ABSTRACT
OBJECTIVES: Incomplete reporting of safety outcomes in quality and availability of safety reporting in published articles of randomized controlled trials (RCTs) were described in different medical areas. The number of RCTs assessing systemic treatments for psoriasis has increased considerably. Complete and precise reporting of safety is mandatory for the efficacy/harms balance evaluation. We aimed to assess the quality and availability of safety reporting in published RCTs assessing systemic treatments for psoriasis, as well as the concordance of data between published trials and ClinicalTrials.gov (CT). STUDY DESIGN AND SETTING: We included all RCTs in adults initiated after September 2009, assessing systemic psoriasis treatments compared with placebo or with an active comparator. All trials were selected in duplicate by 2 independent authors from the latest search of the dedicated Cochrane review. We described quality of safety reporting for all published RCTs, using a modified Consolidated Standards of Reporting Trials harms scale by using descriptive analysis, and a composite score of 3 key items of safety report. For each RCT, data on adverse events (AEs)/serious AEs (SAEs) were extracted from the publication and CT: total number of AEs/SAEs, patients with AEs/SAEs, SAEs by system organ class classification and deaths. These data were compared between sources for each RCT. RESULTS: In total, 128 trials were included in the analysis of reporting quality, and 76 in the analysis of data concordance between sources. The median number of reported Consolidated Standards of Reporting Trials harms items per article was 9 out of 18 (IQR 7-10), and mean number was 8.39 (SD = 3.02). Items in the methods section were the least frequently reported. The proportion of RCTs reporting the number of SAEs and death were significantly higher on CT than in the published article ((100% (76/76) vs 88.2%, McNemar test, P < .0016). At least 1 discrepancy between sources for SAE safety data was found in 30/76 (39.5%) RCTs. CONCLUSION: Shortcomings and gaps in the quality of safety reporting in publications of RCTs of systemic psoriasis treatments have been identified. A lack of data in published articles and discrepancies between published articles and CT data complete this finding.
ABSTRACT
OBJECTIVES: To explore the association between industry funding and network meta-analyses' (NMAs) conclusion, and the use in Clinical Practice Guidelines (CPGs) of NMAs. STUDY DESIGN AND SETTING: This was an overview of NMAs and CPGs. We searched PubMed/MEDLINE, Epistemonikos, and several guideline databases up to February 18th 2023. We included CPGs from the last 5 years and NMAs of randomized controlled trials that evaluated targeted therapies in immune-mediated inflammatory diseases. Data extraction and outcome assessments were done in duplicate by independent authors. RESULTS: We included 216 NMAs and 99 CPGs. 31% (67/216) were industry-funded. The proportion of industry-funded NMAs that cited one treatment as being best was 44% (25/57) compared to 26% (30/116) for nonindustry-funded (OR = 2.24 [1.15-4.39]; aOR = 1.76 [0.81-3.81]). The abstract's conclusion of 39/67 (58%) industry-funded and 69/149 (46%) nonindustry-funded NMAs were considered unsupported by the results (OR = 1.61 [0.90-2.89]; aOR = 1.40 [0.71-2.78]). All industry-funded NMAs that cited one treatment as best cited their own sponsored drug. 59/99 (60%) CPGs included at least one NMA, with 23/59 (39%) of them citing industry-funded NMAs. CONCLUSIONS: We did not find evidence that industry-funded NMAs were more likely to have unsupported conclusions or to cite only one treatment as being best in their conclusions compared to non-industry-funded NMAs. However, almost all industry-funded NMAs favored their own treatments. Even though 40% of the CPGs did not rely on NMA, over a third of those who did used industry-funded NMAs. Limitations include the possible misclassification due to undisclosed funding and potential confounders that have not been accounted for.
