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Your Guide to Managing Psoriasis
Psoriasis is a little-known skin condition in which skin cells are produced more quickly than normal. The result is that dry scales appear on the surface of the skin. Psoriasis is associated with itchy skin, skin rashes, sores, and dry, scabby skin.
The severity of psoriasis can range from minor to pervasive and painful. It can, for example, take over large areas of the skin, such as limbs or on the back. Combating psoriasis involves eating vegan foods, reducing gluten and a range of medical treatments.
Causes of Psoriasis
In psoriasis, layers of skin build up quickly on the surface of the skin. This buildup happens faster than the skin’s normal shedding process for old skin cells. In addition, sores and other itchy scabs begin proliferating on the skin due to the buildup of excess cells.
While the exact biological cause for psoriasis is not understood, doctors suggest that disturbances to the immune system play a role. This results in healthy skin cells being attacked and dying.
In addition, a rapid production of new skin cells results in overcrowding of skin cells on the skin’s surface.
Ultraviolet Therapy for Psoriasis
One of the most effective ways to manage psoriasis is the use of ultraviolet therapy. Ultraviolet B light (UVB) and narrowband UVB therapy are some of the treatments available to combat psoriasis.
The ultraviolet light used as part of these treatments reduces the rapid growth of psoriasis-induced cells. This clears the symptoms and can result in long remissions.
You can ask your doctor if such types of treatments would be suitable in your case.
Topical Ointments and Salicylic Acid
Besides UVB light, you can also use topical ointments to reduce the severity of psoriasis or ease the effect.
Salicylic acid is one of these topical treatments. It results in the clearing of the skin in areas where psoriasis is present. As the skin sheds faster, it resembles the functioning of normal skin and the pain fades away.
Coal tar is also used in shampoos and other ointments to help shed the excess skin cells. Steroid-based ointments can also help reduce the production of excess skin cells, improving your overall skin health.
Cayenne, Fish Oil and Other Home Remedies
While medical treatments will help your condition the most, in case your psoriasis is only mild, home remedies may suffice. Oils tend to be one of the best home remedies available because they can clear away dead skin and reduce inflammation.
Aloe vera cream, applied topically, can reduce psoriasis symptoms. You can also take fish oil supplements, orally, to reduce skin inflammation and pain caused by psoriasis. Cayenne peppers have an ingredient in them that reduces itching in the skin caused by psoriasis. You may apply capsaicin cream, which is cream containing cayenne’s active ingredient, for this benefit.
Reduce Smoking or Quit Entirely
While the exact causes of psoriasis are unknown, medical data has shown that certain factors are correlated with it. Immune system conditions like HIV, for example, make one more prone to psoriasis.
Environmental factors and lifestyle habits, such as smoking, are also capable of promoting psoriasis. To help you manage psoriasis, you should reduce smoking, and, if possible, quit smoking altogether.
Avoid Stress and Other Triggers
When you are stressed, worn down, and getting little sleep, your body’s immune system is weaker than usual. These conditions are particularly ripe for a condition like psoriasis, which festers when the immune system is vulnerable. You should, therefore, avoid conditions that are overly stressful. If you have been battling psoriasis, get your immune system as strong as possible. Eat healthy and get plenty of sleep, to promote the body’s natural abilities to fight adversities.
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Which medicines, taken by mouth or injected, work best to treat a skin condition called plaque psoriasis?
Key messages
- After six months of treatment, medicines called 'biologics' seem to work best to clear patches of psoriasis on the skin.
- Longer studies are needed to assess the benefits and potential harms of longer treatment with medicines that are injected or taken by mouth to treat psoriasis.
- More studies are needed that compare these types of medicines directly against each other.
What is psoriasis?
Psoriasis is an immune condition that affects the skin and, sometimes, the joints. Psoriasis speeds up the production of new skin cells, which build up to form raised patches on the skin known as 'plaques'. Plaques can also be flaky, scaly, itchy, and appear red on white skin, and as darker patches on darker skin tones. Plaque psoriasis is the most common form of psoriasis.
How is psoriasis treated?
Treatments for psoriasis depend on how bad the symptoms are. Around 10% to 20% of people with moderate or severe psoriasis will need to take medicines that affect their immune system, to help control the psoriasis. These medicines are called systemic treatments, because they affect the whole body. These are usually taken by mouth (orally) or injected.
Why did we do this Cochrane Review?
There are three different types of systemic medicines to treat psoriasis:
- 'biologics' – proteins, such as antibodies, that target interleukins and cytokines (parts of the immune system that affect how cells behave); - small molecules – organic compounds that affect immune cells; examples include apremilast; and - non-biologic medicines – medicines that have been in use for a long time to treat psoriasis, such as methotrexate, ciclosporin and retinoids.
We wanted to find out about the benefits and potential harms of taking systemic medicines to treat psoriasis, and to see if some medicines work better than others.
What did we do?
We searched for studies that tested systemic medicines to treat plaque psoriasis.
How up to date is this review?
We included evidence up to October 2021.
What did we find?
We found 167 studies, including 19 new studies since our last search (October 2021). The studies tested 20 different medicines, covering 58,912 adults with psoriasis (average age 44.5 years) and lasted from two to six months. Of 137 studies that reported their source of funding, a pharmaceutical company provided funding for 127 studies and 10 were funded by non-commercial organisations or academic institutions.
Most studies compared the systemic medicine against a placebo (a 'dummy' treatment that does not contain any medicine but looks identical to the medicine being tested). They used a common measurement scale called the PASI (Psoriasis Area and Severity Index) to compare how well each medicine cleared psoriasis plaques from the skin, looking for a 90% improvement (called 'PASI 90'). Few studies reported on participants' well-being.
We compared all the medicines with each other using a mathematical method called a network meta-analysis.
What are the main results of our review?
All the medicines tested worked better than a placebo to treat psoriasis (measured as a 90% improvement in PASI).
Biologic medicines (that targeted interleukins 17, 23 and 12/23, and the cytokine TNF-alpha) treated psoriasis better than the non-biologic medicines.
Compared with placebo, four biologic medicines worked best to treat psoriasis, with little difference between them:
- infliximab (targets TNF-alpha);
- ixekizumab and bimekizumab (targets interleukin-17); and
- risankizumab (targets interleukin-23).
We found no significant difference in the numbers of serious unwanted events for all systemic medicines tested when compared with a placebo. However, the studies did not consistently report results about safety, such as serious unwanted events. We therefore could not create a reliable risk profile of systemic medicines.
Limitations of the evidence
We are confident in our results for the four biologic medicines (infliximab, iwekizumab, bimekizumab and risankizumab) that worked best to treat psoriasis. We are less confident in our results for serious unwanted events, because of the low number of unwanted events reported.
We are also less confident in the results for the non-biologic medicines because of concerns about how some of the studies were conducted. Further research is likely to change these results.
We did not find many studies for some of the 20 medicines included in our review. Participants in the studies often had severe psoriasis at the start of the study, so our results may not be useful for people whose psoriasis is less severe. Our findings relate only to treatment with systemic medicines for up to six months at most.
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.
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.
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.
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.
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.
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).
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).
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.
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Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis
Affiliations.
- 1 Hôpital Henri Mondor, Department of Dermatology, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil, France, 94000.
- 2 Hôpital Henri Mondor, Clinical Investigation Centre, Créteil, France, 94010.
- 3 Université Paris Est Créteil (UPEC), Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE) - EA 7379, Créteil, France.
- 4 Université de Paris, Research Center in Epidemiology and Statistics Sorbonne Paris Cité (CRESS-UMR1153), Inserm, Inra, F-75004, Paris, France.
- 5 Cochrane France, Paris, France.
- 6 Université Paris Est Créteil (UPEC), Epidemiology in dermatology and evaluation of therapeutics (EpiDermE) - EA 7379, Créteil, France.
- 7 Cochrane Skin Group, The University of Nottingham, Centre of Evidence Based Dermatology, A103, King's Meadow Campus, Lenton Lane, Nottingham, UK, NG7 2NR.
- 8 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Division of Evidence Based Medicine, Department of Dermatology, Venerology and Allergology, Charitéplatz 1, Berlin, Germany, 10117.
- 9 Centre Hospitalier Victor Dupouy, Department of Dermatology, Argenteuil, France.
- 10 The University of Nottingham, c/o Cochrane Skin Group, A103, King's Meadow Campus, Lenton Lane, Nottingham, UK, NG7 2NR.
- 11 Texas Christian University (TCU), School of Nurse Anesthesia, Fort Worth, Texas, USA.
- 12 Padiglione Mazzoleni - Presidio Ospedaliero Matteo Rota, Centro Studi GISED (Italian Group for Epidemiologic Research in Dermatology) - FROM (Research Foundation of Ospedale Maggiore Bergamo), Via Garibaldi 13/15, Bergamo, Italy, 24122.
- 13 Complexo Hospitalario Universitario de Vigo, Department of Dermatology, Meixoeiro sn, Vigo, Spain, 36214.
