and Egger's test was used to verify it.
RESULTS
Full 11 high-quality studies (Jadad ≥ 4) including 774 KOA individuals were included in this review for meta-analysis. The results showed that acupuncture combined with active exercise training (combined group) was superior to the acupuncture group in improving the total effective rate [RR = 1.13, 95%CI (1.05, 1.22), I = 0%, P = 0.70], reducing the pain level (VAS) [MD = - 0.74, 95%CI (- 1.04, - 0.43), I = 68%, P < 0.05], improving knee joint function (WOMAC) [MD = - 6.97, 95%CI (- 10.74, - 3.19), I = 76%, P < 0.05] and improving joint range of motion (ROM) [MD = 6.25, 95%CI (2.37, 10.04), I = 0%, P = 0.71]. Similarly, the combined group showed significant improvements in the total effective rate [RR = 1.31, 95% CI (1.18, 1.47), I = 48%, P = 0.10], pain (VAS) [MD = 1.42, 95% CI (- 1.85, - 1.00), I = 65%, P = 0.02] and knee function (WOMAC) [MD = 7.05, 95% CI (- 11.43, - 2.66), I = 86%, P < 0.05] compared with the non-acupuncture group.
CONCLUSION
The combined effect of all studies showed significant benefits of acupuncture combined with active exercise training in improving the total effective rate, reducing pain, promoting recovery of knee function and expanding range of motion. However, some evaluation indicators are highly subjective and need to be further confirmed by more objective and evidence-based high-quality RCTs in future.
SYSTEMATIC REVIEW REGISTRATION
[PROSPERO], identifier [No. CRD42023425823].
Topics: Humans; Osteoarthritis, Knee; Pain; Acupuncture Therapy; Knee Joint; Exercise
PubMed: 38042802
DOI: 10.1186/s13018-023-04403-2 -
The Journal of Rheumatology May 2024To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD).
METHODS
Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series.
RESULTS
Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, 36%), 73% (95% CI 58-84%, 66%), and 77% (95% CI 29-97%, 82%) and CS discontinuation was 57% (95% CI 29-81%, 66%), 47% (95% CI 18-78%, 79%), and 34% (95% CI 6-81%, 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation ( = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy.
CONCLUSION
Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.
Topics: Adult; Humans; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Biological Products; Interleukin 1 Receptor Antagonist Protein; Remission Induction; Still's Disease, Adult-Onset; Treatment Outcome
PubMed: 38302170
DOI: 10.3899/jrheum.2023-0995 -
Frontiers in Immunology 2023With the continuous development of clinical medicine, an increasing number of non-pharmacological interventions have been applied for the treatment of knee... (Meta-Analysis)
Meta-Analysis
Effects of externally-applied, non-pharmacological Interventions on short- and long-term symptoms and inflammatory cytokine levels in patients with knee osteoarthritis: a systematic review and network meta-analysis.
BACKGROUND
With the continuous development of clinical medicine, an increasing number of non-pharmacological interventions have been applied for the treatment of knee osteoarthritis (KOA), with the results of several recent randomized controlled trials (RCTs) showing that a variety of externally-applied, non-pharmacological interventions (EANPI) can improve symptoms and inflammation in patients with KOA. However, the relative benefits and disadvantages of non-drug therapies remain uncertain, and an optimal treatment strategy has not yet been determined.
OBJECTIVE
This study applied network meta-analysis (NMA) to compare and rank the effectiveness of EANPI on the short- and long-term clinical symptoms and inflammatory cytokine levels in patients with KOA.
METHODS
Two independent researchers searched online databases and performed manual retrieval of related citations to identify RCTs that met the selection criteria for the network meta-analysis. These researchers retrieved studies indexed from database inception to August 2023 and performed data extraction and assessment of the risk of bias.
RESULTS
The analysis included 80 RCTs involving 8440 participants and nine externally-applied, non-pharmacological therapies, namely extracorporeal shock wave, radiofrequency, acupotomy, laser therapy, Tuina therapy, kinesio taping, electroacupuncture, platelet-rich plasma injection, and ozone therapy. The treatment courses ranged from 1 to 12 weeks, with follow-up periods ranging from 4 to 24 weeks. The results of the NMA indicated that each non-drug therapy was superior to sham intervention in improving all outcome indicators. Except for the visual analog scale (VAS) and Western Ontario MacMaster (WOMAC) pain outcomes, all non-drug therapies had better efficacy than pharmacological treatments. For short-term VAS and tumor necrosis factor-alpha (TNF-α), extracorporeal shock wave performed better than other therapies (90.2% and 85.2% respectively). Radiofrequency therapy may be the most promising method to reduce long-term VAS, short- and long-term WOMAC pain, and interleukin (IL)-1β level (84.8%, 97.8%, 90.1%, 94.8% respectively). Tuina therapy may be a significant choice for short- and long-term outcomes of WOMAC function and range of motion (ROM).
CONCLUSIONS
The results of the comprehensive comparison of the outcome indicators in 9 different EANPI indicated that radiofrequency and Tuina therapy were more effective and consistently ranked high in improving clinical symptoms in the short and long term. Radiofrequency is effective at relieving pain, and Tuina therapy can be given priority for treatment when hypofunction is the main symptom. EANPI to improve pain symptoms may be related to the regulation of inflammatory cytokine levels, which may be a potential mechanism of action.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42023464177.
Topics: Humans; Osteoarthritis, Knee; Cytokines; Network Meta-Analysis; Pain; Acupuncture Therapy
PubMed: 38155966
DOI: 10.3389/fimmu.2023.1309751