Methotrexate for juvenile idiopathic arthritis.

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. To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis. 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. 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. 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. 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/m2/week to 15 mg/m2/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; I2 = 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. Oral methotrexate (5 mg/m2/week to 15 mg/m2/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.

Tan J ，Renton WD ，Whittle SL ，Takken T ，Johnston RV ，Tiller G ，Munro J ，Buchbinder R ... -  《Cochrane Database of Systematic Reviews》

Infliximab for medical induction of remission in Crohn's disease.

Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α), which is present in high levels in the blood serum, mucosa and stool of people with Crohn's disease. To evaluate the benefits and harms of infliximab alone or in combination with another agent for induction of remission in Crohn's disease compared to placebo or active medical therapies. On 31 August 2021 and 4 March 2023, we searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and World Health Organization ICTRP. Randomised control trials (RCTs) comparing infliximab alone or in combination with another agent to placebo or another active comparator in adults with active Crohn's disease. Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were clinical remission, clinical response and withdrawals due to adverse events. Our secondary outcomes were endoscopic remission, histological remission, endoscopic response, and serious and total adverse events. The search identified 10 RCTs with 1101 participants. They were conducted between 1999 and 2019, and 7/10 RCTs included biologically naive participants. All but one RCT, which did not provide information, were multicentre and funded by pharmaceutical companies, and their authors declared conflicts. The age of the participants ranged from 26 to 65 years. Results were based on one study unless otherwise stated. Infliximab 5 mg/kg to 10 mg/kg may be more effective than placebo at week four for clinical remission (30/55 versus 3/25; RR 4.55, 95% CI 1.53 to 13.50; number needed to treat for an additional beneficial outcome (NNTB) 3) and response (36/55 versus 4/25; RR 4.09, 95% CI 1.63 to 10.25, NNTB 3). The evidence was low certainty. The study did not report withdrawals due to adverse events. We could not draw conclusions on the effects of infliximab 5 mg/kg to 10 mg/kg compared to placebo for fistulating participants for clinical remission (29/63 versus 4/31; RR 3.57, 95% CI 1.38 to 9.25; NNTB 4), response (48/106 versus 15/75; RR 1.94, 95% CI 1.10 to 3.41; NNTB 6; 2 studies) or withdrawals due to adverse events (2/63 versus 0/31; RR 2.50, 95% CI 0.12 to 50.54). The evidence was very low certainty. Infliximab used in combination with purine analogues is probably more effective than purine analogues alone for clinical remission at weeks 24 to 26 (182/301 versus 95/302; RR 1.92, 95% CI 1.59 to 2.32, NNTB 4; 4 studies; moderate-certainty evidence) and clinical response at week 26 (107/177 versus 66/178; RR 1.64, 95% CI 1.31 to 2.05; NNTB 5; 2 studies; moderate-certainty evidence). There may be little or no difference in withdrawals due to adverse events at week 26 (62/302 versus 53/301; RR 0.87, 95% CI 0.63 to 1.21; 4 studies; low-certainty evidence). Infliximab alone may be more effective than purine analogues alone at week 26 for clinical remission (85/177 versus 57/178; RR 1.50, 95% CI 1.15 to 1.95; NNTB 7; 2 studies) and response (94/177 versus 66/178; RR 1.44, 95% CI 1.13 to 1.82; NNTB 7; 2 studies). There may be little or no difference in withdrawals due to adverse events (30/177 versus 43/178; RR 0.70, 95% CI 0.46 to 1.06; 4 studies). The evidence was low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) and response (22/27 versus 24/28; RR 1.63, 95% CI 1.08 to 2.46). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg in an exclusively fistulating population for clinical remission (17/31 versus 12/32; RR 1.46, 95% CI 0.84 to 2.53), response (21/31 versus 18/32; RR 1.20, 95% CI 0.82 to 1.78), or withdrawals due to adverse events (1/31 versus 1/32; RR 1.03, 95% CI 0.07 to 15.79). The evidence was very low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 20 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) or response (22/27 versus 18/28; RR 1.27, 95% CI 0.91 to 1.76). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 10 mg/kg compared to 20 mg/kg for clinical remission (11/28 versus 11/28; RR 1.00, 95% CI 0.52 to 1.92) or response (14/28 versus 18/28; RR 0.78, 95% CI 0.49 to 1.23). The evidence was very low certainty. Withdrawals due to adverse events were not reported. There may be little or no difference between infliximab and a CT-P13 biosimilar at week six for clinical remission (47/109 versus 49/111; RR 0.98, 95% CI 0.72 to 1.32), response (67/109 versus 70/111; RR 0.97, 95% CI 0.79 to 1.20) and withdrawals due to adverse events (21/109 versus 17/111; RR 1.26, 95% CI 0.70 to 2.25). The evidence was low certainty. Infliximab in combination with purine analogues is probably more effective than purine analogues alone in inducing clinical remission and clinical response. Infliximab alone may be more effective in inducing clinical remission and response than purine analogues alone or placebo. Infliximab may be similar in efficacy to a CT-P13 biosimilar and there may be little or no difference in withdrawals due to adverse events. We were unable to draw meaningful conclusions as to whether infliximab alone is effective when used for exclusively fistulating populations. There was evidence that there may be little or no difference in withdrawal due to adverse events between infliximab plus purines compared with purines alone, as well as infliximab alone compared with purines alone. Meaningful conclusions cannot be drawn on all other outcomes related to adverse events due to very low certainty evidence.