- PMID: 31917873
- PMCID: PMC6956468
- DOI: 10.1002/14651858.CD011535.pub3
- Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Sbidian E, Chaimani A, Garcia-Doval I, Doney L, Dressler C, Hua C, Hughes C, Naldi L, Afach S, Le Cleach L. Sbidian E, et al. Cochrane Database Syst Rev. 2021 Apr 19;4(4):CD011535. doi: 10.1002/14651858.CD011535.pub4. Cochrane Database Syst Rev. 2021. PMID: 33871055 Free PMC article. Updated.
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.
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Conflict of interest statement
Emilie Sbidian: grant support came from the French Society of Dermatology and the French Ministry of Health, France, the Programme Hospitalier de Recherche Clinique (DGOS no.APHP180680). The funding agencies have no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation and review of the manuscript. Anna Chaimani: none known. Sivem Afach: none known. Liz Doney: none known. Corinna Dressler: My institution received an unrestricted research grant from Eli Lilly for a time‐effectiveness analysis of psoriasis treatments, and a grant from the European Dermatology Forum to fund a European Guideline Development Centre. Camille Hua: nothing to declare. Canelle Mazaud: nothing to declare. Céline Phan; none known. Carolyn Hughes: none known. Dru Riddle: I serve as a speaker for Merck Pharmaceuticals speaking about sugammadex. Sugammadex is an anesthesia medication, so unrelated to this review. Luigi Naldi: I received compensation for consultancy or participating in advisory board meetings from the following pharmaceutical companies: AbbVie, Almirall, Janssen‐Cilag, Novartis, Sanofi, L'Oreal. My institution also received an unrestricted grant from AbbVie. The money did not fund the review. Ignacio Garcia‐Doval: I received money from Novartis for a presentation unrelated to psoriasis, and Janssen for meeting expenses for the Spanish Academy of Dermatology annual Congress. Laurence Le Cleach: two grants were obtained to support this review work, one from the French Ministry of Health, France (Programme Hospitalier de Recherche Clinique (DGOS no.14‐0322), and one from the French Society of Dermatology (SFD).
Clinical referee Steven Feldman: "I have received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Baxter, Boeringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, AbbVie, Cosmederm, Anacor, Astellas, Janssen, Lilly, Merck, Merz, Novartis, Qurient, National Biological Corporation, Caremark, Advance Medical, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. I am founder and majority owner of www.DrScore.com . I am a founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment."
Study flow diagram
'Risk of bias' summary: review authors'…
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for…
'Risk of bias' graph: review authors'…
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented…
Funnel plot for network meta‐analysis of…
Funnel plot for network meta‐analysis of all the outcomes AE : adverse event; lnRR…
1.1. Analysis
Comparison 1: Primary outcome ‐…
Comparison 1: Primary outcome ‐ PASI 90, Outcome 1: Conventional systemic agents versus…
1.2. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 2: Conventional systemic 1 versus…
1.3. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 3: Anti‐TNF alpha versus placebo
1.4. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 4: Anti‐IL12/23 versus placebo
1.5. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 5: Anti‐IL17 versus placebo
1.6. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 6: Anti‐IL23 versus placebo
1.7. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 7: Biologic versus conventional systemic…
1.8. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 8: Biologic 1 versus biologic…
1.9. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 9: Small molecules versus placebo
1.10. Analysis
Comparison 1: Primary outcome ‐ PASI 90, Outcome 10: Biologic versus small molecules
2.1. Analysis
Comparison 2: Primary outcome ‐…
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 1: Conventional systemic…
2.2. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 2: Conventional systemic…
2.3. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 3: Anti‐TNF alpha…
2.4. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 4: Anti‐IL12/23 versus…
2.5. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 5: Anti‐IL17 versus…
2.6. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 6: Anti‐IL23 versus…
2.7. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 7: Biologic versus…
2.8. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 8: Biologic 1…
2.9. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 9: Small molecules…
2.10. Analysis
Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 10: Biologic versus…
3.1. Analysis
Comparison 3: Secondary outcome ‐…
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 1: Conventional systemic agents versus…
3.2. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 2: Conventional systemic 1 versus…
3.3. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 3: Anti‐TNF alpha versus placebo
3.4. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 4: Anti‐IL12/23 versus placebo
3.5. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 5: Anti‐IL17 versus placebo
3.6. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 6: Anti‐IL23 versus placebo
3.7. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 7: Biologic versus conventional systemic…
3.8. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 8: Biologic 1 versus biologic…
3.9. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 9: Small molecules versus placebo
3.10. Analysis
Comparison 3: Secondary outcome ‐ PASI 75, Outcome 10: Biologic versus small molecules
4.1. Analysis
Comparison 4: Secondary outcome ‐…
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 1: Conventional systemic agents versus…
4.2. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 2: Conventional systemic 1 versus…
4.3. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 3: Anti‐TNF alpha versus placebo
4.4. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 4: Anti‐IL12/23 versus placebo
4.5. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 5: Anti‐IL17 versus placebo
4.6. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 6: Anti‐IL23 versus placebo
4.7. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 7: Biologic versus conventional systemic…
4.8. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 8: Biologic 1 versus biologic…
4.9. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 9: Small molecules versus placebo
4.10. Analysis
Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 10: Biologic versus small molecules
5.1. Analysis
Comparison 5: Secondary outcome ‐…
Comparison 5: Secondary outcome ‐ quality of life, Outcome 1: Conventional systemic agents…
5.2. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 2: Conventional systemic 1…
5.3. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 3: Anti‐TNF alpha versus…
5.4. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 4: Ustekinumab versus placebo
5.5. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 5: Anti‐IL17 versus placebo
5.6. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 6: Anti‐IL23 versus placebo
5.7. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 7: Biologic versus conventional…
5.8. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 8: Biologic 1 versus…
5.9. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 9: Small molecules versus…
5.10. Analysis
Comparison 5: Secondary outcome ‐ quality of life, Outcome 10: Biologic versus small…
6.1. Analysis
Comparison 6: Secondary outcome ‐…
Comparison 6: Secondary outcome ‐ adverse events, Outcome 1: Conventional systemic agents versus…
6.2. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 2: Conventional systemic 1 versus…
6.3. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 3: Anti‐TNF alpha versus placebo
6.4. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 4: Ustekinumab versus placebo
6.5. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 5: Anti‐IL17 versus placebo
6.6. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 6: Anti‐IL23 versus placebo
6.7. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 7: Biologic versus conventional systemic…
6.8. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 8: Biologic 1 versus biologic…
6.9. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 9: Small molecules versus placebo
6.10. Analysis
Comparison 6: Secondary outcome ‐ adverse events, Outcome 10: Biologic versus small molecules
7.1. Analysis
Comparison 7: Secondary outcome ‐…
Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 1: Biologic…
7.2. Analysis
Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 2: Small…
8.1. Analysis
Comparison 8: Secondary outcome ‐…
Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 1: Biologic…
8.2. Analysis
Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 2: Small…
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- Volume 8, Issue 1
- Targeted systemic therapies for psoriatic arthritis: a systematic review and comparative synthesis of short-term articular, dermatological, enthesitis and dactylitis outcomes
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- http://orcid.org/0000-0002-6462-4280 Iain B McInnes 1 ,
- http://orcid.org/0000-0002-0854-6222 Laura M Sawyer 2 ,
- Kristen Markus 2 ,
- Corinne LeReun 3 ,
- Celia Sabry-Grant 2 and
- http://orcid.org/0000-0002-4155-9105 Philip S Helliwell 4
- 1 College of Medical, Veterinary and Life Sciences , University of Glasgow , Glasgow , UK
- 2 Symmetron Limited , London , UK
- 3 Independent Senior Biostatistician , Sainte-Anne , Guadeloupe
- 4 Leeds Institute of Rheumatic and Musculoskeletal Medicine , University of Leeds , Leeds , UK
- Correspondence to Laura M Sawyer; lsawyer{at}symmetron.net
Introduction Randomised controlled trials (RCTs) have compared biological and targeted systemic disease-modifying antirheumatic drugs (DMARDS) against placebo in psoriatic arthritis (PsA); few have compared them head to head.
Objectives To compare the efficacy and safety of all evaluated DMARDs for active PsA, with a special focus on biological DMARDs (bDMARDs) licensed for PsA or psoriasis.
Methods A systematic review identified RCTs and Bayesian network meta-analysis (NMA) compared treatments on efficacy (American College of Rheumatology (ACR) response, Psoriasis Area and Severity Index (PASI) response, resolution of enthesitis and dactylitis) and safety (patients discontinuing due to adverse events (DAE)) outcomes. Subgroup analyses explored ACR response among patients with and without prior biological therapy exposure.
Results The NMA included 46 studies. Results indicate that some tumour necrosis factor inhibitors (anti-TNFs) may perform numerically, but not significantly, better than interleukin (IL) inhibitors on ACR response but perform worse on PASI response. Few significant differences between bDMARDs on ACR response were observed after subgrouping for prior bDMARD exposure. Guselkumab and IL-17A or IL-17RA inhibitors—brodalumab, ixekizumab, secukinumab—were best on PASI response. These IL-inhibitors and adalimumab were similarly efficacious on resolution of enthesitis and dactylitis. Infliximab with and without methotrexate, certolizumab 400 mg every 4 weeks and tildrakizumab showed the highest rates of DAE; abatacept, golimumab and the IL-inhibitors, the lowest.
