Azathioprine for people with multiple sclerosis.
Multiple sclerosis (MS) is an immune-mediated, chronic, inflammatory demyelinating disease of the central nervous system, impacting around 2.8 million people worldwide. Characterised by recurrent relapses or progression, or both, it represents a substantial global health burden, affecting people, predominantly women, at a young age (the mean age of diagnosis is 32 years). Azathioprine is used to treat chronic inflammatory and autoimmune diseases, and it is used in clinical practice as an off-label intervention for MS, especially where access to on-label disease-modifying treatments (DMTs) for MS is limited. Given this, a review of azathioprine's benefits and harms would be timely and valuable to inform shared healthcare decisions.
To evaluate the benefits and harms of azathioprine (AZA) for relapsing and progressive multiple sclerosis (MS), compared to other disease-modifying treatments (DMTs), placebo or no treatment. Specifically, we will assess the following comparisons. AZA compared with other DMTs or placebo as first-choice treatment for relapsing forms of multiple sclerosis AZA compared with other DMTs or placebo for relapsing forms of MS when switching from another DMT AZA compared with other DMTs or placebo as first-choice treatment for progressive forms of MS AZA compared with other DMTs or placebo for progressive forms of MS when switching from another DMT SEARCH METHODS: We conducted an extensive search for relevant literature using standard Cochrane search methods. The most recent search date was 9 August 2023.
We included randomised controlled trials (RCTs) lasting 12 months or more that compared azathioprine versus DMTs, placebo or no intervention in adults with MS. We considered evidence from non-randomised studies of interventions (NRSIs) as these studies may provide additional evidence not available from RCTS. We excluded cluster-randomised trials, cross-over trials, interrupted time series, case reports and studies of within-group design with no control group.
We followed standard Cochrane methodology. There were three outcomes we considered to be critical: disability, relapse and serious adverse events (SAEs, as defined in the studies). We were also interested in other important outcomes: quality-of-life (QoL) impairment (mental score), short-term adverse events (gastrointestinal disorders), long-term adverse events (neoplasms) and mortality.
We included 14 studies: eight RCTs (1076 participants included in meta-analyses) and six NRSIs (1029 participants). These studies involved people with relapsing and progressive MS. Most studies included more women (57 to 83%) than men, with participants' average age at the onset of MS being between 29.4 and 33.4 years. Five RCTs and all six NRSIs were conducted in Europe (1793 participants); two RCTs were conducted in the USA (126 participants) and one in Iran (94 participants). The RCTs lasted two to three years, while NRSIs looked back up to 10 years. Four studies received some funding or support from commercial interests and five were funded by government or philanthropy; the other five provided no information about funding. There are three ongoing studies. Comparison groups included other DMTs (interferon beta and cyclosporine A), placebo or no treatment. Below, we report on azathioprine as a 'first choice' treatment compared to interferon beta for people with relapsing MS. None of the studies reported on any critical or important outcome for this comparison for progressive MS. No study was retrieved comparing azathioprine to placebo or other DMTs for either relapsing or progressive MS. Furthermore, the NRSIs did not provide information not already covered in the RCTs. Azathioprine as a first-choice treatment compared to other DMTs (specifically, interferon beta) for relapsing MS - The evidence is very uncertain about the effect of azathioprine on the number of people with disability progression over two years compared to interferon beta (risk ratio (RR) 0.19, 95% confidence interval (CI) 0.02 to 1.58; 1 RCT, 148 participants; very low certainty evidence). - Azathioprine may decrease the number of people with relapses over a one- to two-year follow-up compared to interferon beta (RR 0.61, 95% CI 0.43 to 0.86; 2 RCTs, 242 participants; low-certainty evidence). - Azathioprine may result in a possible increase in the number of people with SAEs over two years in comparison with interferon beta (RR 6.64, 95% CI 0.35 to 126.27; 1 RCT, 148 participants; low-certainty evidence). - The evidence is very uncertain about the effect of azathioprine on the number of people with the short-term adverse event of gastrointestinal disorders over two years compared to interferon beta (RR 5.30, 95% CI 0.15 to 185.57; 2 RCTs, 242 participants; very low certainty evidence). We found no evidence comparing azathioprine to other DMTs for QoL impairment (mental score), long-term adverse events (neoplasms) or mortality.
Azathioprine has been proposed as an alternative treatment for MS when access to approved, on-label DMTs is limited, especially in resource-limited settings. The limited evidence available suggests that azathioprine may result in a modest benefit in terms of relapse frequency, with a possible increase in SAEs, when compared to interferon beta-1b, for people with relapsing-remitting multiple sclerosis. The evidence for the effect on disability progression and short-term adverse events is very uncertain. Caution is required in interpreting the conclusions of this review since our certainty in the available evidence on the benefits and harms of azathioprine in multiple sclerosis is low to very low, implying that further evidence is likely to change our conclusions. An important limitation we noted in the available evidence is the lack of long-term comparison with other treatments and the failure of most studies to measure outcomes that are important to people with multiple sclerosis, such as quality of life and cognitive decline. This is especially the case in the evidence relevant to people with progressive forms of multiple sclerosis.
Ridley B
，Nonino F
，Baldin E
，Casetta I
，Iuliano G
，Filippini G
... -
《Cochrane Database of Systematic Reviews》
Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.
Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC).
To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor.
We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021).
We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)).
Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses.
We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty).
In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).
Bryant A
，Hiu S
，Kunonga PT
，Gajjar K
，Craig D
，Vale L
，Winter-Roach BA
，Elattar A
，Naik R
... -
《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》
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