Gordon M ，Sinopoulou V ，Akobeng AK ，Radford SJ ，Eldragini MEAA ，Darie AM ，Moran GW ... -  《Cochrane Database of Systematic Reviews》

Manual therapy and exercise for lateral elbow pain.

Manual therapy and prescribed exercises are often provided together or separately in contemporary clinical practice to treat people with lateral elbow pain. To assess the benefits and harms of manual therapy, prescribed exercises or both for adults with lateral elbow pain. We searched the databases CENTRAL, MEDLINE and Embase, and trial registries until 31 January 2024, unrestricted by language or date of publication. We included randomised or quasi-randomised trials. Participants were adults with lateral elbow pain. Interventions were manual therapy, prescribed exercises or both. Primary comparators were placebo or minimal or no intervention. We also included comparisons of manual therapy and prescribed exercises with either intervention alone, with or without glucocorticoid injection. Exclusions were trials testing a single application of an intervention or comparison of different types of manual therapy or prescribed exercises. Two review authors independently selected studies for inclusion, extracted trial characteristics and numerical data, and assessed study risk of bias and certainty of evidence using GRADE. The main comparisons were manual therapy, prescribed exercises or both compared with placebo treatment, and with minimal or no intervention. Major outcomes were pain, disability, heath-related quality of life, participant-reported treatment success, participant withdrawals, adverse events and serious adverse events. The primary endpoint was end of intervention for pain, disability, health-related quality of life and participant-reported treatment success and final time point for adverse events and withdrawals. Twenty-three trials (1612 participants) met our inclusion criteria (mean age ranged from 38 to 52 years, 47% female, 70% dominant arm affected). One trial (23 participants) compared manual therapy to placebo manual therapy, 12 trials (1124 participants) compared manual therapy, prescribed exercises or both to minimal or no intervention, six trials (228 participants) compared manual therapy and exercise to exercise alone, one trial (60 participants) compared the addition of manual therapy to prescribed exercises and glucocorticoid injection, and four trials (177 participants) assessed the addition of manual therapy, prescribed exercises or both to glucocorticoid injection. Twenty-one trials without placebo control were susceptible to performance and detection bias as participants were not blinded to the intervention. Other biases included selection (nine trials, 39%, including two quasi-randomised), attrition (eight trials, 35%) and selective reporting (15 trials, 65%) biases. We report the results of the main comparisons. Manual therapy versus placebo manual therapy Low-certainty evidence, based upon a single trial (23 participants) and downgraded due to indirectness and imprecision, indicates manual therapy may reduce pain and elbow disability at the end of two to three weeks of treatment. Mean pain at the end of treatment was 4.1 points with placebo (0 to 10 scale) and 2.0 points with manual therapy, MD -2.1 points (95% CI -4.2 to -0.1). Mean disability was 40 points with placebo (0 to 100 scale) and 15 points with manual therapy, MD -25 points (95% CI -43 to -7). There was no follow-up beyond the end of treatment to show if these effects were sustained, and no other major outcomes were reported. Manual therapy, prescribed exercises or both versus minimal intervention Low-certainty evidence indicates manual therapy, prescribed exercises or both may slightly reduce pain and disability at the end of treatment, but the effects were not sustained, and there may be little to no improvement in health-related quality of life or number of participants reporting treatment success. We downgraded the evidence due to increased risk of performance bias and detection bias across all the trials, and indirectness due to the multimodal nature of the interventions included in the trials. At four weeks to three months, mean pain was 5.10 points with minimal treatment and manual therapy, prescribed exercises or both reduced pain by a MD of -0.53 points (95% CI -0.92 to -0.14, I2 = 43%; 12 trials, 1023 participants). At four weeks to three months, mean disability was 63.8 points with minimal or no treatment and manual therapy, prescribed exercises or both reduced disability by a MD of -5.00 points (95% CI -9.22 to -0.77, I2 = 63%; 10 trials, 732 participants). At four weeks to three months, mean quality of life was 73.04 points with minimal treatment on a 0 to 100 scale and prescribed exercises reduced quality of life by a MD of -5.58 points (95% CI -10.29 to -0.99; 2 trials, 113 participants). Treatment success was reported by 42% of participants with minimal or no treatment and 57.1% of participants with manual therapy, prescribed exercises or both, RR 1.36 (95% CI 0.96 to 1.93, I2 = 73%; 6 trials, 770 participants). We are uncertain if manual therapy, prescribed exercises or both results in more withdrawals or adverse events. There were 83/566 participant withdrawals (147 per 1000) from the minimal or no intervention group, and 77/581 (126 per 1000) from the manual therapy, prescribed exercises or both groups, RR 0.86 (95% CI 0.66 to 1.12, I2 = 0%; 12 trials). Adverse events were mild and transient and included pain, bruising and gastrointestinal events, and no serious adverse events were reported. Adverse events were reported by 19/224 (85 per 1000) in the minimal treatment group and 70/233 (313 per 1000) in the manual therapy, prescribed exercises or both groups, RR 3.69 (95% CI 0.98 to 13.97, I2 = 72%; 6 trials). Low-certainty evidence from a single trial in people with lateral elbow pain indicates that, compared with placebo, manual therapy may provide a clinically worthwhile benefit in terms of pain and disability at the end of treatment, although the 95% confidence interval also includes both an important improvement and no improvement, and the longer-term outcomes are unknown. Low-certainty evidence from 12 trials indicates that manual therapy and exercise may slightly reduce pain and disability at the end of treatment, but this may not be clinically worthwhile and these benefits are not sustained. While pain after treatment was an adverse event from manual therapy, the number of events was too small to be certain.

Wallis JA ，Bourne AM ，Jessup RL ，Johnston RV ，Frydman A ，Cyril S ，Buchbinder R ... -  《Cochrane Database of Systematic Reviews》

Treatment for women with postpartum iron deficiency anaemia.

