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Annals of the Rheumatic Diseases Jan 2024Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several...
BACKGROUND
Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update.
METHODS
Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.
RESULTS
Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV.
CONCLUSIONS
In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Cyclophosphamide; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Remission Induction; Rituximab; Practice Guidelines as Topic
PubMed: 36927642
DOI: 10.1136/ard-2022-223764 -
The Lancet. Gastroenterology &... Dec 2021Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease.
METHODS
We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values.
FINDINGS
The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias.
INTERPRETATION
Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission.
FUNDING
None.
Topics: Adalimumab; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Benzene Derivatives; Biological Therapy; Carboxylic Acids; Case-Control Studies; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Interleukin-12 Subunit p40; Interleukin-23 Subunit p19; Male; Network Meta-Analysis; Placebos; Randomized Controlled Trials as Topic; Remission Induction; Safety; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Ustekinumab
PubMed: 34688373
DOI: 10.1016/S2468-1253(21)00312-5 -
World Journal of Gastroenterology Sep 2017Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive... (Review)
Review
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
Topics: Adult; Age Factors; Azathioprine; Child; Complementary Therapies; Drug Hypersensitivity; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 28970719
DOI: 10.3748/wjg.v23.i33.6030 -
Seminars in Arthritis and Rheumatism Feb 2021The neurological and psychiatric manifestations of systemic lupus erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical presentation and... (Review)
Review
BACKGROUND
The neurological and psychiatric manifestations of systemic lupus erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical presentation and significant morbidity and mortality.
OBJECTIVES
Our aim was to comprehensively assess and present the evidence for treatments used in the management of inflammatory NPSLE.
METHODS
Medline, Embase, CINHAL and Cochrane CENTRAL were searched from 1990 to end of March 2019 using key words that related to NPSLE and treatment. Included studies comprised clinical trials, observational studies or case series with ≥5 patients and sufficient data related to treatment and outcome in NPSLE patients.
RESULTS
There were 7222 studies identified in the search, of which 90 were included in the review. There was a notable paucity of clinical trials, with only two randomised controlled trials and one pilot study. Treatment categories included corticosteroids (14 studies), cyclophosphamide (18 studies), synthetic DMARDs (7 studies), biologic therapies (14 studies), therapeutic plasma exchange (6 studies), intravenous immunoglobulin (2 studies), autologous stem cell transplant (3 studies), other therapies (8 studies), combination therapies (6 studies), studies with grouped outcome data (5 studies) and observational studies with therapy-specific associations (7 studies). Corticosteroids are accepted as first line treatment in NPSLE and there is low-moderate evidence supporting their benefit. Moderate evidence, based on consistent data in numerous studies and some trial data, supports the use of cyclophosphamide in the treatment of NPSLE. Limited data support some synthetic DMARDs such as mycophenolate, azathioprine and intrathecal methotrexate. In refractory disease, low-moderate evidence supports rituximab therapy and limited evidence supports benefit following autologous stem cell transplant. Regarding adjuvant treatments, limited evidence favours addition of plasma exchange, intravenous immunoglobulin and hydroxychloroquine. There exists very limited data for other therapies.
CONCLUSION
There are multiple therapeutic options for the management of inflammatory NPSLE including systemic, biologic and interventional therapies; however, currently there is a paucity of high-quality trial data to guide firm recommendations. In order to better understand the optimal treatment of NPSLE and its different subtypes, further well-designed clinical trials are needed.
Topics: Azathioprine; Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Vasculitis, Central Nervous System; Pilot Projects; Randomized Controlled Trials as Topic
PubMed: 33360230
DOI: 10.1016/j.semarthrit.2020.12.004 -
JAMA Dermatology Jun 2020Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled.
IMPORTANCE
Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled.
OBJECTIVE
To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis.
DATA SOURCES
The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019.
STUDY SELECTION
English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included.
DATA EXTRACTION AND SYNTHESIS
Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria.
MAIN OUTCOMES AND MEASURES
Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events.
RESULTS
A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, -1.1; 95% CrI, -1.7 to -0.5 [low certainty]) and dupilumab (standardized mean difference, -0.9; 95% CrI, -1.0 to -0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, -0.6; 95% CrI, -1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, -0.4; 95% CrI, -0.8 to -0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates.