Conclusions Despite similar efficacy for ACR response, IL-17A and IL-17RA inhibitors and guselkumab offered preferential efficacy to anti-TNFs in skin manifestations, and for enthesitis and dactylitis, thereby supporting drug selection based on predominant clinical phenotype.
- arthritis, psoriatic
- biological therapy
- outcome assessment, health care
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .
http://dx.doi.org/10.1136/rmdopen-2021-002074
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Key messages
What is already known about this subject.
Increasingly, choice of psoriatic arthritis (PsA) treatments are being tailored based on a patient’s exposure to prior therapies, disease severity, comorbidities and individual manifestations of disease, including enthesitis, dactylitis and axial disease.
What does this study add?
This is a contemporary and comprehensive analysis of the efficacy and safety of systemic therapies for moderate to severe active PsA, with a focus on biological disease-modifying anti-rheumatic drugs licensed in PsA or psoriasis.
In addition to American College of Rheumatology and Psoriasis Area and Severity Index responses, we report resolution of enthesitis and dactylitis, both highly relevant and for which comparative evidence is limited.
How might this impact on clinical practice or further developments?
Faced with a multitude of therapeutic options, these study results could help clinicians tailor treatment choice according to different domains of disease and provides additional evidence for developing patient-centred treatment guidelines.
Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis (PsO). 1 Up to 30% of patients with PsO may go on to develop PsA during their lifetime. 2 Annual incidence rates of PsA are estimated at approximately six per 100 000 (0.006%) in the general population, and in those with PsO, 2.7%. Affecting males and females equally, the majority of patients with PsA develop skin symptoms first, some develop skin and joint symptoms at the same time and in 10%–15% of patients, joint symptoms develop first. 1 PsA is a heterogeneous condition characterised by sore, painful and stiff joints, involving both articular and dermatological manifestations. 3 4 Due to the different patterns of involvement, PsA can mimic different inflammatory arthritides. 5 Delayed diagnosis has been identified as a contributor to poorer quality of life and disease outcomes in the long term. 6
Traditionally PsA was treated with non-steroidal anti-inflammatory drugs, corticosteroids and conventional systemic disease-modifying antirheumatic drugs (csDMARDs). 2 7 Therapy for PsA has advanced, with an improved understanding of the immunological processes underlying the pathogenesis of disease and the introduction of biological treatment (biological DMARDs, bDMARDs). Antitumour necrosis factor (TNF) agents have been shown to be successful in treating PsA across different domains of the disease. 8 Newer biological agents approved by the European Medicine Agency or the US Food and Drug Administration, or both, for the treatment of PsA include the interleukin (IL)−12/IL-23 inhibitor ustekinumab, 9 IL-17A inhibitors secukinumab 10 and ixekizumab, 11 IL-23 inhibitor guselkumab 12 and the selective T-cell costimulation modulator abatacept, 13 as well as non-biological treatments such as phosphodiesterase 4 inhibitor apremilast 14 and the Janus kinase (JAK) inhibitors tofacitinib 15 and upadacitinib. 16 Interleukin-23 inhibitors tildrakizumab and risankizumab, and IL-17RA inhibitor brodalumab, all currently licensed for the treatment of PsO, have been evaluated in the treatment of PsA and shown to be efficacious 8 17–25 as has the new JAK inhibitor filgotinib. 26
Active PsA as defined by the American College of Rheumatology (ACR) and National Psoriasis Foundation (NPF), is disease causing symptoms at an unacceptably bothersome level as reported by the patient, and judged by the examining clinician to be due to PsA based on ≥1 of the following: swollen joints, tender joints, dactylitis, enthesitis, axial disease, active skin and/or nail involvement, and extraarticular inflammatory manifestations such as uveitis or inflammatory bowel disease. 1 Current pharmacological therapy options for treating long-term active PsA vary depending on prior treatments, disease severity and comorbidities. General recommendations involve treating with anti TNF agents first, followed by IL-17A and IL-12/23 inhibitor therapies. Oral small molecule therapies apremilast and tofacitinib may also be recommended. More recently, the ACR/NPF, EULAR and GRAPPA guidelines have put greater emphasis on tailoring treatments based on the individual manifestations of PsA, including enthesitis, dactylitis and axial disease, recognising that the efficacy of bDMARDs may vary across these different domains based on their mode of action. 1 7 27
The aim of this systematic literature review (SLR) and network meta-analysis (NMA) was to identify the latest evidence and compare the efficacy and safety of all evaluated systemic therapies for the treatment of active PsA.
Materials and methods
Search strategy.
An initial search was performed on 11 March 2020 and updated on 18 August 2020 in Embase, MEDLINE, MEDLINE In-Process via Ovid and the Cochrane Library ( online supplemental table S1 ). These were supplemented by searching conference abstracts and clinical trial databases for ongoing or recently completed studies ( online supplemental table S2 ). In addition, reference lists of included studies and any relevant SLRs or NMAs identified during the screening were searched to identify further studies.
Supplemental material
Study selection.
Titles and abstracts were assessed for inclusion by one reviewer, with another reviewer performing a 40% check. Full-text articles were fully assessed by two independent reviewers. Randomised controlled trials (RCTs) in patients who were at least 16 years old with active PsA, with ≥50 patients randomised to at least one trial arm, were included in the review. Interventions of interest were limited to abatacept, apremilast, adalimumab, bimekizumab, brodalumab, certolizumab pegol, etanercept, filgotinib, golimumab, guselkumab, infliximab, ixekizumab, netakimab, risankizumab, secukinumab, tildrakizumab, tofacitinib, upadacitinib and ustekinumab. Treatments could be reported as monotherapy or in combination with another systemic therapy. Only articles published in English were considered eligible. A full set of inclusion and exclusion criteria can be found in online supplemental table S3 .
Data extraction and quality assessment
Details of the study design, baseline patient characteristics, interventions, outcomes and results were extracted by one reviewer and quality checked by another. The methodological quality of included studies was assessed by one reviewer using the Cochrane Risk of Bias tool 28 and checked by a second reviewer.
To reduce the risk of statistical heterogeneity in our analysis, we assessed clinical heterogeneity in our evidence by closely examining variability in the participants, interventions and outcomes studied. We also assessed methodological heterogeneity by looking for variability in study design and risk of bias. The aim of these assessments was to identify imbalances between trials in potential treatment effect modifiers and use this information to inform the statistical analysis plan.
Network meta-analysis
Using recommended methods for evidence synthesis, 29 a Bayesian NMA compared the relative efficacy and safety of licensed and unlicensed systemic therapies for the treatment of active PsA. Efficacy endpoints included ACR response rates (ACR20, ACR50 and ACR70), Psoriasis Area and Severity Index (PASI) response rates (PASI75 and PASI90), and the resolution of enthesitis and dactylitis (measured by any scale that represents resolution with a score of zero); safety end points included the proportion patients discontinuing due to adverse events (DAE). Relative efficacy for all endpoints was based on results reported at 12–16 weeks, where available, or up to 26 weeks if the earlier time point was unavailable. Safety outcomes were evaluated at study endpoint. All outcomes were assessed in the overall population regardless of prior bDMARD exposure, while ACR response rates were also explored in bDMARD-naïve and bDMARD-experienced subgroups.
ACR and PASI responses were analysed using a multinomial likelihood model with a probit link. Resolution of enthesitis and dactylitis, and DAE were analysed using a binomial likelihood model with a logit link. Both random-effects and fixed-effects models were run, and the goodness of fit was assessed using the deviance information criterion. For efficacy outcomes, network meta-regressions to control for cross-trial variation in placebo-arm responses were also carried out on the model with the best fit. 30 Adjusted and unadjusted models were then compared for fit, informed by the statistical significance of the regression coefficient. The model with the best fit was used to draw conclusions.
Inconsistency between direct and indirect estimates of effect was assessed for any loops in the evidence the network using the two-stage Bucher method. 31 32 Across the networks for all outcomes, there were up to four closed loops, made up of placebo, adalimumab and either ixekizumab, secukinumab, tofacitinib or upadacitinib. No evidence of inconsistency was found.
WinBUGS V.1.4 33 was used to perform all statistical analyses, using non-informative priors. After an initial burn-in of at least 20 000 simulations, convergence was confirmed through visual inspection the Brook-Gelman-Rubin diagnostic and history plots. Sampled parameters were then estimated using 50 000 simulations on three chains. Results were calculated as the absolute probabilities of response for each treatment and as treatment effects for each pairwise comparison vs placebo for each endpoint. Point estimates reflecting the median value are presented, along with 95% credible intervals (95% CrI), reflecting the range of true effects with 95% probability. For results presented on a scale that requires a baseline for calculation, a meta-analysis estimate of the placebo arm effect across the placebo-controlled trials was used. 34 Significance between comparators was determined from the 95% CrI of the treatment effect. Where it excludes the line of null effect, we can describe the difference as statistically significant.
Results for key comparators—biological therapies at doses licensed for use in PsO or PsA—are presented below. Results for all comparators, including conventional and targeted oral systemic and unlicensed biological therapies or unlicensed doses of licensed biological therapies) are presented in online supplemental file 1 along with pairwise comparisons between key comparators and selected systemic therapies.