Postpartum iron deficiency anaemia is caused by antenatal iron deficiency or excessive blood loss at delivery and might affect up to 50% of labouring women in low- and middle-income countries. Effective and safe treatment during early motherhood is important for maternal well-being and newborn care. Treatment options include oral iron supplementation, intravenous iron, erythropoietin, and red blood cell transfusion. To assess the benefits and harms of the available treatment modalities for women with postpartum iron deficiency anaemia. These include intravenous iron, oral iron supplementation, red blood cell transfusion, and erythropoietin. A Cochrane Information Specialist searched for all published, unpublished, and ongoing trials, without language or publication status restrictions. We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, LILACS, WHO ICTRP, and ClinicalTrials.gov, together with reference checking, citation searching, and contact with study authors to identify eligible studies. We applied date limits to retrieve new records since the last search on 9 April 2015 until 11 April 2024. We included published, unpublished, and ongoing randomised controlled trials (RCTs) that compared treatments for postpartum iron deficiency anaemia with placebo, no treatment, or alternative treatments. Cluster-randomised trials were eligible for inclusion. We included RCTs regardless of blinding. Participants were women with postpartum haemoglobin ≤ 12 g/dL, treated within six weeks after childbirth. We excluded non-randomised, quasi-randomised, and cross-over trials. The critical outcomes of this review were maternal mortality and fatigue. The important outcomes included persistent anaemia symptoms, persistent postpartum anaemia, psychological well-being, infections, compliance with treatment, breastfeeding, length of hospital stay, serious adverse events, anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort/reaction, constipation, gastrointestinal pain, number of red blood cell transfusions, and haemoglobin levels. We assessed risk of bias in the included studies using the Cochrane RoB 1 tool. Two review authors independently performed study screening, risk of bias assessment, and data extraction. We contacted trial authors for supplementary data when necessary. We screened all trials for trustworthiness and scientific integrity using the Cochrane Trustworthiness Screening Tool. We conducted meta-analyses using a fixed-effect model whenever feasible to synthesise outcomes. In cases where data were not suitable for meta-analysis, we provided a narrative summary of important findings. We evaluated the overall certainty of the evidence using GRADE. We included 33 RCTs with a total of 4558 postpartum women. Most trials were at high risk of bias for several risk of bias domains. Most of the evidence was of low or very low certainty. Imprecision due to few events and risk of bias due to lack of blinding were the most important factors. Intravenous iron versus oral iron supplementation The evidence is very uncertain about the effect of intravenous iron on mortality (risk ratio (RR) 2.95, 95% confidence interval (CI) 0.12 to 71.96; P = 0.51; I² = not applicable; 3 RCTs; 1 event; 572 women; very low-certainty evidence). One woman died of cardiomyopathy, and another developed arrhythmia, both in the groups treated with intravenous iron. Intravenous iron probably results in a slight reduction in fatigue within 8 to 28 days (standardised mean difference -0.25, 95% CI -0.42 to -0.07; P = 0.006; I² = 47%; 2 RCTs; 515 women; moderate-certainty evidence). Breastfeeding was not reported. Oral iron probably increases the risk of constipation compared to intravenous iron (RR 0.12, 95% CI 0.06 to 0.21; P < 0.001; I² = 0%; 10 RCTs; 1798 women; moderate-certainty evidence). The evidence is very uncertain about the effect of intravenous iron on anaphylaxis or hypersensitivity (RR 2.77, 95% CI 0.31 to 24.86; P = 0.36; I² = 0%; 12 RCTs; 2195 women; very low-certainty evidence). Three women treated with intravenous iron experienced anaphylaxis or hypersensitivity. The trials that reported on haemoglobin