3D bioprinting of liver models: A systematic scoping review of methods, bioinks, and reporting quality.

Background: Effective communication is crucial for broad acceptance and applicability of alternative methods in 3R biomedical research and preclinical testing. 3D bioprinting is used to construct intricate biological structures towards functional liver models, specifically engineered for deployment as alternative models in drug screening, toxicological investigations, and tissue engineering. Despite a growing number of reviews in this emerging field, a comprehensive study, systematically assessing practices and reporting quality for bioprinted liver models is missing. Methods: In this systematic scoping review we systematically searched MEDLINE (Ovid), EMBASE (Ovid) and BioRxiv for studies published prior to June 2nd, 2022. We extracted data on methodological conduct, applied bioinks, the composition of the printed model, performed experiments and model applications. Records were screened for eligibility and data were extracted from included articles by two independent reviewers from a panel of seven domain experts specializing in bioprinting and liver biology. We used RAYYAN for the screening process and SyRF for data extraction. We used R for data analysis, and R and Graphpad PRISM for visualization. Results: Through our systematic database search we identified 1042 records, from which 63 met the eligibility criteria for inclusion in this systematic scoping review. Our findings revealed that extrusion-based printing, in conjunction with bioinks composed of natural components, emerged as the predominant printing technique in the bioprinting of liver models. Notably, the HepG2 hepatoma cell line was the most frequently employed liver cell type, despite acknowledged limitations. Furthermore, 51% of the printed models featured co-cultures with non-parenchymal cells to enhance their complexity. The included studies offered a variety of techniques for characterizing these liver models, with their primary application predominantly focused on toxicity testing. Among the frequently analyzed liver markers, albumin and urea stood out. Additionally, Cytochrome P450 (CYP) isoforms, primarily CYP3A and CYP1A, were assessed, and select studies employed nuclear receptor agonists to induce CYP activity. Conclusion: Our systematic scoping review offers an evidence-based overview and evaluation of the current state of research on bioprinted liver models, representing a promising and innovative technology for creating alternative organ models. We conducted a thorough examination of both the methodological and technical facets of model development and scrutinized the reporting quality within the realm of bioprinted liver models. This systematic scoping review can serve as a valuable template for systematically evaluating the progress of organ model development in various other domains. The transparently derived evidence presented here can provide essential support to the research community, facilitating the adaptation of technological advancements, the establishment of standards, and the enhancement of model robustness. This is particularly crucial as we work toward the long-term objective of establishing new approach methods as reliable alternatives to animal testing, with extensive and versatile applications.

Ingrown Toenails: A Survey Among Dermatologists on Current Treatments.

BACKGROUND: To date, there is no formal consensus on how to treat ingrown toenails. Despite the risk of causing irreparable damage to the nail, highly invasive procedures are still common. Less-invasive, matrix-directed techniques with shorter downtime and high cure rates exist, but, perhaps because of a lack of awareness, appear not to have been universally adopted. OBJECTIVE: The authors' study sought to generate data on common practices in the treatment of ingrown toenails. MATERIALS AND METHODS: The authors developed and conducted an online survey to ask dermatologists/dermatosurgeons how they would proceed in 9 different cases of ingrown toenails based on photographs. RESULTS: The authors received 154 replies. Nonsurgical interventions, including advice on nail care/foot baths/ointments/wraps/padding, were always the most frequently chosen option. Removal of the lateral nail plate followed by chemical partial matricectomy (phenolization) was the most or second-most frequently chosen surgical intervention. The answers were highly heterogeneous, and there was no unanimity based on morphology alone. CONCLUSION: Except for a preference for nonsurgical interventions, the authors could not identify any clear treatment standards. The heterogeneity of treatment approaches suggests the need for a guideline.

Perioperative management of antithrombotic drugs in skin surgery - A survey of dermatologists in Germany.

BACKGROUND: We identified substantial heterogeneity in the perioperative management of antithrombotic drugs in skin surgery in Germany in 2012 and 2017 in two cross-sectional surveys. The first national guideline on this subject was published in 2014 and updated in 2021. We sought to identify whether the management of these drugs had changed. METHODS: We sent a paper-based survey to 1115 dermatologists throughout Germany asking them about their perioperative management of antithrombotic drugs in skin surgery, as well as their familiarity with the guideline. RESULTS: We received responses from 65 hospital- and 202 office-based dermatologists. Most dermatologists reported continuing antithrombotic drugs in their patients when performing minor surgeries. A notable proportion of dermatologists reported discontinuing phenprocoumon treatment perioperatively and bridging patients with heparin when performing more invasive surgeries. Continuation was less common during combination therapies. CONCLUSIONS: The proportion of physicians in Germany who reported managing antithrombotic drugs during skin surgery in ways that are in concordance with the national guideline has increased since 2012. However, continuing antithrombotic drugs during large excisions and sentinel lymph node biopsies, abstaining from bridging patients on phenprocoumon with heparin, and continuing antithrombotic combination therapies perioperatively need to be further encouraged, especially among office-based dermatologists.