Subject(s)
Molecular Targeted Therapy , Network Meta-Analysis , Humans , Drug Industry/economics , Inflammation/drug therapy , Molecular Targeted Therapy/economics , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/statistics & numerical data , Practice Guidelines as Topic , Randomized Controlled Trials as Topic/economics , Research Support as Topic/statistics & numerical dataSubject(s)
Antifungal Agents , Axilla , Paracoccidioidomycosis , Humans , Antifungal Agents/therapeutic use , Antifungal Agents/administration & dosage , Paracoccidioides/isolation & purification , Paracoccidioidomycosis/diagnosis , Paracoccidioidomycosis/drug therapy , Skin/pathology , Skin/microbiologyABSTRACT
BACKGROUND: Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the benefits and harms of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their benefits and harms. SEARCH METHODS: For this update of the living systematic review, we updated our searches of the following databases monthly to October 2022: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). DATA COLLECTION AND ANALYSIS: We conducted duplicate study selection, data extraction, risk of bias assessment, and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). MAIN RESULTS: This update includes an additional 12 studies, taking the total number of included studies to 179, and randomised participants to 62,339, 67.1% men, mainly recruited from hospitals. Average age was 44.6 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (56%). We assessed a total of 20 treatments. Most (152) trials were multicentric (two to 231 centres). One-third of the studies (65/179) had high risk of bias, 24 unclear risk, and most (90) low risk. Most studies (138/179) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 49.16, 95% CI 20.49 to 117.95), bimekizumab (RR 27.86, 95% CI 23.56 to 32.94), ixekizumab (RR 27.35, 95% CI 23.15 to 32.29), risankizumab (RR 26.16, 95% CI 22.03 to 31.07). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab and ixekizumab were significantly more likely to reach PASI 90 than secukinumab. Bimekizumab, ixekizumab, and risankizumab were significantly more likely to reach PASI 90 than brodalumab and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab, and brodalumab), and anti-IL23 drugs except tildrakizumab were significantly more likely to reach PASI 90 than ustekinumab, three anti-TNF alpha agents, and deucravacitinib. Ustekinumab was superior to certolizumab. Adalimumab, tildrakizumab, and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with very low- to moderate-certainty evidence for all the comparisons. The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.6 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was very low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Subject(s)
Biological Products , Psoriasis , Adult , Male , Humans , Female , Ustekinumab/therapeutic use , Methotrexate/therapeutic use , Infliximab/therapeutic use , Network Meta-Analysis , Systematic Reviews as Topic , Psoriasis/drug therapy , Tumor Necrosis Factor-alpha , Biological Products/therapeutic useABSTRACT
Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (>5 g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2 months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.
Subject(s)
Lichen Planus, Oral , Lichen Planus , Adult , Humans , Female , Middle Aged , Male , Clobetasol/adverse effects , Anti-Inflammatory Agents/therapeutic use , Retrospective Studies , Lichen Planus/drug therapy , Pruritus/drug therapy , Pruritus/etiology , Treatment Outcome , Lichen Planus, Oral/drug therapyABSTRACT
BACKGROUND: Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: For this update of the living systematic review, we updated our searches of the following databases monthly to October 2021: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). DATA COLLECTION AND ANALYSIS: We conducted duplicate study selection, data extraction, risk of bias assessment and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). MAIN RESULTS: This update includes an additional 19 studies, taking the total number of included studies to 167, and randomised participants to 58,912, 67.2% men, mainly recruited from hospitals. Average age was 44.5 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (57%). We assessed a total of 20 treatments. Most (140) trials were multicentric (two to 231 centres). One-third of the studies (57/167) had high risk of bias; 23 unclear risk, and most (87) low risk. Most studies (127/167) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions, except anti-IL23. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23 and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 50.19, 95% CI 20.92 to 120.45), bimekizumab (RR 30.27, 95% CI 25.45 to 36.01), ixekizumab (RR 30.19, 95% CI 25.38 to 35.93), risankizumab (RR 28.75, 95% CI 24.03 to 34.39). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab showed a higher proportion of patients reaching PASI 90 than other anti-IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti-IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti-TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with low- to moderate-certainty for all the comparisons (except methotrexate versus placebo, which was high-certainty). The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.5 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies and postmarketing reports from regulatory agencies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Subject(s)
Biological Products , Psoriasis , Adalimumab/adverse effects , Adult , Biological Products/therapeutic use , Etanercept/therapeutic use , Female , Humans , Infliximab/therapeutic use , Male , Methotrexate/therapeutic use , Network Meta-Analysis , Psoriasis/drug therapy , Systematic Reviews as Topic , Tumor Necrosis Factor-alpha , Ustekinumab/therapeutic useABSTRACT
BACKGROUND: Network meta-analyses (NMAs) have become successful in addressing gaps in the comparative effectiveness of systemic treatments in moderate-to-severe psoriasis. However, their increasing number carries both a risk of overlap and reproducibility issues that can hamper clinical decision-making. OBJECTIVES: In this overview, we aimed to assess redundancy across these NMAs and to describe their characteristics. MATERIALS AND METHODS: We considered all systematic reviews with NMAs of randomized controlled trials that included adult patients with moderate-to-severe psoriasis and that evaluated the efficacy and/or safety of systemic treatments compared with placebo or with an active comparator. PubMed/MEDLINE, Epistemonikos, PROSPERO and the Evidence update of the Centre of Evidence-Based Dermatology of the University of Nottingham were searched up to 25 February 2021. Our main outcome was the number per year of redundant NMAs and the extent of their overlap. We also described their features, especially, the confidence in the results of the reviews, the funding of the studies and the presence of spin (a description that overstates efficacy and/or understates harm), reporting issues and methodological characteristics. RESULTS: In total, 47 redundant NMAs were included. Only two of 47 (4%) included all available treatments. Both efficacy and safety were evaluated in 14 of 47 (30%) NMAs and both short- and long-term evaluations were assessed in five of 47 (11%). Confidence in the results was critically low for 39 of 47 (83%) NMAs and only 10 of 47 (21·3%) registered a protocol. Twenty-six of 47 NMAs (55%) received pharmaceutical funding. Contract research organizations were involved in 19 of 47 (40%) NMAs. Reporting was poor across most of the NMA abstracts and spin was present in all of the abstracts. Almost half of the NMAs failed to consider important limitations such as heterogeneity (considered in 32%) or consistency (considered in 66%). CONCLUSIONS: In addition to a duplication of efforts, our overview showed heterogeneous methods and poor confidence in the results in a majority of the included NMAs, further distorted by reporting issues and spin. Clinicians need to interpret NMAs with caution when looking for the most reliable and comprehensive evidence.