Identification of trials
Electronic database searches identified 6701 articles. After deduplication, 4926 titles and abstracts were screened for inclusion and a subsequent 871 publication assessed for their eligibility. A further 45 articles were identified and included through searching conferences and clinical trial databases. A total of 64 RCTs reported in 478 articles were included in the SLR. Seventeen trials were not included in the NMA either because they did not report results or did not report them at a time point of interest or because the dosing regimen during the randomised treatment phase was unclear. One further trial was considered for the NMA, but due to a lack of common comparator with other studies in the network it could not be included. 35 Data from 46 unique RCTs were included in at least one NMA. Details are shown in figure 1 .
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PRISMA flow diagram. NMA, network meta-analysis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs, randomised controlled trial; SLR, systematic literature review.* Bibliographies of eligible SLR/ NMAs were reviewed to identify any RCTs that met the inclusion criteria and then excluded. # Bibliographies of eligible pooled analyses were reviewed to identify relevent RCTs that met the inclusion criteria.and included only if data were not reported in the individual RCTs.
Study and patient characteristics
Key details of trials included in the NMA are summarised in table 1 . Further details of baseline and patient characteristics from studies included in the NMA are provided in online supplemental table S4 .
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Studies included in the NMA
Patient eligibility criteria across the included studies were largely consistent. Thirty-eight trials required patients to have been diagnosed with PsA for a minimum of 3 months, 17–20 22 23 26 36–65 and 36 trials used CASPAR as PsA diagnostic criteria. 17–20 22 24 26 35 37–40 42 45–57 60–62 64 66–69 All trials except for GO-DACT 64 and MAXIMISE 69 reported the number of swollen and tender joints required at baseline.
Patients mean age at baseline was reasonably consistent across the included studies, ranging from 41.2 65 to 53.4 years. 57 More variable characteristics were the duration of PsA (ranging from 3.2 66 to 11.4 years), 43 and the percentage of females (ranging from 37.1% 63 and 64.6% 22 ). The number of patients with prior exposure to biological therapies varied across trials from 100% exposure in three trials, 47 54 57 to no exposure in twenty. 18 35 41–46 49 53 59 62–66 69–72 Twenty further RCTs reported the percentage of patients previously exposed to biologics, ranging from 3.2% 55 to 61.1%. 24 Ten trials included 100% of patients with prior exposure to csDMARDs. 24 26 35 43 45 47 53 55 56 71 Twelve further RCTs reported the percentage of patients previously exposed to csDMARDs, ranging from 13.1% 66 to 88.1%. 19
A summary of the risk of bias of included studies, as measured by the Cochrane risk of bias tool, is presented in online supplemental figures S1 and S2 . Statistics used to assess goodness of model fit for each network of evidence are presented in online supplemental table S5 .
ACR response
The ACR network for the overall population is presented in figure 2 and included 45 studies 17–20 22–24 26 36–47 49–62 65–68 70 71 of 19 treatments broken down across 44 unique treatment regimens. Figures for the evidence networks broken down by bDMARD-exposure subgroup are presented in online supplemental figures S3 and S4 .
Network diagram for ACR response note that the node size denotes total number of patients randomised to that treatment; edge line thickness denotes total number of studies informing that comparison. ACR, American College of Rheumatology; BID, twice daily; BIW, twice weekly; IV, intravenous; LD, loading dose; MTX, methotrexate; QD, once daily; QW, weekly; Q2W, every two weeks; Q4W, every four weeks; Q8W, every eight weeks; Q12W, every twelve weeks.
Figure 3 presents the ACR treatment effects of each key comparator vs placebo on the probit scale, where 0 represents no difference and negative values indicate higher response rates associated with treatment. All key comparators were more efficacious than placebo. Infliximab 5 mg in combination with or without methotrexate showed the greatest effect, followed by all regimens of etanercept: 50 mg QW, 50 mg two times in a week and 50 mg in combination with methotrexate. The poorest performing licensed biological therapies were ustekinumab (45 mg and 90 mg) and abatacept, which tended to be significantly less effective than TNFi therapies and a subset of IL-17A and IL-23 inhibitor therapies ( online supplemental table S6 ).
Forest plot of treatment effects for key comparators versus placebo on ACR response. ACR overall treatment effect was based on a random-effects model with placebo adjustment. median treatment effects and 95% credible intervals are plotted on the probit scale. Key comparators include bDMARDs at doses licensed for use in PSA or PSO. ACR, American College of Rheumatology; bDMARD, biological disease modifying anti-rheumatic drug; BIW, twice weekly; MTX, methotrexate; PSA, psoriatic arthritis; PSO, psoriasis; QD, once daily; QW, weekly; Q2W, every two weeks; Q4W, every four weeks; Q8W, every eight weeks; Q12W, every twelve weeks.
Treatment effects for other comparators included in the NMA are reported in online supplemental figure S5 . Of these comparators, the licensed oral therapies—upadacitinib, tofacitinib and apremilast—performed similarly to golimumab, IL-23 inhibitors and ustekinumab, respectively. Unlicensed comparators, such as filgotinib and remtolumab showed a strong response, though the evidence for each come from small phase 2 studies.
Treatment effects from subgroup analyses of ACR response based on prior bDMARD exposure are presented in online supplemental figures S6 and S7 . Expected probabilities of ACR 20, 50 and 70 response for the overall population as well as bDMARD-naïve and bDMARD-experienced patients are presented together in table 2 for key comparators and in online supplemental table S7 for all evaluated interventions.
Expected probabilities of ACR response by bDMARD exposure subgroup for key comparators
Thirty-six studies 17–19 23 24 26 37–46 49–53 55 59 60 62 63 65–72 assessing 33 unique treatment regimens were included in the bDMARD-naïve network and findings were consistent with the overall analysis: all key comparators were more effective than placebo. Similarly, infliximab showed the greatest efficacy, followed by etanercept. Most key comparators performed the same or slightly better among bDMARD-naive patients than in the overall analysis; only the efficacy of guselkumab appeared to decrease slightly. Ustekinumab, abatacept and apremilast remained the least efficacious licensed therapies in this subgroup.
For the subgroup of bDMARD-experienced patients, 20 studies 17 19 22–24 26 37–40 47 50–52 54 57 60 67 68 evaluating 25 unique treatment regimens were included. All key comparators, except ustekinumab, were more effective than placebo. Certolizumab performed best, followed by ixekizumab and secukinumab. The treatment effect of abatacept showed a slight improvement and brodalumab, a slight deterioration compared with the overall population analysis.
PASI response
Twenty-two studies reported PASI 75 and/or PASI 90 at 12–16 weeks and a further 14 studies reported PASI outcomes at 24 weeks, allowing for the evaluation of 37 treatment regimens (see online supplementary figure S8 for network diagram). 17–20 23 24 26 37–55 58–61 63 67 68 70 72 Figure 4 presents the PASI treatment effects of each key comparator versus placebo on the probit scale and table 3 presents the expected probabilities of PASI 75 and 90 response. Treatment effects for other comparators included in the NMA are reported in online supplementary figure S9 and online supplemental table S8 .
Forest plot of treatment effects for key comparators versus placebo on PASI response. *Based on a combination of studies reporting outcomes at week 12 or 16 and week 24; †Based on studies reporting outcomes at week 24 only note that PASI treatment effect was based on a fixed-effects model with placebo adjustment. Median treatment effects and 95% credible intervals are plotted on the probit scale. Key comparators include bDMARDs at doses licensed for use in PSA or PSO. bDMARD, biological disease modifying antirheumatic drug; BIW, twice weekly; PASI, Psoriasis Area and Severity Index; PSA, psoriatic arthritis; PSO, psoriasis; Q2W, every two weeks; Q4W, every four weeks; Q8W, every eight weeks; Q12W, every twelve weeks.
Expected probabilities of response by outcome for key comparators
All key comparators were more efficacious than placebo. Guselkumab 100 mg Q8W was associated with the largest treatment effect versus placebo, followed by brodalumab 210 mg, an IL-17RA inhibitor and the other IL-17A inhibitors—ixekizumab 80 mg (Q2W and Q4W) and secukinumab 300 mg—and infliximab. Differences between guselkumab, brodalumab and infliximab were not found to be statistically significantly different, nor were differences between brodalumab and infliximab and the other IL-17A inhibitors. Brodalumab and guselkumab were shown to be more efficacious than ustekinumab (45 and 90 mg); the 300 mg dose of secukinumab and the fortnightly dose of ixekizumab were also more efficacious than the 45 mg dose of ustekinumab. Brodalumab, ixekizumab and secukinumab 300 mg along with guselkumab, ustekinumab and infliximab were shown to be significantly more efficacious than adalimumab, certolizumab (200 mg and 400 mg), etanercept (50 mg weekly or two times in a week), golimumab 50 mg, abatacept, secukinumab 150 mg and tildrakizumab ( online supplemental table S9 ).
Of the other comparators included in the NMA, the licensed oral therapies—tofacitinib and apremilast—were associated with smaller effect sizes than most biological therapies. Unlicensed comparators, such as filgotinib and remtolumab showed a similar level of PASI response to the licensed comparators, though the evidence for each come from small phase 2 studies.