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.

Risk of complications due to antithrombotic agents in cutaneous surgery: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: We aimed to determine the risk of complications during cutaneous surgery for the perioperative discontinuation in comparison to the continuation of antithrombotic agents and the bridging of vitamin K antagonists with heparin in comparison to their continuation. METHODS: We conducted a systematic review, searching three databases for eligible studies. Methods followed the Cochrane Handbook. We used RoB 2 and ROBINS-I to assess risk of bias. The quality of evidence was judged (GRADE). Fixed-effect meta-analyses were performed. RESULTS: Two randomized-controlled trials and 19 prospective cohort studies were included. It is uncertain whether, compared to its discontinuation, continuing acetylsalicylic acid (risk difference (RD) 0.004, 95 % confidence interval (CI) -0.003 to 0.019) perioperatively increases the risk of significant postoperative bleedings (SPB). Compared to its discontinuation, continuing phenprocoumon perioperatively may increase the risk of SPB (RD 0.02, 95 % CI 0.00 to 0.05). Bridging phenprocoumon with heparin perioperatively may increase the risk of SPB when compared to its continuation (RD 0.07, 95 % CI 0.01 to 0.22). No evidence was found regarding bleeding risks for direct oral anticoagulants. CONCLUSIONS: No clear indications of major risks of bleedings when continuing antithrombotic agents during minor skin surgeries were identified. However, the quality of evidence was very low.

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.

Measuring importance of outcomes to patients: a cross-sectional survey for the German anal cancer guideline.

OBJECTIVE: We aimed to generate evidence on patients' values and preferences to inform the development of the German national Evidence-based Anal Cancer Guideline. STUDY DESIGN AND SETTING: We developed a list of health outcomes based on a systematic search. We then asked anal cancer patients and experts of the guideline development group in an online survey to (a) rate the relative importance of the outcomes in different clinical situations using a nine-point, three-category scale, and (b) select seven outcomes they considered most important for decision-making in each situation. RESULTS: Participants rated almost half of the outcomes (45%) as critical for decision-making, and more than half (53%) as important. Only two outcomes (2%) were rated as low in importance. Agreement between expert and patient ratings was low to fair, and we found important discrepancies in how the relative importance of the outcomes was perceived. However, the rankings of outcomes were highly correlated. CONCLUSION: Determining the relative importance placed by anal cancer patients on outcomes provided useful information for developing guideline recommendations. Our approach may be useful for guideline developers who aim to include the patient perspective. Moreover, our findings may help health professionals caring for anal cancer patients in joint decision-making.

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.

Time until onset of action when treating psoriatic arthritis: meta-analysis and novel approach of generating confidence intervals.

Psoriatic arthritis (PsA) is associated with progressive joint destruction and reduced quality of life. The time until a drug treatment starts to show an effect (TOA) is important for preventing joint destruction. The objective was to assess the time until onset of action of drugs when treating PsA. A systematic review of PsA drug trials was performed. Outcomes were: time until 25% of patients (TOA) reached (1) ≥ 20%, (2) ≥ 50% improvement in modified American College of Rheumatology response criteria (ACR), (3) ≥ 75% reduction in Psoriasis Area and Severity Index (PASI75). 95% confidence intervals were calculated extracting data from graphs using a novel method. Meta-analysis was conducted. Two head-to-head trials show no difference between ixekizumab and adalimumab or adalimumab and tofacitinib for TOA-ACR outcomes. For PASI75, ixekizumab had a faster onset than adalimumab. Infliximab plus MTX was faster than MTX alone. Pooled results from 32 study arms for TOA-ACR20 (week [95% CI]) are: < 2 weeks: infliximab (1.18 [0.72-1.65]), ixekizumab (1.04 [0.80-1.28]), tofacitinib (10 mg 1.56 [1.14-1.98]); ≤ 4 weeks: adalimumab (1.95 [1.35-2.55]), secukinumab (75 mg 1.89 [0.16-3.62], 150 mg 2.13 [1.34-2.91], 300 mg 2.26 [1.75-2.76]), tofacitinib (5 mg 2.20 [1.41-2.99]); 4 + weeks: apremilast, ustekinumab. For TOA-ACR50, all pooled point estimates are > 4 weeks. For TOA-PASI75, the range is between 2.24 [1.65-2.84] for ixekizumab and 6.03 [3.76-8.29] for adalimumab. Indirect, mixed comparison suggest a faster onset of infliximab, ixekizumab and tofacitinib compared to apremilast, methotrexate and ustekinumab for ACR20, not ACR50. For PASI75, ixekizumab is faster than adalimumab.