CONCLUSIONS AND RELEVANCE
Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.
Topics: Adult; Antibodies, Monoclonal, Humanized; Azathioprine; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunologic Factors; Methotrexate; Network Meta-Analysis; Pruritus; Quality of Life; Severity of Illness Index; Treatment Outcome
PubMed: 32320001
DOI: 10.1001/jamadermatol.2020.0796 -
The Cochrane Database of Systematic... Nov 2021Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Without treatment, approximately 30% of patients will experience spontaneous... (Review)
Review
BACKGROUND
Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Without treatment, approximately 30% of patients will experience spontaneous remission and one third will have persistent proteinuria. Approximately one-third of patients progress toward end-stage kidney disease (ESKD) within 10 years. Immunosuppressive treatment aims to protect kidney function and is recommended for patients who do not show improvement of proteinuria by supportive therapy, and for patients with severe nephrotic syndrome at presentation due to the high risk of developing ESKD. The efficacy and safety of different immunosuppressive regimens are unclear. This is an update of a Cochrane review, first published in 2004 and updated in 2013.
OBJECTIVES
The aim was to evaluate the safety and efficacy of different immunosuppressive treatments for adult patients with PMN and nephrotic syndrome.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 1 April 2021 with support from the Cochrane Kidney and Transplant Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) investigating effects of immunosuppression in adults with PMN and nephrotic syndrome were included.
DATA COLLECTION AND ANALYSIS
Study selection, data extraction, quality assessment, and data synthesis were performed using Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Sixty-five studies (3807 patients) were included. Most studies exhibited a high risk of bias for the domains, blinding of study personnel, participants and outcome assessors, and most studies were judged unclear for randomisation sequence generation and allocation concealment. Immunosuppressive treatment versus placebo/no treatment/non-immunosuppressive treatment In moderate certainty evidence, immunosuppressive treatment probably makes little or no difference to death, probably reduces the overall risk of ESKD (16 studies, 944 participants: RR 0.59, 95% CI 0.35 to 0.99; I² = 22%), probably increases total remission (complete and partial) (6 studies, 879 participants: RR 1.44, 95% CI 1.05 to 1.97; I² = 73%) and complete remission (16 studies, 879 participants: RR 1.70, 95% CI 1.05 to 2.75; I² = 43%), and probably decreases the number with doubling of serum creatinine (SCr) (9 studies, 447 participants: RR 0.46, 95% CI 0.26 to 0.80; I² = 21%). However, immunosuppressive treatment may increase the number of patients relapsing after complete or partial remission (3 studies, 148 participants): RR 1.73, 95% CI 1.05 to 2.86; I² = 0%) and may lead to a greater number experiencing temporary or permanent discontinuation/hospitalisation due to adverse events (18 studies, 927 participants: RR 5.33, 95% CI 2.19 to 12.98; I² = 0%). Immunosuppressive treatment has uncertain effects on infection and malignancy. Oral alkylating agents with or without steroids versus placebo/no treatment/steroids Oral alkylating agents with or without steroids had uncertain effects on death but may reduce the overall risk of ESKD (9 studies, 537 participants: RR 0.42, 95% CI 0.24 to 0.74; I² = 0%; low certainty evidence). Total (9 studies, 468 participants: RR 1.37, 95% CI 1.04 to 1.82; I² = 70%) and complete remission (8 studies, 432 participants: RR 2.12, 95% CI 1.33 to 3.38; I² = 37%) may increase, but had uncertain effects on the number of patients relapsing, and decreasing the number with doubling of SCr. Alkylating agents may be associated with a higher rate of adverse events leading to discontinuation or hospitalisation (8 studies 439 participants: RR 6.82, 95% CI 2.24 to 20.71; I² = 0%). Oral alkylating agents with or without steroids had uncertain effects on infection and malignancy. Calcineurin inhibitors (CNI) with or without steroids versus placebo/no treatment/supportive therapy/steroids We are uncertain whether CNI with or without steroids increased or decreased the risk of death or ESKD, increased or decreased total or complete remission, or reduced relapse after complete or partial remission (low to very low certainty evidence). CNI also had uncertain effects on decreasing the number with a doubling of SCr, temporary or permanent discontinuation or hospitalisation due to adverse events, infection, or malignancy. Calcineurin inhibitors (CNI) with or without steroids versus alkylating agents with or without steroids We are uncertain whether CNI with or without steroids increases or decreases the risk of death or ESKD. CNI with or without steroids may make little or no difference to total remission (10 studies, 538 participants: RR 1.01, 95% CI 0.89 to 1.15; I² = 53%; moderate certainty evidence) or complete remission (10 studies, 538 participants: RR 1.15, 95% CI 0.84 to 1.56; I² = 56%; low certainty evidence). CNI with or without steroids may increase relapse after complete or partial remission. CNI with or without steroids had uncertain effects on SCr increase, adverse events, infection, and malignancy. Other immunosuppressive treatments Other interventions included azathioprine, mizoribine, adrenocorticotropic hormone, traditional Chinese medicines, and monoclonal antibodies such as rituximab. There were insufficient data to draw conclusions on these treatments.
