Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

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.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

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.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

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.

IgG1 Subclass Restriction and Biochemical Peculiarities of Monoclonal Immunoglobulins in Scleromyxedema.

BACKGROUND: Scleromyxedema (SME) is a rare mucinosis associated with monoclonal gammopathy. Several biochemical peculiarities of monoclonal immunoglobulins (Ig) in SME patients were reported in case reports or short series, such as IgGλ over-representation, cationic migration, and partial deletion. METHODS: Monoclonal immunoglobulins (Ig) from the serum of 12 consecutive patients diagnosed with scleromyxedema (SME) were analyzed using electrophoretic and immunoblotting techniques. RESULTS: All monoclonal Ig from 12 SME were of IgG1 subclass, with an overrepresentation of the lambda-type light chain and a cationic mobility on standard zone electrophoresis, as compared with 21 cases of monoclonal gammopathy of undetermined significance (MGUS) of IgG1 subclass. Reactivity with specific monoclonal antibodies demonstrated no evident deletion of the heavy chain constant domains, which was also confirmed by analysis of Ig heavy chain molecular weight on a purified monoclonal component from one case. CONCLUSIONS: Significant isotype restriction of both heavy and light chains, and peculiar biochemical properties suggest that monoclonal Ig might be involved in pathophysiological events of SME.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

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.

Incidence of bloodstream infections and predictive value of qualitative and quantitative skin cultures of patients with overlap syndrome or toxic epidermal necrolysis: A retrospective observational cohort study of 98 cases.

BACKGROUND: Epidermal necrolysis (EN) involving ≥10% of the body surface area (BSA) is often complicated by bacterial infections. OBJECTIVE: We sought to describe the epidemiology of bloodstream infections (BSIs) in EN involving a BSA ≥10% and the diagnostic performances of skin cultures for predicting the pathogen(s) isolated from BSIs. METHODS: This retrospective single-center observational study was conducted between 2009 and 2017. All patients referred at the acute phase for EN involving a BSA ≥10% were included. All clinical and bacteriologically relevant data were collected (blood and skin cultures results, number, and severity and time of BSI). Sensitivity, specificity, and predictive values of skin cultures and impact of the bacterial inoculum were investigated. RESULTS: Of 98 patients, 46 (46.9%) had ≥1 BSI episode during the hospital stay (BSIs were caused by Staphylococcus aureus [n = 17, 36.9%] and Pseudomonas aeruginosa [n = 17, 36.9%]). Skin cultures were concordant with blood cultures in 32 cases (71.1%). The positive and negative predictive values were 57.7% and 89.4% for S aureus and 50.0% and 80.9% for P aeruginosa, respectively. BSI increased with cutaneous inoculum of S aureus. LIMITATIONS: This was a retrospective single-center design with a low total number of BSIs. CONCLUSION: Skin cultures for S aureus and P aeruginosa may help predict the pathogens involved in BSIs.