Subject(s)
Psoriasis , Adult , Humans , Immunotherapy , Network Meta-Analysis , Psoriasis/drug therapy , Reproducibility of ResultsABSTRACT
IMPORTANCE: Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM. OBJECTIVE: The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission). RESULTS: Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration. CONCLUSIONS AND RELEVANCE: In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.
Subject(s)
Erythema Multiforme , Thalidomide , Adolescent , Adult , Cohort Studies , Erythema Multiforme/chemically induced , Erythema Multiforme/diagnosis , Erythema Multiforme/drug therapy , Female , Humans , Remission Induction , Retrospective Studies , Thalidomide/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. OBJECTIVES: To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: For this living systematic review we updated our searches of the following databases monthly to September 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched two trials registers to the same date. We checked the reference lists of included studies and relevant systematic reviews for further references to eligible RCTs. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse events (SAEs) at induction phase. We did not evaluate differences in specific adverse events. DATA COLLECTION AND ANALYSIS: Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse events). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes and all comparisons, according to CINeMA, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer on treatment hierarchy: 0% (treatment is the worst for effectiveness or safety) to 100% (treatment is the best for effectiveness or safety). MAIN RESULTS: We included 158 studies (18 new studies for the update) in our review (57,831 randomised participants, 67.2% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (58%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 20 treatments. In all, 133 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (53/158) as being at high risk of bias; 25 were at an unclear risk, and 80 at low risk. Most studies (123/158) declared funding by a pharmaceutical company, and 22 studies did not report their source of funding. Network meta-analysis at class level showed that all of the interventions (non-biological systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in reaching PASI 90. At class level, in reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the non-biological systemic agents. At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti-TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab was more effective than certolizumab, and the clinical effectiveness of ustekinumab and adalimumab was similar. There was no significant difference between tofacitinib or apremilast and three non-biological drugs: fumaric acid esters (FAEs), ciclosporin and methotrexate. Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab, and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness of these drugs was similar, except for ixekizumab which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab. The clinical effectiveness of these seven drugs was: infliximab (versus placebo): risk ratio (RR) 50.29, 95% confidence interval (CI) 20.96 to 120.67, SUCRA = 93.6; high-certainty evidence; ixekizumab (versus placebo): RR 32.48, 95% CI 27.13 to 38.87; SUCRA = 90.5; high-certainty evidence; risankizumab (versus placebo): RR 28.76, 95% CI 23.96 to 34.54; SUCRA = 84.6; high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86; SUCRA = 81.4; high-certainty evidence; secukinumab (versus placebo): RR 25.79, 95% CI 21.61 to 30.78; SUCRA = 76.2; high-certainty evidence; guselkumab (versus placebo): RR 25.52, 95% CI 21.25 to 30.64; SUCRA = 75; high-certainty evidence; and brodalumab (versus placebo): RR 23.55, 95% CI 19.48 to 28.48; SUCRA = 68.4; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to moderate certainty for all the comparisons. Thus, the results have to be viewed with caution and we cannot be sure of the ranking. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab and brodalumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the evidence for all the interventions was of low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies. In terms of future research, randomised trials directly comparing active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between non-biological systemic agents and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunosuppressive Agents/therapeutic use , Psoriasis/drug therapy , Antibodies, Monoclonal, Humanized , Chronic Disease , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Female , Humans , Male , Middle Aged , Molecular Targeted Therapy , Network Meta-Analysis , Placebos/therapeutic use , Randomized Controlled Trials as Topic , Remission Induction , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