at 8 to 28 days were too heterogeneous to pool. However, 5 of 6 RCTs favoured intravenous iron, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL (low-certainty evidence). Red blood cell transfusion versus intravenous iron No women died in the only trial that reported on mortality (1 RCT; 7 women; very low-certainty evidence). The evidence is very uncertain about the effect of red blood cell transfusion on fatigue at 8 to 28 days (mean difference (MD) 1.20, 95% CI -2.41 to 4.81; P = 0.51; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence) and breastfeeding more than six weeks postpartum (RR 0.43, 95% CI 0.12 to 1.57; P = 0.20; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence). Constipation and anaphylaxis were not reported. Red blood cell transfusion may result in little to no difference in haemoglobin within 8 to 28 days (MD -1.00, 95% CI -2.02 to 0.02; P = 0.05; I² = not applicable; 1 RCT; 12 women; low-certainty evidence). Intravenous iron and oral iron supplementation versus oral iron supplementation Mortality and breastfeeding were not reported. One trial reported a greater improvement in fatigue in the intravenous and oral iron group, but the effect size could not be calculated (1 RCT; 128 women; very low-certainty evidence). Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone (RR 0.21, 95% CI 0.07 to 0.69; P = 0.01; I² = not applicable; 1 RCT; 128 women; low-certainty evidence). There were no anaphylaxis or hypersensitivity events in the trials (2 RCTs; 168 women; very low-certainty evidence). Intravenous iron and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD 0.00, 95% CI -0.48 to 0.48; P = 1.00; I² = not applicable; 1 RCT; 60 women; low-certainty evidence). Red blood cell transfusion versus no transfusion Mortality, fatigue at day 8 to 28, constipation, anaphylaxis, and haemoglobin were not reported. Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum (RR 0.91, 95% CI 0.78 to 1.07; P = 0.24; I² = not applicable; 1 RCT; 297 women; low-certainty evidence). Oral iron supplementation versus placebo or no treatment Mortality, fatigue, breastfeeding, constipation, anaphylaxis, and haemoglobin were not reported. Two trials reported on gastrointestinal symptoms, but did not report results by study arm. Intravenous iron probably reduces fatigue slightly in the early postpartum weeks (8 to 28 days) compared to oral iron tablets, but probably results in little to no difference after four weeks. It is very uncertain if intravenous iron has an effect on mortality and anaphylaxis/hypersensitivity. Breastfeeding was not reported. Intravenous iron may increase haemoglobin slightly more than iron tablets, but the data were too heterogeneous to pool. However, changes in haemoglobin levels are a surrogate outcome, and treatment decisions should preferentially be based on patient-relevant outcomes. Iron tablets probably result in a large increase in constipation compared to intravenous iron. The effect of red blood cell transfusion compared to intravenous iron on mortality, fatigue, and breastfeeding is very uncertain. No studies reported on constipation or anaphylaxis/hypersensitivity. Red blood cell transfusion may result in little to no difference in haemoglobin at 8 to 28 days. The effect of intravenous iron and oral iron supplementation on mortality, fatigue, breastfeeding, and anaphylaxis/hypersensitivity is very uncertain or unreported. Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone, and in little to no difference in haemoglobin. The effect of red blood cell transfusion compared to non-transfusion on mortality, fatigue, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. Red blood cell transfusion may result in little to no difference in breastfeeding. The effect of oral iron supplementation on mortality, fatigue, breastfeeding, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. This Cochrane review had no dedicated funding. Protocol and previous versions are available: Protocol (2013) [DOI: 10.1002/14651858.CD010861] Original review (2004) [DOI: 10.1002/14651858.CD004222.pub2] Review update (2015) [DOI: 10.1002/14651858.CD010861.pub2].