Interventions for necrotizing soft tissue infections in adults.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are severe and rapidly spreading soft tissue infections of the subcutaneous tissue, fascia, or muscle, which are mostly caused by bacteria. Associated rates of mortality and morbidity are high, with the former estimated at around 23%, and disability, sequelae, and limb loss occurring in 15% of patients. Standard management includes intravenous empiric antimicrobial therapy, early surgical debridement of necrotic tissues, intensive care support, and adjuvant therapies such as intravenous immunoglobulin (IVIG). OBJECTIVES: To assess the effects of medical and surgical treatments for necrotizing soft tissue infections (NSTIs) in adults in hospital settings. SEARCH METHODS: We searched the following databases up to April 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers, pharmaceutical company trial results databases, and the US Food and Drug Administration and the European Medicines Agency websites. We checked the reference lists of included studies and reviews for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: RCTs conducted in hospital settings, that evaluated any medical or surgical treatment for adults with NSTI were eligible for inclusion. Eligible medical treatments included 1) comparisons between different antimicrobials or with placebo; 2) adjuvant therapies such as intravenous immunoglobulin (IGIV) therapy compared with placebo; no treatment; or other adjuvant therapies. Eligible surgical treatments included surgical debridement compared with amputation, immediate versus delayed intervention, or comparisons of number of interventions.RCTs of hyperbaric oxygen (HBO) therapy for NSTI were ineligible because HBO is the focus of another Cochrane Review. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome measures were 1) mortality within 30 days, and 2) proportion of participants who experience a serious adverse event. Secondary outcomes were 1) survival time, and 2) assessment of long-term morbidity. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: We included three trials randomising 197 participants (62% men) who had a mean age of 55 years. One trial compared two antibiotic treatments, and two trials compared adjuvant therapies with placebo. In all trials, participants concomitantly received standard interventions, such as intravenous empiric antimicrobial therapy, surgical debridement of necrotic tissues, intensive care support, and adjuvant therapies. All trials were at risk of attrition bias and one trial was not blinded.Moxifloxacin versus amoxicillin-clavulanate One trial included 54 participants who had a NSTI; it compared a third-generation quinolone, moxifloxacin, at a dose of 400 mg given once daily, against a penicillin, amoxicillin-clavulanate, at a dose of 3 g given three times daily for at least three days, followed by 1.5 g three times daily. Duration of treatment varied from 7 to 21 days. We are uncertain of the effects of these treatments on mortality within 30 days (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.39 to 23.07) and serious adverse events at 28 days (RR 0.63, 95% CI 0.30 to 1.31) because the quality of the evidence is very low.AB103 versus placebo One trial of 43 randomised participants compared two doses, 0.5 mg/kg and 0.25 mg/kg, of an adjuvant drug, a CD28 antagonist receptor (AB103), with placebo. Treatment was given via infusion pump for 10 minutes before, after, or during surgery within six hours after the diagnosis of NSTI. We are uncertain of the effects of AB103 on mortality rate within 30 days (RR of 0.34, 95% CI 0.05 to 2.16) and serious adverse events measured at 28 days (RR 1.49, 95% CI 0.52 to 4.27) because the quality of the evidence is very low.Intravenous immunoglobulin (IVIG) versus placebo One trial of 100 randomised participants assessed IVIG as an adjuvant drug, given at a dose of 25 g/day, compared with placebo, given for three consecutive days. There may be no clear difference between IVIG and placebo in terms of mortality within 30 days (RR 1.17, 95% CI 0.42 to 3.23) (low-certainty evidence), nor serious adverse events experienced in the intensive care unit (ICU) (RR 0.73 CI 95% 0.32 to 1.65) (low-certainty evidence).Serious adverse events were only described in one RCT (the IVIG versus placebo trial) and included acute kidney injury, allergic reactions, aseptic meningitis syndrome, haemolytic anaemia, thrombi, and transmissible agents.Only one trial reported assessment of long-term morbidity, but the outcome was not defined in the way we prespecified in our protocol. The trial used the Short Form Health Survey (SF36). Data on survival time were provided upon request for the trials comparing amoxicillin-clavulanate versus moxifloxacin and IVIG versus placebo. However, even with data provided, it was not possible to perform survival analysis. AUTHORS' CONCLUSIONS: We found very little evidence on the effects of medical and surgical treatments for NSTI. We cannot draw conclusions regarding the relative effects of any of the interventions on 30-day mortality or serious adverse events due to the very low quality of the evidence.The quality of the evidence is limited by the very small number of trials, the small sample sizes, and the risks of bias in the included trials. It is important for future trials to clearly define their inclusion criteria, which will help with the applicability of future trial results to a real-life population.Management of NSTI participants (critically-ill participants) is complex, involving multiple interventions; thus, observational studies and prospective registries might be a better foundation for future research, which should assess empiric antimicrobial therapy, as well as surgical debridement, along with the placebo-controlled comparison of adjuvant therapy. Key outcomes to assess include mortality (in the acute phase of the condition) and long-term functional outcomes, e.g. quality of life (in the chronic phase).