Resolution of enthesitis and dactylitis
Fourteen RCTs reported evidence on the resolution of enthesitis and 12 RCTs reported evidence on the resolution of dactylitis at 12–16 weeks and a further 10 RCTs reported evidence for both outcomes at 24 weeks, allowing for the evaluation of 22 treatment regimens in each network ( online supplemental figures S10 and S11 ). 17–19 23 24 26 37–39 45–47 50–55 59 60 62 67 68
Figure 5A,B presents the ORs for each key comparator vs placebo for resolution of enthesitis and dactylitis, respectively, and table 3 presents the expected probabilities of achieving each endpoint.
Forest plot of treatment effects for key comparators versus placebo on resolution of enthesitis (A) and dactylitis (B). *Based on a combination of studies reporting outcomes at week 12 or 16 and week 24; †Based on studies reporting outcomes at week 24 only. Note that treatment effect on resolution of enthesitis was based on a random-effects model with placebo adjustment. Treatment effect on resolution of dactylitis was based on a fixed-effects model with placebo adjustment. Key comparators include bDMARDs at doses licensed for use in PSA or PSO. bDMARD, biological disease modifying antirheumatic drug; CrI, credible interval; PSA, psoriatic arthritis; PSO, psoriasis; Q2W, every two weeks; Q4W, every four weeks; Q8W, every eight weeks.
All treatments were more efficacious than placebo in terms of the proportion of patients achieving a resolution of enthesitis, though the effects were not statistically significant for ustekinumab 45 mg and abatacept. Among the key comparators, there was little differentiation between adalimumab, ustekinumab 90 mg, secukinumab (150 or 300 mg), ixekizumab every 2 weeks, brodalumab 210 mg or guselkumab 100 mg every 8 weeks ( online supplemental table 9 ).
For the resolution of dactylitis, all key interventions except abatacept were statistically superior to placebo. Based on the median effects, the IL-17A, IL-17RA and IL-23 inhibitors ranked best followed by adalimumab and then ustekinumab. Statistically significant differences between key comparators were limited to secukinumab 300 mg, which was more efficacious than both ustekinumab and abatacept ( online supplemental table 9 ).
Among the other licensed therapies included in the resolution of enthesitis and dactylitis analyses, tofacitinib 10 mg was significantly more effective than placebo on the outcome of dactylitis, but neither tofacitinib 5 mg nor apremilast were significantly more efficacious on either outcome ( online supplemental figures 1213 and online supplemental table 9 ). Results showed filgotinib, an unlicensed therapy, to be significantly more efficacious than placebo on the outcome of enthesitis, but not dactylitis.
Discontinuation due to adverse events
Discontinuations due to AEs were reported in two ways: discontinuation from study drug, which was used in the analysis where available, or discontinuation from study. The analysis relied on DAE reported at the end of study follow-up, howsoever defined by study authors. The DAE network included 43 studies 17–20 23 24 26 36–47 49–63 65–68 70–72 2 of which were pooled 23 and 43 unique treatment regimens ( online supplementary figure S14 ). Table 3 presents the probability of patient discontinuation due to AEs for key interventions.
Withdrawal was least likely for patients on abatacept 125 mg (0.6%) and ustekinumab 45 mg (0.6%) and 90 mg (0.7%). The analysis showed that patients receiving 50 mg or 100 mg golimumab or brodalumab 210 mg would have a low probability of DAE (0.8% and 1.4%, respectively). Treatments with the greatest risk of DAE were infliximab in combination with (12.4%) and without (8.2%) MTX, tildrakizumab 100 mg every 12 weeks (11.8%) and certolizumab 400 mg every 4 weeks (8.2%) and 200 mg every 2 weeks (5.2%). All other treatments were associated with a risk between 1.9% (guselkumab every 8 weeks and secukinumab 300 mg) to 4.2% (etanercept 100 mg two times weekly). Only the differences between ustekinumab and placebo and adalimumab and placebo reached statistical significance.
Probabilities of DAE for other comparators included in the NMA are reported along with their relative effects versus placebo in in online supplemental figures S15 and S16 . Due to the low frequency of DAEs overall, there was substantial uncertainty. Although filgotinib and tildrakizumab were associated with relatively high absolute risks of DAE, there was insufficient evidence to conclude a difference. Only apremilast 30 mg and upadacitinib 30 mg were found to have a statistically significantly greater risk of DAE than placebo.
Our SLR identified 46 RCTs for inclusion in an NMA evaluating the efficacy and safety of systemic therapies for the treatment of patients with active PsA. Data for at least one outcome of interest were available for a total of 19 638 patients receiving one of 19 treatments, divided out into up to 43 unique doses or dosing regimens. We compared these treatments on the outcomes of ACR response, PASI response and resolution of enthesitis and dactylitis as well as discontinuation due to AEs and showed that most therapies licensed for active PsA or moderate to severe PsO were better than placebo and similar to one another.
In the last several years, numerous NMAs have been published comparing the efficacy of various treatments in active PsA. 73–83 This largely reflects the rapid evolution of the treatment landscape, in terms of new treatments and new clinical trials and the demand for up-to-date, rigorous comparative analyses from health technology assessment agencies. That said, none of the currently published NMAs include all evaluated treatments in this patient population. The results presented here are not dissimilar from those reported by other authors but extends the possible comparisons by taking a more inclusive approach to the available evidence.
To our knowledge, this NMA provides the most recent and comprehensive comparison of treatments evaluated for active PsA. Specifically, it is the first to include the recently published clinical trial data from EXCEED, AMVISION-1 and −2, SELECT-PsA 1 and 2 and GO-DACT. 23 53 56 57 64 Though several of the most recent clinical trials have included a head-to-head comparison of targeted therapies, such direct comparisons are still a rarity and many comparisons remain unobserved. 45 46 53 55 56 61 In their absence, the network meta-analytical approach gives the most reliable estimate of comparative efficacy and safety. Indeed, where it is possible to compare the results from a head-to-head RCT with those generated in our NMA, they are in broad agreement. For example, EXCEED 53 directly compared secukinumab and adalimumab and reported a risk ratio of 1.05 (95% CI 0.89 to 1.26) for the outcome of ACR50. The risk ratio generated from the NMA for the same comparison was 1.02 (95% CrI: 0.85 to 1.21). Similarly, SPIRIT H2H 45 and SPIRIT P1 46 both compared ixekizumab and adalimumab and ACR 50 outcomes at week 16 result in risk ratios of 0.96 (95% CI 0.69 to 1.33) and 1.57 (0.88 to 2.8), respectively. Meta-analysing these results in a pairwise fashion gives rise to a pooled treatment effect of 1.05 (0.89 to 1.23) which is comparable to the effect of 1.01 (95% CrI 0.76 to 1.3) generated in the NMA.
This NMA was based on a systematic review of RCTs evaluating a range of treatments, licensed and unlicensed. We followed a protocol designed for the systematic review; however, this was not registered online. English-language publications were searched, which has the potential to introduce bias; however, we believe this was unlikely to have had a substantial impact on our findings.
We intentionally took a broader approach to the comparators of interest than other recent NMAs, which restricted their inclusion criteria to licensed therapies only. We were interested in comparing any drug, at any dose, that has been evaluated in an RCT among patients with active PsA. This approach meant we could include evidence for recently approved drugs or those in late-stage development, but not yet approved. It also meant that we could assess drugs or doses of drugs that are licensed for the treatment of PsO and see how they performed in patients with PsA, on both dermatological and rheumatological outcomes. Results from our analysis of PASI response among patients with PsA show a similar pattern to those from other NMAs among patients with PsO, which indicate the highest levels of response among IL-17A, IL-17RA and IL-23 inhibitor therapies. 84–90
We opted to evaluate unique doses and dosing regimens of different treatments rather than pooling across treatments in order to ensure the usefulness of the data to clinical decision-making. Although pooling all doses and dosing regimens for a given treatment would simplify the networks and streamline the analysis, the results could be misleading. Combining any evaluated dose of a drug included in phase 2 dose-finding studies with ultimately licensed doses could introduce bias by failing to take account of potential dose-response relationships and heterogeneity. The sheer volume of strategies evaluated in RCTs of PsA are reflected in our networks and are presented in full in online supplemental materials , but for the easier interpretation of results, we focused on a subset of 20 key comparators—biological therapies licensed for the treatment of PsA or PsO—that would be most relevant to clinicians.
The SLR identified phase 2, dose-finding studies for risankizumab and bimekizumab, but their small sample size failed to meet the inclusion criteria for further consideration. 21 91 Results from the two KEEPsAKE phase 3 studies for risankizumab are anticipated, with preliminary results suggesting that risankizumab is associated with strong ACR and PASI responses. Phase 3 studies of bimekizumab in PsA are ongoing ( NCT03895203 , NCT03896581 ) however, completed studies in moderate to severe PsO suggest that bimekizumab will at least have a significant effect on PASI outcomes. 92 93 Future updates of these NMAs should include these studies and assess the comparative efficacy and safety of both new therapies.