Jensen MCH ，Holm C ，Jørgensen KJ ，Schroll JB ... -  《Cochrane Database of Systematic Reviews》

Exercise for osteoarthritis of the knee.

Knee osteoarthritis (OA) is a major public health issue causing chronic pain, impaired physical function, and reduced quality of life. As there is no cure, self-management of symptoms via exercise is recommended by all current international clinical guidelines. This review updates one published in 2015. We aimed to assess the effects of land-based exercise for people with knee osteoarthritis (OA) by comparing: 1) exercise versus attention control or placebo; 2) exercise versus no treatment, usual care, or limited education; 3) exercise added to another co-intervention versus the co-intervention alone. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and World Health Organisation International Clinical Trials Registry Platform), together with reference lists, from the date of the last search (1st May 2013) until 4 January 2024, unrestricted by language. We included randomised controlled trials (RCTs) that evaluated exercise for knee OA versus a comparator listed above. Our outcomes of interest were pain severity, physical function, quality of life, participant-reported treatment success, adverse events, and study withdrawals. We used the standard methodological procedures expected by Cochrane for systematic reviews of interventions. We included 139 trials (12,468 participants): 30 (3065 participants) compared exercise to attention control or placebo; 60 (4834 participants) compared exercise with usual care, no intervention or limited education; and 49 (4569 participants) evaluated exercise added to another intervention (e.g. weight loss diet, physical therapy, detailed education) versus that intervention alone. Interventions varied substantially in duration, ranging from 2 to 104 weeks. Most of the trials were at unclear or high risk of bias, in particular, performance bias (94% of trials), detection bias (94%), selective reporting bias (68%), selection bias (57%), and attrition bias (48%). Exercise versus attention control/placebo Compared with attention control/placebo, low-certainty evidence indicates exercise may result in a slight improvement in pain immediately post-intervention (mean 8.70 points better (on a scale of 0 to 100), 95% confidence interval (CI) 5.70 to 11.70; 28 studies, 2873 participants). Moderate-certainty evidence indicates exercise likely results in an improvement in physical function (mean 11.27 points better (on a scale of 0 to 100), 95% CI 7.64 to 15.09; 24 studies, 2536 participants), but little to no improvement in quality of life (mean 6.06 points better (on a scale of 0 to 100), 95% CI -0.13 to 12.26; 6 studies, 454 participants). There was moderate-certainty evidence that exercise likely increases participant-reported treatment success (risk ratio (RR) 1.46, 95% CI 1.11 to 1.92; 2 studies 364 participants), and likely does not increase study withdrawals (RR 1.08, 95% CI 0.92 to 1.26; 29 studies, 2907 participants). There was low-certainty evidence that exercise may not increase adverse events (RR 2.02, 95% CI 0.62 to 6.58; 11 studies, 1684 participants). Exercise versus no treatment/usual care/limited education Compared with no treatment/usual care/limited education, low-certainty evidence indicates exercise may result in an improvement in pain immediately post-intervention (mean 13.14 points better (on