BACKGROUND: The availability of effective treatments for psoriasis raises ethical questions about the use of a placebo group in therapeutic trials. We evaluated the use of the placebo over time in such trials. METHODS: From trials in a living Cochrane review and network meta-analysis for psoriasis, we included trials comparing a biologic to a placebo or other systemic treatment. First, we tested the changes in placebo rate from 2001 to 2019 by linear regression, then constructed networks for 2004-2019 and evaluated the contribution of the placebo to the network meta-analysis estimates per trial and per comparison. RESULTS: We included 81 trials (36,774 patients). The placebo rate did not decrease significantly over time. The proportion contribution of trials with a placebo decreased from 100% in 2004 to 86% in 2008 and 75% in 2019. However, the proportion contribution of trials without a placebo remained low (from 0% in 2004 to 25% in 2019). CONCLUSION: The design of future psoriasis trials should be reviewed to improve the number of patients to be included in a placebo group.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Biomedical Research/standards , Guidelines as Topic , Placebos/therapeutic use , Psoriasis/drug therapy , Randomized Controlled Trials as Topic/statistics & numerical data , Randomized Controlled Trials as Topic/standards , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Research Design/statistics & numerical data , Research Design/trendsABSTRACT
We sought to assess the quality of dermatological systematic reviews (SRs) and identify factors that predict high methodological quality. We searched for all SRs published in 2017 using PubMed, Epistemonikos, and the Cochrane Database of SRs. We included studies identified as SRs or meta-analysis in the title or abstract and dealing with a dermatological topic. Study selection and data extraction were carried out and Preferred Reporting Items for SRs and Meta-Analyses and rating by A MeaSurement Tool to Assess SRs 2 were used independently by two authors. On the basis of A MeaSurement Tool to Assess SRs 2, confidence in SRs results was classified as high, moderate, low, or very low. We included 732 studies. We described a random sample of 140. The overall rating of confidence in the results according to a tool called A MeaSurement Tool to Assess SRs 2 was high or moderate for nine reviews (6%). A total of 20 reviews (15%) had a registered protocol. Independent factors associated with moderate or high rating of A MeaSurement Tool to Assess SRs 2 were publication in a journal where Preferred Reporting Items for SRs and Meta-Analyses was mandatory (OR [95% confidence interval] = 27.0 [1.4-528]) and journal impact factor (OR of 1.9 [1.3-3]) for each increase in one more point. The observation that 90% of published dermatology SRs are of very low quality is alarming. Review registration in the International Prospective Register of SRs and full reporting according to Preferred Items for SRs and Meta-Analyses should be mandatory for publication. This study is registered in the International Prospective Register of SRs (CRD42018093856).
Subject(s)
Dermatology/standards , Quality Improvement , Databases, Factual , HumansSubject(s)
Drug-Related Side Effects and Adverse Reactions , Pharmacovigilance , Stevens-Johnson Syndrome/etiology , Adverse Drug Reaction Reporting Systems , Antibodies, Monoclonal, Humanized/adverse effects , Databases, Factual , Humans , Pharmaceutical Preparations , Retrospective Studies , Stevens-Johnson Syndrome/epidemiology , World Health OrganizationABSTRACT
Topical drugs are often used as first-line treatment for dermatological conditions. Depending on the disease and the drug, three main designs can be used for randomized controlled trials assessing topical drugs: the classical individual parallel design, the cluster randomized design, and designs allowing within-individual comparisons, including the cross-over design (in which patients are randomized to a sequence of interventions) and the within-person design (also called the split-body design). Within-person design can be used to compare different drugs concomitantly in the same patient. Randomization does not concern patients but rather lesions or body sites within patients, and the drugs to be compared are applied to the different lesions (or sites). This design considerably reduces interobservation variability, and thus, the number of patients to be included in the trial (sample size). However, this design has major methodological constraints, especially the need to resolve the problem of a possible carry-across effect. First, we describe the specificities of randomized controlled trials evaluating a topical drug. Second, we present the different designs available and discuss the methodological points that should be considered, especially for a within-person design. Finally, we compare the relevance of the within-person design with that of other trial designs by considering three different scenarios.