Incidence of sexually transmitted infections in men who have sex with men and who are at substantial risk of HIV infection - A meta-analysis of data from trials and observational studies of HIV pre-exposure prophylaxis.

BACKGROUND: Men who have sex with men (MSM) and who engage in condomless anal intercourse with casual partners are at high risk of acquiring sexually transmitted infections (STIs), but reliable epidemiological data are scarce. Studies on HIV pre-exposure prophylaxis (PrEP) enrol MSM who indicate that they engage in behaviour that puts them at high risk of acquiring HIV. Because they also screen for STIs at regular intervals, these studies may serve as a valuable source to estimate incidence rates of STIs in this subpopulation of MSM. METHODS: We systematically searched for trials and observational studies of PrEP in MSM that reported data on the incidence of STIs during the study period. Incidence rates were calculated as events per 100 person-years (py) with 95% confidence intervals (CI). Data from individual studies were pooled building subgroups along study types and geography. We performed sensitivity analyses, including data only from studies that met pre-defined quality criteria. RESULTS: Twenty-four publications on 20 studies were included. The majority of studies reported that sexual behaviour and/or STI incidence remained stable or decreased during the study period. For syphilis, incidence rates ranged from 1.8/100py to 14.9/100py, the pooled estimate was 9.1/100py (95%-CI: 7.7-10.9). Incidence rates for gonorrhoea and chlamydia of any site ranged from 13.3/100py to 43.0/100py and 15.1/100py to 48.5/100py, respectively. Considering only studies that met the criteria for sensitivity analysis yielded pooled estimates of 39.6/100py (95%-CI: 32.9-47.6) and 41.8/100py (95%-CI: 33.9-51.5), respectively. The overall estimate for hepatitis C incidence was 1.3/100py (95%-CI: 1.0-1.8). CONCLUSIONS: Despite partly heterogeneous results, the data depict high incidence rates of STIs among MSM who engage in higher-risk sexual behaviours such as condomless sex with casual partners. This subpopulation of MSM requires access to STI screening at close intervals. By offering access to structures that provide regular STI monitoring and prompt treatment, PrEP may not only decrease HIV incidence but also have beneficial effects in decreasing the burden of STIs.

S3-Leitlinie zur Therapie der Psoriasis vulgaris Update - Kurzfassung Teil 2 - Besondere Patientengruppen und spezielle Behandlungssituationen.

Die deutsche Psoriasis-Leitlinie zur Behandlung der Psoriasis vulgaris wurde unter Verwendung der GRADE-Methodik aktualisiert. Die Leitlinie wurde aufbauend auf einer systematischen Literaturrecherche (letzte Update-Recherche am 01.12.2016) entwickelt und in einem formalen Konsensus- und Freigabeverfahren verabschiedet. Der zweite Teil dieser Kurzfassung stellt die Empfehlungen zum Tuberkulose-Screening vor und unter Therapie, zur Therapieauswahl bei Kinderwunsch, Schwangerschaft und Stillzeit, vorliegender Gelenkbeteiligung sowie zum Umgang mit Impfungen dar. Zudem werden die Empfehlungen zur Therapieauswahl bei Komorbidität mit Hepatitis und Leberfunktionseinschränkungen, HIV, Tumorerkrankungen, Erkrankungen aus dem neurologischen und psychiatrischen Formenkreis, koronarer Herzkrankheit und Herzinsuffizienz, Diabetes mellitus, Niereninsuffizienz sowie chronisch entzündlicher Darmerkrankung dargestellt.

S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 2 - Special patient populations and treatment situations.

The German guideline for the treatment of psoriasis vulgaris was updated using GRADE methodology. The guideline is based on a systematic literature review completed on December 1, 2016, and on a formal consensus and approval process. The second part of this short version of the guideline covers the following special patient populations and treatment situations: tuberculosis screening before and during psoriasis treatment, choice of psoriasis treatment for individuals wishing to have children, as well as during pregnancy and breast-feeding, and patients with joint involvement and vaccinations. In addition, recommendations on the choice of treatment are presented for patients with the following comorbidities: hepatitis and other hepatic impairment, HIV, malignancies, neurological and psychiatric disorders, ischemic heart disease and congestive heart failure, diabetes mellitus, renal impairment and inflammatory bowel disease.