AUTHORS' CONCLUSIONS
This updated review strengthened the evidence that immunosuppressive therapy is probably superior to non-immunosuppressive therapy in inducing remission and reducing the number of patients that progress to ESKD. However, these benefits need to be balanced against the side effects of immunosuppressive drugs. The number of included studies with high-quality design was relatively small and most studies did not have adequate follow-up. Clinicians should inform their patients of the lack of high-quality evidence. An alkylating agent (cyclophosphamide or chlorambucil) combined with a corticosteroid regimen had short- and long-term benefits, but this was associated with a higher rate of adverse events. CNI (tacrolimus and cyclosporin) showed equivalency with alkylating agents however, the certainty of this evidence remains low. Novel immunosuppressive treatments with the biologic rituximab or use of adrenocorticotropic hormone require further investigation and validation in large and high-quality RCTs.
Topics: Azathioprine; Cyclosporine; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Nephrotic Syndrome
PubMed: 34778952
DOI: 10.1002/14651858.CD004293.pub4 -
The Cochrane Database of Systematic... Nov 2023Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains.
OBJECTIVES
To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs).
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies.
SELECTION CRITERIA
We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high.
MAIN RESULTS
This NMA included 123 trials with 57,682 participants Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes.
AUTHORS' CONCLUSIONS
We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.
Topics: Male; Female; Young Adult; Humans; Adolescent; Adult; Interferon beta-1a; Immunosuppressive Agents; Glatiramer Acetate; Network Meta-Analysis; Cladribine; Natalizumab; Interferon beta-1b; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Azathioprine; Rituximab; Fingolimod Hydrochloride; Multiple Sclerosis; Immunotherapy
PubMed: 38032059
DOI: 10.1002/14651858.CD012186.pub2 -
The Cochrane Database of Systematic... Mar 2021Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many...
BACKGROUND
Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits.
OBJECTIVES
To assess the effects of interventions for cutaneous disease in SLE.
SEARCH METHODS
We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence.
MAIN RESULTS
Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate.
AUTHORS' CONCLUSIONS
Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.
Topics: Age of Onset; Azathioprine; Bias; Biological Factors; Chloroquine; Cosmetic Techniques; Cyclosporine; Dermatologic Agents; Exanthema; Female; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Systemic; Male; Medicine, Chinese Traditional; Methotrexate; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Skin Diseases; Symptom Flare Up
PubMed: 33687069
DOI: 10.1002/14651858.CD007478.pub2 -
Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis.Thorax Dec 2022Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments.
METHODS
We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework.
RESULTS
We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (-88.35 to 411.12)), pirfenidone (2.47% (-0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty).
CONCLUSION AND RELEVANCE
Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.
Topics: Adult; Humans; Idiopathic Pulmonary Fibrosis; Network Meta-Analysis; Sildenafil Citrate; Azathioprine; Acetylcysteine
PubMed: 35145039
DOI: 10.1136/thoraxjnl-2021-217976 -
The Cochrane Database of Systematic... Jan 2017Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory... (Review)
Review
BACKGROUND
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective.
OBJECTIVES
To summarise the evidence from Cochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments.