We focused on commonly investigated outcomes in PsA, including ACR and PASI response rates for efficacy and DAE for safety and tolerability. In addition, we presented results for the resolution of enthesitis and dactylitis, symptoms experienced by more than half of people with PsA and which contribute to disability and quality of life impairment. 94 Both outcomes are highly relevant for PsA, for which comparisons in the literature are limited. 79–82 Looking at this suite of outcomes helps to contextualise the evidence across disease markers relevant to the patient, including intra-articular, extraarticular and dermatological manifestations of PsA as well as the tolerability of the drugs. Outcomes such as Psoriatic Arthritis Response Criteria (PsARC) and the Health Assessment Questionnaire (HAQ) are also well reported secondary endpoints across the RCT evidence base and have been compared in other NMAs. 78 80 81 95 One recent NMA also compared therapies in terms of their efficacy against structural damage using the van der Heijde-Sharp score. 83 Outcomes such as PsARC and HAQ have been associated with issues of reliability, in that the former is not fully validated and may be easily achieved, as evidenced by high placebo response rates 96 and the latter may be influenced by other factors, including co-morbidities and duration of disease. 97
Wherever possible, outcomes reported at 12–16 weeks were synthesised. In the few cases where data were not available at this time point, outcomes reported at week 24 were extracted and included in the analysis. For the outcome of ACR response among the full study populations, all RCTs reported outcomes at the earlier time point; however, there was more diversity for the subgroup analyses on ACR response and for the secondary outcomes of PASI and resolution of enthesitis or dactylitis. For example, the DISCOVER studies 17 18 of guselkumab, the ASTRAEA study 24 of abatacept and the PSUMMIT studies 59 60 of ustekinumab reported PASI, dactylitis and enthesitis outcomes at week 24 only. Similarly, the only PASI response evidence for etanercept was reported at week 24. 63 72 For therapies such as adalimumab, ixekizumab and secukinumab, evidence was available for each from studies of varied follow-up, such that the effect sizes reflect a pooling of evidence at week 12 or 16 and week 24. These effects were synthesised with the evidence for drugs evaluated in studies reporting outcomes at week 12 or 16. 22 23 26 40–44 54–58 65
Pooling across a narrower time range may have been more appropriate as relative efficacy, particularly for outcomes defined by larger percentage improvements from baseline, continues to increase between 4 and 6 months. This trend is particularly marked for PASI 75, PASI 90 and PASI 100 outcomes, as illustrated in the trends over time from studies such as RAPID-PsA, GO-REVEAL, SPIRIT P1, SPIRIT P2 and Gottlieb et al . 20 40 41 46 47 The pooling of evidence across time points has the potential to introduce an important source of heterogeneity leading to bias against drugs studied over a shorter period, such as brodalumab, tildrakizumab, certolizumab, golimumab, infliximab and tofacitinib. This limitation had to be weighed against the fact that excluding evidence beyond 16 weeks would have limited the ability to make comparisons between some of the most relevant comparators. Authors of a recent NMA chose to synthesise all outcomes reported at the study defined endpoint, anywhere from 12 to 26 weeks, regardless of the potential heterogeneity introduced. 83 Their results were broadly aligned with those presented here and not dissimilar from the results of evaluations in patients with moderate to severe PsO. 84–88
Finally, the focus of these comparative analyses has been on outcomes reported between 3 and 6 months because this is the minimum duration of most RCTs in PsA. PsA is a chronic, lifelong condition, therefore, a better understanding of the biological drugs and targeted therapies beyond this short induction period would be worthwhile. Future work could explore the feasibility and appropriateness of comparisons of longer-term outcomes and possibly the synthesis of real-world registry studies. Indeed, an extension to other types of evidence, may be helpful to assess the durability of response and to detect rarer safety endpoints that may only emerge with long-term treatment.
Conclusions
Results of this NMA confirm the efficacy and acceptability of bDMARDs in patients with active PsA. The anti-TNF therapies infliximab, etanercept, golimumab and certolizumab were among the most effective therapies for ACR response, though the differences between them and other key interventions in these networks including adalimumab, the interleukin-17 inhibitors and guselkumab were small and not statistically significant. Results were consistent across subgroups of patients with and without prior exposure to bDMARDs. Interleukin-17 inhibitors—brodalumab, ixekizumab and secukinumab—along with guselkumab, were the most effective therapies on the outcome of PASI response, followed closely by infliximab and then golimumab, ustekinumab and adalimumab. Although data on the outcomes of enthesitis and dactylitis resolution were comparatively sparse, the analysis showed that adalimumab, guselkumab and IL-17 inhibitors were broadly similar. Tolerability was similar across drugs, though infliximab, certolizumab and tildrakizumab were associated with higher levels of discontinuation due to adverse events.
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Acknowledgments.
The authors would like to thank Emma Borg, Rikke Kongerslev and Bryony Langford for project management support and technical advice during the systematic review and Michala Mangor Bandier and Samuel Haftel for editorial assistance in writing up the research.
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Supplementary materials
Supplementary data.
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- Data supplement 1
Contributors All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, contributed substantially to the conception and design (IBM, LMS, KM, CML, CS-G and PH), acquisition of data (LMS, KM and CS-G), analysis of the data (LMS and CML), interpretation of data and drafting of the manuscript (IBM, LMS, KM, CML, CS-G and PH). All authors revised the manuscript critically for important intellectual content, approved the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. On behalf of all authors, LMS acts as the guarantor of the work.
Funding This study was funded by LEO Pharma A/S.
Competing interests IBM has received consulting fees and research funding from Astra Zeneca, Abbvie, Amgen, Boehringer Ingleheim, BMS, Cabaletta, Compugen, Causeway Therapeutics, Eli-Lilly, Evelo, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB. LMS is an employee of Symmetron Limited and CML was contracted by Symmetron Limited, which received funding from LEO Pharma for this research. CS-G and KM were employed by Symmetron Limited at the time the review was undertaken and the manuscript was written. PH received consulting fees (Eli Lilly) and fees for educational services (Abbvie, Amgen, Pfizer, Novartis, Janssen).
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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- Original Research
- Open Access
- Published: 07 July 2022
Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis
- April Armstrong 1 ,
- Kyle Fahrbach 2 ,
- Craig Leonardi 3 ,
- Matthias Augustin 4 ,
- Binod Neupane 5 ,
- Paulina Kazmierska 6 ,
- Marissa Betts 2 ,
- Andreas Freitag 6 ,
- Sandeep Kiri 7 ,
- Vanessa Taieb 8 ,
- Mahmoud Slim 5 ,
- Natalie Nunez Gomez 9 &
- Richard B. Warren 10
Dermatology and Therapy volume 12 , pages 1777–1792 ( 2022 ) Cite this article
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Introduction
Biologic treatments are increasingly being used in the management of moderate to severe plaque psoriasis (PSO). Bimekizumab is a selective inhibitor of both interleukin (IL)-17A and IL-17F approved for the treatment of moderate to severe PSO. Although bimekizumab trials provide comparisons to secukinumab, adalimumab and ustekinumab, there are no further head-to-head comparisons of bimekizumab to other biologics. This network meta-analysis (NMA) aimed to compare the short-term efficacy of bimekizumab versus other biologic systemic therapies for moderate to severe PSO.
A systematic literature review was conducted to identify randomised controlled trials (RCTs) in patients with moderate to severe PSO. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews and PsycINFO were searched on July 1, 2020. An enhanced multinomial Bayesian NMA model was used to evaluate the comparative efficacy in 50%, 75%, 90% and 100% improvement from baseline Psoriasis Area and Severity Index (PASI 50/75/90/100) at 10–16 weeks. The model was also adjusted for baseline risk, given the variable placebo responses across the trials.
Eighty-six RCTs (including 34,476 patients) were included in the NMA. IL-17 and IL-23 inhibitors were the most effective treatments across all PASI levels. At 10–16 weeks, bimekizumab had the highest probability of achieving PASI 75 (92.3%), PASI 90 (84.0%) and PASI 100 (57.8%). Bimekizumab demonstrated statistical superiority over all biologics in achieving PASI 90 and PASI 100 thresholds. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab and ixekizumab.
This analysis demonstrated that IL-17 and IL-23 inhibitors were highly effective in achieving short-term improvement among patients with moderate to severe PSO. Patients receiving bimekizumab were significantly more likely to achieve PASI 90 or PASI 100 within 10–16 weeks of the first injection than all other biologics.
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Plaque psoriasis (PSO) is an immune-mediated disease characterised by flaky, scaly, itchy and red skin plaques [ 1 ] and accounts for up to 90% of psoriasis cases [ 2 ]. PSO affects approximately 1.5% to 2% of the general population of Western Europe and North America with incidence rates peaking in the 4th decade of life [ 3 ]. Severity of PSO depends on location, symptom profile and intensity, surface area involved and impact on daily functioning [ 4 ]. About 20% of patients with PSO have moderate to severe disease, which is commonly defined as involving > 10% of the body or affecting crucial body parts [ 2 , 5 ]. Severe disease is associated with increased mortality, substantial impact on quality of life and major economic burden to health systems [ 6 , 7 ].