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

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 conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We searched the following databases to December 2016: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports. We checked the reference lists of included and excluded studies for further references to relevant RCTs. We searched the trial results databases of a number of pharmaceutical companies and handsearched the conference proceedings of a number of dermatology meetings. SELECTION CRITERIA: Randomised controlled trials (RCTs) of systemic and biological 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. DATA COLLECTION AND ANALYSIS: Three 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 Psoriasis Area and Severity Index score (PASI) 90) 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; we evaluated evidence as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. MAIN RESULTS: We included 109 studies in our review (39,882 randomised participants, 68% men, all recruited from a hospital). The overall average age was 44 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo controlled (67%), 23% were head-to-head studies, and 10% were multi-armed studies with both an active comparator and placebo. We have assessed all treatments listed in the objectives (19 in total). In all, 86 trials were multicentric trials (two to 231 centres). All of the trials included in this review were limited to the induction phase (assessment at less than 24 weeks after randomisation); in fact, all trials included in the network meta-analysis were measured between 12 and 16 weeks after randomisation. We assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk.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.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. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents.At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments.Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab (risk ratio (RR) 32.45, 95% confidence interval (CI) 23.61 to 44.60; Surface Under the Cumulative Ranking (SUCRA) = 94.3; high-certainty evidence), followed by secukinumab (RR 26.55, 95% CI 20.32 to 34.69; SUCRA = 86.5; high-certainty evidence), brodalumab (RR 25.45, 95% CI 18.74 to 34.57; SUCRA = 84.3; moderate-certainty evidence), guselkumab (RR 21.03, 95% CI 14.56 to 30.38; SUCRA = 77; moderate-certainty evidence), certolizumab (RR 24.58, 95% CI 3.46 to 174.73; SUCRA = 75.7; moderate-certainty evidence), and ustekinumab (RR 19.91, 95% CI 15.11 to 26.23; SUCRA = 72.6; high-certainty evidence).We found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs (RR 0.23, 95% CI 0.05 to 0.99; SUCRA = 90.7; moderate-certainty evidence), followed by ciclosporin (RR 0.23, 95% CI 0.01 to 5.10; SUCRA = 78.2; very low-certainty evidence), certolizumab (RR 0.49, 95% CI 0.10 to 2.36; SUCRA = 70.9; moderate-certainty evidence), infliximab (RR 0.56, 95% CI 0.10 to 3.00; SUCRA = 64.4; very low-certainty evidence), alefacept (RR 0.72, 95% CI 0.34 to 1.55; SUCRA = 62.6; low-certainty evidence), and fumaric acid esters (RR 0.77, 95% CI 0.30 to 1.99; SUCRA = 57.7; very low-certainty evidence). Major adverse cardiac events, serious infections, or malignancies were reported in both the placebo and intervention groups. Nevertheless, the SAEs analyses were based on a very low number of events with low to very low certainty for just over half of the treatment estimates in total, moderate for the others. Thus, the results have to be considered with caution.Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability.Regarding the 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 a third of the interventions. AUTHORS' CONCLUSIONS: Our review shows that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high-certainty evidence. At class level, 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, too. This NMA evidence is limited to induction therapy (outcomes were measured between 12 to 16 weeks after randomisation) and is not sufficiently relevant for a chronic disease. Moreover, low numbers of studies were found for some of the interventions, and the young age (mean age of 44 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. Methotrexate appeared to have the best safety profile, but as the evidence was of very low to moderate quality, we cannot be sure of the ranking. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies as well.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 patients, 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.

Prognostic factors in necrotizing soft-tissue infections (NSTI): A cohort study.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is uncommon but life-threatening. A recent meta-analysis estimated the overall mortality at 23.5%. OBJECTIVE: We sought to identify risk factors associated with mortality in a cohort of patients with NSTI in a tertiary care center. METHODS: We identified 512 patients with NSTI between 1996 and 2012 in the national hospital database Program for Medicalization of Information Systems and examined risk factors of mortality with NSTI by univariate and multivariate analysis. RESULTS: We included 109 patients with a confirmed diagnosis of NSTI; 31 (28%) died at a median follow-up of 274 days (range 2-6135 days). On multivariate analysis, independent risk factors of mortality were age older than 75 years (hazard ratio [HR] 4.4, 95% confidence interval [CI] 1.8-10.3), multifocal NSTI (HR 5.9, 95% CI 1.9-18.5), severe peripheral vascular disease (HR 5.1, 95% CI 1.5-17.0), hospital-acquired infection (HR 3.9, 95% CI 1.4-10.7), severe sepsis (HR 7.4, 95% CI 1.7-33.1), and septic shock on hospital admission (HR 13.9, 95% CI 3.8-50.4). LIMITATIONS: This was a retrospective cohort, which disallows a precise record of the delay between diagnosis and surgery. CONCLUSION: Our findings for this robust cohort of patients with a definite diagnosis of NSTI could help clinicians stratify NSTI severity at clinical course onset.