Management of antithrombotic agents in dermatologic surgery before and after publication of the corresponding German evidence-based guideline.

BACKGROUND: A survey in 2012 revealed marked heterogeneity in the management of antithrombotic agents in dermatologic surgery in Germany. An evidence-based guideline on this topic was published for the first time in 2014. METHODS: Using the same study sample, we conducted an anonymous survey on the management of antithrombotic agents and familiarity with the guideline. We reported the results as relative frequencies and compared them with those from 2012. RESULTS: We analyzed a total of 208 questionnaires (response rate: 36.6 %). A large majority of dermatologists reported performing minor procedures without discontinuing low-dose aspirin (≤ 100 mg), clopidogrel, or direct oral anticoagulants. In contrast, antithrombotic management was still heterogeneous in the context of major procedures, especially among office-based dermatologists. Overall, there was an increase in the proportion of dermatologists who managed phenprocoumon, aspirin, and clopidogrel in compliance with the guideline. For example, while 53.8 % of hospital-based dermatologists and 36.3 % of office-based dermatologists had performed large excisions on continued low-dose aspirin treatment in 2012, these figures showed an increase to 90.2 % and 57.8 %, respectively, by 2017 (phenprocoumon: from 33.8 % and 11.9 % to 63.9 % and 29.9 %, respectively; clopidogrel: from 36.9 % and 23.2 % to 63.9 % and 30.6 %, respectively). Among hospital dermatologists a large proportion was familiar with the guideline and considered it to be useful. CONCLUSIONS: Our results suggest that compliance with the German guideline on the perioperative management of antithrombotics in dermatologic surgery has increased for all procedures. Despite this positive development, greater efforts are needed to improve implementation of the guideline and address barriers to its use in everyday practice.

Adjuvant treatment of anogenital warts with systemic interferon: a systematic review and meta-analysis.

BACKGROUND: Interferons are natural messenger proteins that are used to treat various disease entities. Due to their immunomodulating, antiviral and antiproliferative effects, the systemic administration of interferons after ablative treatment for anogenital warts (AGWs) has been advocated to increase clearance and decrease recurrence rates. However, studies investigating the efficacy of adjuvant systemic interferon have yielded inconsistent results. The objective of this systematic review and meta-analysis was to comprehensively assess and evaluate the available evidence from randomised controlled trials. METHODS: A literature search was conducted in Cochrane Central Register of Controlled Trials, Embase and MEDLINE. Available data were classified according to the interferon type and dosage. Pooled effect estimates were calculated for predefined outcomes. The Cochrane Collaboration's risk of bias tool was used to assess the included trials and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate our confidence in the effect estimates. RESULTS: Twelve trials were identified that met the inclusion criteria and assessed immunocompetent patients with external AGW. Compared with placebo, adjuvant alpha-, beta- and gamma-interferon were generally not significantly superior in terms of complete clearance over the short, intermediate or long term, nor with regard to intermediate- or long-term recurrence. However, the low-dose subgroup of adjuvant alpha-interferon was significantly superior compared with placebo regarding intermediate-term complete clearance and recurrence. Further data were available for the comparison of different dosages of alpha- and beta-interferon and for comparisons of the three interferon types. No significant differences were seen in these comparisons regarding efficacy. Data on quality of life were not available. CONCLUSIONS: The GRADE quality of the evidence ranged from 'very low' to 'high'. The significantly higher efficacy of low-dose alpha-interferon compared with placebo was based on a single trial, and our confidence in the effect estimates rated as 'low'. Overall, we found no reliable evidence favouring the systemic use of interferon after ablative treatment of AGW.

Off-label prescriptions and decisions on reimbursement requests in Germany - a retrospective analysis.

BACKGROUND AND OBJECTIVES: "Off-label use" is defined as the prescription of pharmaceutical products outside their approved indications. Rare diseases frequently lack "on-label" treatment options. In order to avoid reimbursement claims following the prescription of off-label drugs, physicians in Germany can - on a case-by-case basis - file an application for cost coverage with the competent health insurance prior to treatment initiation. PATIENTS AND METHODS: We conducted a chart review for cost coverage requests submitted by two outpatient clinics at a university-affiliated dermatology department between 2010 and 2012 (clinic for autoimmune diseases and urticaria clinic). Insurance providers, acceptance rates, reasons for rejection, and processing times were analyzed. RESULTS: The analysis showed that 56.8 % of applications for off-label use (n = 44) were approved during the first round. The rate increased to 75.0 % when including approvals granted after up to two rejections. The time between initial application and the response of health insurers was 49 days (median). In case of cost coverage approval, treatments were initiated 92 days (median) after the initial request. CONCLUSIONS: The present case series shows that, in the majority of cases, health insurers in Germany have agreed to reimburse the costs of proposed off-label therapies. A prospective study is required in order to evaluate whether current changes to legal regulations (GKV-Versorgungsstrukturgesetz, Patientenrechtegesetz) adequately address the problems identified.

Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review.

BACKGROUND: The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM. METHODS: We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies. RESULTS: Out of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3mg/kg in 5 trials (n=186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10mg/kg (n=45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3months and the median overall survival was 5.2-9.8months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2mg/kg) and nivolumab (3mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9months. CONCLUSIONS: UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.

Anogenital warts and other HPV-associated anogenital lesions in the HIV-positive patient: a systematic review and meta-analysis of the efficacy and safety of interventions assessed in controlled clinical trials.

OBJECTIVES: Anogenital warts (AGW, condylomata acuminata) and intraepithelial neoplasia (IEN) do not only impact health and social well-being, they are also associated with considerable costs for the healthcare systems. Immunocompromised and HIV-positive patients carry the highest epidemiological burden of human papillomavirus (HPV) infection and comprise a population specifically susceptible to treatment failures and recurrences. This systematic review aimed at identifying and appraising the available evidence from controlled studies of interventions for the treatment of AGW and IEN in immunocompromised patients. METHODS: We conducted a comprehensive literature search. The Cochrane Collaboration's tool was used to assess risk of bias in included studies. Our confidence in the (pooled) effect-estimates was evaluated according to the Grading of Recommendations Assessment, Development and Evaluation approach. All evaluations were based on data independently extracted by two review authors. RESULTS: Nine randomised controlled trials and two controlled studies were eligible, investigating external AGW, intra-anal and/or vaginal warts, and intra-anal and/or perianal IEN. The identified studies assessed imiquimod, cidofovir, fluorouracil, electrocautery, systemic interferon-α and interferon-ß, and the combination of intralesional interferon-α and podophyllin. Four studies combined an ablational intervention with either imiquimod, cidofovir, intralesional or systemic interferon-α. One study investigated an experimental therapeutic vaccination (HPV 16 E7) at different concentrations. CONCLUSIONS: The quality of the evidence ranged from 'very low' to 'moderate' and was limited by the often small samples. Evidence was available for the efficacy of electrocautery for intra-anal IEN, and imiquimod cream for external AGW. Some further interventions should be subjected to investigations in larger samples. No data on some interventions established for the treatment of AGW in immunocompetent patients such as podophyllotoxin, sinecatechins, laser ablation or trichloroacetate were available. Future trials should address these gaps and include relevant patient-reported outcomes such as health-related quality of life.

Self-administered interventions for anogenital warts in immunocompetent patients: a systematic review and meta-analysis.

BACKGROUND: Anogenital warts (AGWs, condylomata acuminata) are among the most common STIs and may severely impact quality of life (QoL). Available treatment options are characterised by a high proportion of non-responders and recurrences. OBJECTIVE: To systematically review and meta-analyse the available evidence from randomised controlled trials (RCTs) on topical treatments for AGWs considering short-term and long-term efficacy, effects on QoL and adverse events (AE). METHODS: A comprehensive literature search was performed in Cochrane Central Register of Controlled Trials, Embase and MEDLINE. Included studies were evaluated with the Cochrane Collaboration's risk of bias tool. The confidence in the pooled effect estimates was evaluated according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and categorised as 'very low', 'low', 'moderate' or 'high'. RESULTS: Eighteen RCTs met the inclusion criteria. Regarding complete clearance (CC), imiquimod 3.75% and 5% cream, podophyllotoxin 0.5% solution and gel and polyphenon E 10% and 15% ointment were superior to placebo. Although more local AE and pain occurred in the actively treated groups, differences regarding dropouts due to AE were not statistically significant. For podophyllotoxin 0.15% cream, no placebo-controlled trials were available; however, in an active-controlled trial, it was inferior to podophyllotoxin 0.5% solution with respect to CC. No significant differences were detected between imiquimod 5% cream and podophyllotoxin 0.5% solution and between polyphenon E 10% and 15% ointment. No data on the influence on health-related QoL were available. CONCLUSION: Our confidence in the pooled estimates (GRADE quality of the evidence) ranged from very low to high. Apart from the given results, other aspects such as availability, costs or patient preference have to be considered when making a treatment choice. Due to the limited number of direct comparisons, conclusions on the relative efficacy of the different treatment options are restricted.