METHODS
We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months.Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments.On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus.
MAIN RESULTS
Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. CorticosteroidsIt is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the evidence was very low (1 trial, 28 participants). According to moderate-quality evidence (1 trial, 41 participants), six months' treatment with high-dose monthly oral dexamethasone did not improve disability more than daily oral prednisolone. Observational studies tell us that prolonged use of corticosteroids sometimes causes serious side-effects. Plasma exchangeAccording to moderate-quality evidence (2 trials, 59 participants), twice-weekly plasma exchange produced more short-term improvement in disability than sham exchange. In the largest observational study, 3.9% of plasma exchange procedures had complications. Intravenous immunoglobulinAccording to high-quality evidence (5 trials, 269 participants), intravenous immunoglobulin (IVIg) produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high-quality evidence), but serious adverse events were not (moderate-quality evidence, 3 trials, 315 participants). One trial with 19 participants provided moderate-quality evidence of little or no difference in short-term improvement of impairment with plasma exchange in comparison to IVIg. There was little or no difference in short-term improvement of disability with IVIg in comparison to oral prednisolone (moderate-quality evidence; 1 trial, 29 participants) or intravenous methylprednisolone (high-quality evidence; 1 trial, 45 participants). One unpublished randomised open trial with 35 participants found little or no difference in disability after three months of IVIg compared to oral prednisone; this trial has not yet been included in a CSR. We know from observational studies that serious adverse events related to IVIg do occur. Other immunomodulatory treatmentsIt is uncertain whether the addition of azathioprine (2 mg/kg) to prednisone improved impairment in comparison to prednisone alone, as the quality of the evidence is very low (1 trial, 27 participants). Observational studies show that adverse effects truncate treatment in 10% of people.According to low-quality evidence (1 trial, 60 participants), compared to placebo, methotrexate 15 mg/kg did not allow more participants to reduce corticosteroid or IVIg doses by 20%. Serious adverse events were no more common with methotrexate than with placebo, but observational studies show that methotrexate can cause teratogenicity, abnormal liver function, and pulmonary fibrosis.According to moderate-quality evidence (2 trials, 77 participants), interferon beta-1a (IFN beta-1a) in comparison to placebo, did not allow more people to withdraw from IVIg. According to moderate-quality evidence, serious adverse events were no more common with IFN beta-1a than with placebo.We know of no other completed trials of immunosuppressant or immunomodulatory agents for CIDP. Other treatmentsWe identified no trials of treatments for fatigue or pain in CIDP. Adverse effectsNot all trials routinely collected adverse event data; when they did, the quality of evidence was variable. Adverse effects in the short, medium, and long term occur with all interventions. We are not able to make reliable comparisons of adverse events between the interventions included in CSRs.
AUTHORS' CONCLUSIONS
We cannot be certain based on available evidence whether daily oral prednisone improves impairment compared to no treatment. However, corticosteroids are commonly used, based on widespread availability, low cost, very low-quality evidence from observational studies, and clinical experience. The weakness of the evidence does not necessarily mean that corticosteroids are ineffective. High-dose monthly oral dexamethasone for six months is probably no more or less effective than daily oral prednisolone. Plasma exchange produces short-term improvement in impairment as determined by neurological examination, and probably produces short-term improvement in disability. IVIg produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. There is no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or plasma exchange. According to observational studies, adverse events related to difficult venous access, use of citrate, and haemodynamic changes occur in 3% to17% of plasma exchange procedures.It is uncertain whether azathioprine is of benefit as the quality of evidence is very low. Methotrexate may not be of benefit and IFN beta-1a is probably not of benefit.We need further research to identify predictors of response to different treatments and to compare their long-term benefits, safety and cost-effectiveness. There is a need for more randomised trials of immunosuppressive and immunomodulatory agents, routes of administration, and treatments for symptoms of CIDP.
Topics: Adrenal Cortex Hormones; Azathioprine; Dexamethasone; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interferon beta-1a; Methotrexate; Methylprednisolone; Plasma Exchange; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Prednisone; Randomized Controlled Trials as Topic; Review Literature as Topic
PubMed: 28084646
DOI: 10.1002/14651858.CD010369.pub2