Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

https://www.huidziekten.nl/richtlijnen/european-guideline-psoriasis-2009.pdf

European S3-guidelines on the systemic treatment of psoriasis vulgaris

mTOR-targeted therapy of cancer with rapamycin derivatives

Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.

/pdf/recent-insights-into-the-immunopathogenesis-of-psoriasis-4ih2lwo60t.pdf

Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5% to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, surveys have shown that patients still do not received optimal treatments. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologi sche Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. They were first published in 2006 and updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate and severe plaque-type psoriasis in adults including systemic therapy, UV therapy and topical therapies. The therapeutic recommendations were developed based on the results of a systematic literature search and were finalized during a consensus meeting using structured consensus methods (nominal group process).

S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update

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-naive 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.

/pdf/systemic-pharmacological-treatments-for-chronic-plaque-2dhth415p9.pdf

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

Background The identification of a highly potent immunosuppressive/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis. Objectives To investigate the efficacy and safety of sirolimus (Rapamune) for severe psoriasis when given alone or in association with cyclosporin. Methods In a randomized, double-blind, eight parallel group, pilot study in 24 out-patient centres in seven European countries, 150 patients, 18 years and older, with severe chronic plaque psoriasis were given sirolimus 0.5, 1.5 and 3.0 mg m(-2) daily for 8 weeks, either alone or in association with a subtherapeutic dose of cyclosporin (1.25 mg kg(-1) daily). Cyclosporin 5 mg kg(-1) daily was the positive control and cyclosporin 1.25 mg kg(-1) daily the negative control. The primary efficacy variable was the mean percentage reduction in Psoriasis Area and Severity Index (PASI). Safety assessments included monitoring of adverse events, clinical laboratory parameters and sirolimus/cyclosporin blood concentrations. Results The greatest mean percentage decreases in PASI were seen with cyclosporin 5.0 mg kg(-1) daily (70.5%) and with sirolimus 3.0 mg m(-2) daily + cyclosporin 1.25 mg kg(-1) daily (63.7%). Both groups demonstrated significantly better results than cyclosporin 1.25 mg kg(-1) daily (mean decrease 33.4%). Serum creatinine levels were significantly lower for groups with sirolimus alone and sirolimus plus reduced-dose cyclosporin when compared with cyclosporin 5.0 mg kg(-1) daily. Adverse events associated with sirolimus included thrombocytopenia (5%), hyperlipidaemia (9%), aphthous stomatitis (9%) and acne (13%), whereas adverse events associated with cyclosporin included hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%). Conclusions The concomitant administration of sirolimus with a subtherapeutic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.

Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial.

Background  The identification of a highly potent immunosuppressive/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis.

Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial: SIROLIMUS PLUS CYCLOSPORIN FOR PSORIASIS

A. Claudy

Papers

Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial.

Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial: SIROLIMUS PLUS CYCLOSPORIN FOR PSORIASIS