Conventional therapies, including systemic non-biologic drugs such as methotrexate and cyclosporine, are widely used and recommended by several practice guidelines including the Joint American Academy of Dermatology and the British Association of Dermatologists guidelines for the management of psoriasis [ 8 , 9 ]; however, their efficacy is limited in patients with moderate to severe PSO, and they are associated with a risk of major long-term toxicity [ 10 ]. Biologic therapies have revolutionised the management of PSO, offering highly effective and tolerable treatment options to healthcare providers and patients. They are generally recommended for patients who have a total Psoriasis Area and Severity Index (PASI) score ≥ 10, a Dermatology Life Quality Index (DLQI) score > 10 and are resistant to treatment with traditional systematic drugs based on intolerance, contraindications or failure in response [ 11 ]. Currently approved groups of biologic therapies for PSO include interleukin (IL) antagonists and tumour necrosis factor (TNF)-α targeting agents. IL antagonists target pro-inflammatory cytokines, including the IL-12/23p40 antibody (ustekinumab), and, more recently, inhibitors of IL-17A (secukinumab and ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab and risankizumab) [ 12 ]. Bimekizumab, presently approved in Australia, Canada, the European Union, Japan and the UK [ 13 , 14 , 15 , 16 , 17 ], is the only approved selective inhibitor of both IL-17A and IL-17F. IL-17F is abundant in skin lesions and can drive inflammation independently of IL-17A [ 18 ]. Bimekizumab prevents these cytokines from binding to their cellular targets, inhibiting them from promoting inflammation, and thus reducing the symptoms of PSO. With its novel dual inhibition mechanism of IL-17A and IL-17F, bimekizumab has recently been reported to offer a rapid and durable skin clearance in patients with moderate to severe PSO [ 19 , 20 , 21 , 22 ].
Evidence on the role of biologic treatments in the management of moderate to severe PSO is largely based on placebo-controlled randomised controlled trials (RCTs). Although bimekizumab trials (BE RADIANT, BE SURE, BE VIVID) [ 20 , 21 , 22 ] provide head-to-head comparisons to secukinumab, adalimumab and ustekinumab, there are no direct comparisons of bimekizumab to other biologics. Indirect or mixed treatment comparisons are necessary for informing decisions about treatment choices by clinicians and patients. The objective of this network meta-analysis (NMA) was to compare the efficacy of bimekizumab and other approved biologic systemic therapies for moderate to severe PSO. The analysis focused on the efficacy data at the end of induction treatment (10 to 16 weeks)—specifically, the proportions of patients achieving commonly reported percentage changes with the PASI relative to baseline.
Systematic Literature Review
This systematic literature review (SLR) was conducted in accordance with the Cochrane Collaboration [ 23 ] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [ 24 ] guidelines to identify RCTs assessing the short-term efficacy and safety of biologic and non-biologic therapies in the management of moderate to severe PSO. Searches of MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and PsycINFO were conducted on March 5, 2019, and updated on July 1, 2020, to identify English-language studies conducted on humans. Database searches were conducted using search terms and keywords for moderate to severe PSO, approved treatments for the disease and study design of interest (i.e., RCTs) (Table S1 to Table S4 in the electronic Supplementary Material), and were supplemented by a review of proceedings from seven PSO-related conferences published between 2016 to 2020 . Bibliographies of relevant SLRs identified in the search (published between 2016 and 2020) were manually examined for any studies not identified by the searches.
Data from five bimekizumab trials were included in the SLR. These included the published phase 2b (BE ABLE 1 [ 19 ]) and four phase 3/3b trials that were not yet published at the time of the review (data on file for BE READY, BE SURE, BE VIVID and BE RADIANT were made available [ 25 , 26 , 27 , 28 ]).
Study Selection
Articles identified through database searching were screened against the pre-defined inclusion/exclusion criteria, defined by the population, interventions, comparators, outcomes, study design, and time framework (Table S5 in the electronic Supplementary Material). Articles were included if they reported on RCTs investigating the efficacy (assessed via percentage improvement in the PASI from baseline) of biologic therapies (at dosages approved by the European Medicines Agency) and non-biologic therapies at the end of the induction treatment phase (10 to 16 weeks) for adults with moderate to severe PSO. Phase 2 trials were considered for inclusion only if two treatments arms were evaluated (i.e., a licensed dose strength of a biologic intervention of interest and placebo); additional treatment arms of unlicensed dose strengths were excluded from the evidence base. Title and abstract screening and full-text review were conducted independently by two reviewers. Discrepancies were resolved by consensus or by a third, more senior reviewer.
Data Extraction and Risk-of-Bias Assessment
Data from the included studies were extracted by one researcher into pre-designed standardised data extraction forms. Data elements included study characteristics and patient characteristics (including demographic characteristics, comorbidities, disease duration and prior treatment), treatment details and outcomes of interest for each RCT. All extractions were independently validated by a second investigator. The quality of all RCTs was assessed using the Cochrane Risk of Bias Assessment Tool 2.0 [ 29 ].
When more than one publication was identified for the same RCT, data extracted from the primary publication were supplemented with more recent data available in related publications.
NMA Assumptions
NMAs are based on the assumption that the underlying relative treatment effects (between any two specific treatments, after disregarding the sampling error) are the same in all trials [ 30 ]. This study assessed the presence of potential effect modifiers [ 31 ], such as disease duration, baseline PASI scores, prior biologic therapy use, and presence of comorbidities to confirm consistency and similarity among the eligible trials that connected to the network. Since placebo response may also interact with relative treatment effect, these differences were examined and are presented in Figure S1 in the electronic Supplementary Material. Small differences in treatment doses and schedule in the non-biologic treatments cyclosporine and methotrexate were assumed to have no impact on relative effects; this assumption was based on expert clinical review and allowed for network connectivity.
A Bayesian multinomial likelihood NMA model (probit link) was conducted to compare the relative effects for 50%, 75%, 90% or 100% improvement from baseline (PASI 50/75/90/100) across treatments at 10 to 16 weeks. This time frame encompasses the range of stated primary end point time points across studies, and we selected PASI findings at the stated primary end point for each of the studies included in the NMA. This study explored clinical heterogeneity and the performance of NMA models using unadjusted and adjusted models per the National Institute for Health and Care Excellence (NICE) Decision Support Unit recommendations [ 32 , 33 , 34 ]. This NMA focused on efficacy outcomes, and safety data were not incorporated.
The NMA was based on the NICE NMA model for standard multinomial analysis [ 34 ] including a component for baseline risk. Baseline risk was considered as the relative effects of drugs in autoimmune diseases, particularly for treatment response, may depend on baseline risk (i.e., the placebo rate and relative effect of a treatment versus placebo are often related [ 34 ]).
Furthermore, because the standard multinomial model assumes that a relative treatment effect (i.e., probit difference) is identical for all PASI levels, we modified the model to allow the relative treatment effects to vary across PASI thresholds. This modification, introduced by Fahrbach et al. in another NMA of moderate to severe PSO [ 35 ], added a random-effects (RE) component to the parameter z and is referred to below as the ‘REZ’ model. This addition models each treatments’ increase in difficulty to the next-highest PASI cut-off as varying around a common mean while the standard model assumes all treatments have exactly the same mean difficulty (in probit terms) in achieving a higher PASI cut-off. The practical impact of this model addition is that it allows treatment rankings to differ across different PASI cut-offs, which is not possible under the standard model.
All analyses were run with fixed-effects (FE) and RE modelling for relative treatment effects. Eight different analytic scenarios were tested by crossing FE/RE for treatment effects with the aforementioned modelling modifications (i.e., the inclusion/exclusion of baseline risk and the use of standard versus REZ modelling). Binomial analyses with a logit link for all PASI responses were performed as sensitivity analyses; however, some interventions were not compared because of lack of trial data. In addition, the rarity of events for PASI 100, particularly in the placebo arms of numerous trials, precluded the conduct of the binomial sensitivity analysis for this threshold.
The posterior mean residual deviance and deviance information criteria (DIC) were used to compare the goodness of fit of the eight analytic multinomial models (i.e., a better-fitting model is generally one with a DIC smaller by > 5 points) [ 34 , 36 ]. Other considerations for the selection of the base case model included the current understanding of PSO (i.e., relative effects depend on placebo rates) [ 31 ], practice of the analytic approaches, expert opinion and data availability.
A Bayesian NMA was conducted (see the appendix in the electronic Supplementary Material for detailed description of the prior choice, Monte-Carlo simulations and model convergence assessment) from which the median and (2.5th and 97.5th) percentiles of the posterior samples for each effect were used to estimate the effect (e.g., probit differences between treatments) and its 95% credible interval (CrI) and to obtain the rank probability of a treatment being the best or better than each comparator. The estimate of the response probability of achieving each threshold (e.g., PASI 90) for a treatment was similarly obtained by summarizing the corresponding samples of probability. For easier interpretation, the risk ratio and risk difference at each threshold were calculated similarly. The number needed to treat (NNT) for each treatment vs placebo was estimated as the reciprocal of the corresponding treatment’s risk difference with placebo at each threshold. In the binomial analysis, we only estimated the odds ratios and the corresponding CrIs. We only reported the findings of PASI 75, PASI 90 and PASI 100 here although PASI 50 (threshold not of clinical relevance) data were used in our analytical models to improve the model stability given that PASI responses in the placebo arm tended to be low or completely absent with increasing PASI thresholds.