Subject(s)
Dermatologic Agents/therapeutic use , Dermatology/methods , Skin Diseases/drug therapy , Administration, Topical , Cross-Over Studies , Humans , Observer Variation , Randomized Controlled Trials as Topic , Research Design , Sample SizeABSTRACT
BACKGROUND: Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. This is the baseline update of a Cochrane Review first published in 2017, in preparation for this Cochrane Review becoming a living systematic review. OBJECTIVES: To compare the efficacy and safety of conventional systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis, and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We updated our research using the following databases to January 2019: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the conference proceedings of a number of dermatology meetings. We also searched five trials registers and the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports (until June 2019). We checked the reference lists of included and excluded studies for further references to relevant RCTs. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate-to-severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate-to-severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse effects (SAEs) at induction phase. We did not evaluate differences in specific adverse effects. DATA COLLECTION AND ANALYSIS: Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse effects). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. MAIN RESULTS: We included 140 studies (31 new studies for the update) in our review (51,749 randomised participants, 68% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo-controlled (59%), 30% were head-to-head studies, and 11% were multi-armed studies with both an active comparator and a placebo. We have assessed a total of 19 treatments. In all, 117 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (57/140) as being at high risk of bias; 42 were at an unclear risk, and 41 at low risk. Most studies (107/140) declared funding by a pharmaceutical company, and 22 studies did not report the source of funding. Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90. At class level, in terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. At drug level, in terms of reaching PASI 90, infliximab, all of the anti-IL17 drugs (ixekizumab, secukinumab, bimekizumab and brodalumab) and the anti-IL23 drugs (risankizumab and guselkumab, but not tildrakizumab) were significantly more effective in reaching PASI 90 than ustekinumab and 3 anti-TNF alpha agents: adalimumab, certolizumab and etanercept. Adalimumab and ustekinumab were significantly more effective in reaching PASI 90 than certolizumab and etanercept. There was no significant difference between tofacitinib or apremilast and between two conventional drugs: ciclosporin and methotrexate. Network meta-analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness for these seven drugs was similar: infliximab (versus placebo): risk ratio (RR) 29.52, 95% confidence interval (CI) 19.94 to 43.70, Surface Under the Cumulative Ranking (SUCRA) = 88.5; moderate-certainty evidence; ixekizumab (versus placebo): RR 28.12, 95% CI 23.17 to 34.12, SUCRA = 88.3, moderate-certainty evidence; risankizumab (versus placebo): RR 27.67, 95% CI 22.86 to 33.49, SUCRA = 87.5, high-certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86, SUCRA = 83.5, low-certainty evidence; guselkumab (versus placebo): RR 25.84, 95% CI 20.90 to 31.95; SUCRA = 81; moderate-certainty evidence; secukinumab (versus placebo): RR 23.97, 95% CI 20.03 to 28.70, SUCRA = 75.4; high-certainty evidence; and brodalumab (versus placebo): RR 21.96, 95% CI 18.17 to 26.53, SUCRA = 68.7; moderate-certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to very low certainty for just under half of the treatment estimates in total, and moderate for the others. Thus, the results have to be viewed with caution and we cannot be sure of the ranking. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were very similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. AUTHORS' CONCLUSIONS: Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, guselkumab, secukinumab and brodalumab were the best choices for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of moderate- to high-certainty evidence (low-certainty evidence for bimekizumab). This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly-reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs, but the evidence for all the interventions was of very low to moderate quality. In order to provide long-term information on the safety of the treatments included in this review, it will also be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies. In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunosuppressive Agents/therapeutic use , Psoriasis/drug therapy , Antibodies, Monoclonal, Humanized , Chronic Disease , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Humans , Molecular Targeted Therapy , Network Meta-Analysis , Randomized Controlled Trials as Topic , Remission Induction , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
BACKGROUND: Deep cutaneous fungal infections (DCFIs) are varied in immunosuppressed patients, with few data for such infections in solid-organ transplant recipients (s-OTRs). OBJECTIVE: To determine DCFI diagnostic characteristics and outcome with treatments in s-OTRs. METHODS: A 20-year retrospective observational study in France was conducted in 8 primary dermatology-dedicated centers for s-OTRs diagnosed with DCFIs. Relevant clinical data on transplants, fungal species, treatments, and outcomes were analyzed. RESULTS: Overall, 46 s-OTRs developed DCFIs (median delay, 13 months after transplant) with predominant phaeohyphomycoses (46%). Distribution of nodular lesions on limbs and granulomatous findings on histopathology were helpful diagnostic clues. Treatments received were systemic antifungal therapies (48%), systemic antifungal therapies combined with surgery (28%), surgery alone (15%), and modulation of immunosuppression (61%), leading to complete response in 63% of s-OTRs. LIMITATIONS: Due to the retrospective observational design of the study. CONCLUSIONS: Phaeohyphomycoses are the most common DCFIs in s-OTRs. Multidisciplinary teams are helpful for optimal diagnosis and management.