a scale of 0 to 100), 95% CI 10.36 to 15.91; 56 studies, 4184 participants). Moderate-certainty evidence indicates exercise likely results in an improvement in physical function (mean 12.53 points better (on a scale of 0 to 100), 95% CI 9.74 to 15.31; 54 studies, 4352 participants) and a slight improvement in quality of life (mean 5.37 points better (on a scale of to 100), 95% CI 3.19 to 7.54; 28 studies, 2328 participants). There was low-certainty evidence that exercise may result in no difference in participant-reported treatment success (RR 1.33, 95% CI 0.71 to 2.49; 3 studies, 405 participants). There was moderate-certainty evidence that exercise likely results in no difference in study withdrawals (RR 1.03, 95% CI 0.88 to 1.20; 53 studies, 4408 participants). There was low-certainty evidence that exercise may increase adverse events (RR 3.17, 95% CI 1.17 to 8.57; 18 studies, 1557 participants). Exercise added to another co-intervention versus the co-intervention alone Moderate-certainty evidence indicates that exercise when added to a co-intervention likely results in improvements in pain immediately post-intervention compared to the co-intervention alone (mean 10.43 points better (on a scale of 0 to 100), 95% CI 8.06 to 12.79; 47 studies, 4441 participants). It also likely results in a slight improvement in physical function (mean 9.66 points better, 95% CI 7.48 to 11.97 (on a 0 to 100 scale); 44 studies, 4381 participants) and quality of life (mean 4.22 points better (on a 0 to 100 scale), 95% CI 1.36 to 7.07; 12 studies, 1660 participants) immediately post-intervention. There was moderate-certainty evidence that exercise likely increases participant-reported treatment success (RR 1.63, 95% CI 1.18 to 2.24; 6 studies, 1139 participants), slightly reduces study withdrawals (RR 0.82, 95% CI 0.70 to 0.97; 41 studies, 3502 participants), and slightly increases adverse events (RR 1.72, 95% CI 1.07 to 2.76; 19 studies, 2187 participants). Subgroup analysis and meta-regression We did not find any differences in effects between different types of exercise, and we found no relationship between changes in pain or physical function and the total number of exercise sessions prescribed or the ratio (between exercise group and comparator) of real-time consultations with a healthcare provider. Clinical significance of the findings To determine whether the results found would make a clinically meaningful difference to someone with knee OA, we compared our results to established 'minimal important difference' (MID) scores for pain (12 points on a 0 to 100 scale), physical function (13 points), and quality of life (15 points). We found that the confidence intervals of mean differences either did not reach these thresholds or included both a clinically important and clinically unimportant improvement. We found low- to moderate-certainty evidence that exercise probably results in an improvement in pain, physical function, and quality of life in the short-term. However, based on the thresholds for minimal important differences that we used, these benefits were of uncertain clinical importance. Participants in most trials were not blinded and were therefore aware of their treatment, and this may have contributed to reported improvements.

Lawford BJ ，Hall M ，Hinman RS ，Van der Esch M ，Harmer AR ，Spiers L ，Kimp A ，Dell'Isola A ，Bennell KL ... -  《Cochrane Database of Systematic Reviews》