The methods to detect network inconsistency were based on NICE Technical Support Documents, which recommended the use of an unrelated mean effect model [ 37 ]. Residual deviance in each arm in each study was also obtained in the multinomial model (for which average deviance over all PASI responses was computed) to evaluate absolute fit to the data. No substantive examples of inconsistency or heterogeneity were detected from investigation of arm-level deviances from the different models that were investigated (badly fitting data contribute to high heterogeneity, inconsistency, or both in a network). Below, we use the frequentist terminology ‘statistically significant’ to refer to 95% CrIs that do not include 1.0 (for odds ratios or risk ratios) or 0 (for probit differences).
Bayesian NMAs of multinomial models were conducted in JAGS (version 4.3.0), and binomial NMAs were conducted in OpenBUGS (version 3.2.3).
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
SLR Search Results
The SLR searches yielded 4922 unique publications from the electronic literature databases and 107 from other sources. After screening, 354 publications met the inclusion criteria for the comparative efficacy and safety outcomes. Eighty-six of these trials (reported across 80 publications), including 34,476 patients, met the inclusion criteria for the planned efficacy NMAs. The flow of included studies in the SLR and NMA is summarised in Fig. 1 .
PRISMA Flow Diagram of Study Inclusion and Exclusion of Clinical Efficacy and Safety. NMA network meta-analysis, OLE open-label extension, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RCT randomised controlled trial, SLR systematic literature review
Study and Patient Characteristics
Among the included studies, 56 reported on phase 3 or phase 3b trials, 10 were phase 2, 3 were phase 2/3, 2 were phase 4 and 15 did not report trial phase. Total sample sizes of included studies ranged from 20 [ 38 ] to 1306 [ 39 ] patients, with most studies analysing at least 100 patients. All had similar inclusion/exclusion criteria and definitions of PSO severity. Trial populations were generally similar with respect to age and sex. The mean age of participants in the different treatment arms ranged from 38.3 [ 40 ] to 55.3 years old [ 41 ] and were mostly males. The proportion of patients with comorbid psoriatic arthritis (PsA) ranged from 2.4% [ 40 ] to 36.8% [ 42 ]. Patients had moderate to severe PSO for an average of 11 [ 42 ] to 24 years [ 41 ]. Additional details on patient characteristics are presented in Table S6 in the electronic Supplementary Material. Non-biologic and biologic systemic therapies were evaluated in 16 and 76 trials, respectively. IL inhibitors were more commonly investigated biologics (k = 46) compared to TNF-α inhibitors (k = 40) with etanercept and secukinumab being the most commonly studied interventions as they were evaluated in 11 and 13 trials, respectively.
A total of 67 trials were deemed to have a low risk of bias, 14 were rated as having some concerns, and 5 had a high risk of bias. Summary assessments for each domain and the overall risk of bias are presented in Table S7 in the electronic Supplementary Material.
The feasibility assessment demonstrated that the main sources of heterogeneity among included trials were variation in geography, study years, comorbid PsA, time since diagnosis, prior phototherapy or non-biologic treatment use and prior biologic treatment use (Table S6 in the electronic Supplementary Material). Studies varied widely in reported placebo rates (Figure S1 in the electronic Supplementary Material). Accordingly, baseline-risk adjustment model was undertaken to address this heterogeneity across trials. Network diagrams for the base case analysis and the different sensitivity analyses are presented in Fig. 2 .
Network diagram for trials reporting PASI outcomes. ACTR acitretin, ADA adalimumab, APR apremilast, BKZ bimekizumab, BRO brodalumab, CSP cyclosporine, CZP certolizumab pegol, DF dimethyl fumarate, ETN etanercept, GUS guselkumab, IL interleukin, IFX infliximab, IXE ixekizumab, MTX methotrexate, PASI Psoriasis Area and Severity Index, PBO placebo, RZB risankizumab, SEC secukinumab, TIL tildrakizumab, TNF tumour necrosis factor, UST ustekinumab
NMA Results
Model fit and diagnostics.
The best-fitting model for the base case analytic scenario, which included all eligible evidence, was the baseline-unadjusted FE, REZ model. However, given the small differences in the DIC and based on clinical recommendations, the a priori choice of considering the baseline risk-adjusted model (RE REZ) was selected as our base case model. Model fit results are summarised in Table S8 in the electronic Supplementary Material. No substantive evidence of inconsistency or heterogeneity was detected across the different NMAs.
Efficacy of Bimekizumab Relative to Other Biologic Therapies at 10–16 Weeks
The base case model demonstrated that IL-17 and IL-23 (including bimekizumab 320 mg, risankizumab 150 mg, ixekizumab 80 mg, brodalumab 210 mg, guselkumab 100 mg and secukinumab 300 mg) were the most effective treatments in the network across all PASI response levels. At 10–16 weeks, bimekizumab 320 mg had the highest probability of achieving PASI 75, PASI 90 and PASI 100, with response probabilities of 92.3%, 84.0% and 57.8%, respectively (Fig. 3 , and Table S9 in the electronic Supplementary Material). Risankizumab 150 mg and brodalumab 210 mg had the second and third highest probabilities of PASI 90 and PASI 100, respectively.
Probit probabilities (95% CrI) of achieving PASI outcomes (REZ, adjusted, random-effects multinomial model). Treatments are sorted by the highest to lowest probabilities of reaching PASI 75. CrI credible interval, IL interleukin, PASI Psoriasis Area and Severity Index, TNF tumour necrosis factor
Among the TNF-α inhibitors, infliximab 5 mg/kg demonstrated the highest probability of response across all PASI response levels. Both doses of etanercept (25 mg and 50 mg) had the lowest response probabilities among the biologics (Fig. 3 ). The full results, including non-biologic treatments, can be found in Table S9, Figure S2, and Figure S3 in the electronic Supplementary Material.
Bimekizumab 320 mg was superior in achieving PASI 90 and PASI 100 at the specific thresholds compared with all other treatments in the base case model (Fig. 4 ). Differences were statistically significant for achieving PASI 90 and PASI 100 compared to all other treatments. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab 150 mg and ixekizumab 80 mg. Findings of the sensitivity analyses conducted using the binomial models were mostly consistent with the base case results for PASI 75 and PASI 90 (Figure S3).
Risk ratios (95% CrI) of achieving PASI 75, PASI 90 and PASI 100 for bimekizumab 320 mg versus other treatments (REZ, adjusted, random-effects multinomial model). Treatments are sorted by the highest to lowest probabilities of reaching PASI 75. CrI credible interval, IL interleukin, PASI Psoriasis Area and Severity Index, TNF tumour necrosis factor
Bimekizumab had the lowest NNT to achieve PASI 75, PASI 90 and PASI 100 when compared with placebo, followed by risankizumab 150 mg, ixekizumab 80 mg and brodalumab 210 mg (Table S10 in the electronic Supplementary Material). The NNTs (95% CrI) for bimekizumab to achieve PASI 75, PASI 90 and PASI 100 were 1.16 (CrI: 1.12, 1.20), 1.22 (CrI: 1.16, 1.29) and 1.74 (CrI: 1.58, 1.96), respectively.
Results of the best fitting model (i.e., baseline-unadjusted FE, REZ model) were consistent with those obtained using our base case model selected a priori (baseline-adjusted RE, REZ), whereby bimekizumab 320 mg had the highest probability of achieving PASI 75, PASI 90 and PASI 100 (Table S11 in the electronic Supplementary Material) and was superior in achieving the different PASI responses compared with all other treatments.
This SLR and NMA assessed the comparative efficacy of bimekizumab and other licensed biologic therapies for the treatment of moderate to severe PSO. These findings suggested that IL-17 and IL-23 inhibitors were the most effective treatments in the network across all PASI response levels.
Interleukin-12/23, -17 and -23 inhibitors, except tildrakizumab and secukinumab 150 mg, had a > 70% probability of achieving PASI 75 after 10–16 weeks of treatment. The superiority of IL inhibitors over TNF-α inhibitors and non-biologics in moderate to severe PSO has been well documented in several NMAs. Armstrong et al. [ 43 ] and Sawyer et al. [ 44 ] demonstrated that ixekizumab, risankizumab and brodalumab had higher response rates at 10–16 weeks versus TNF-α inhibitors and non-biologics. Wright et al. [ 45 ] showed that most NMAs evaluating the efficacy of biologic therapies concluded that IL inhibitors were superior to other available therapies in treatment of moderate to severe PSO. These findings align with the central roles IL-17 and -23 cytokines play in the pathogenesis of PSO [ 46 ]. In addition, the differences in the efficacy among IL inhibitors evaluated in our NMA can be attributed to the distinct roles played by the different cytokines in the pathogenesis of PSO. Specifically, IL-23 has been shown to play a key role in activating the Th17 pathway and the downstream production of the IL-17 cytokines such as IL-17A and IL-17F. Thus, biologic therapies targeting IL-23, including risankizumab, guselkumab and tildrakizumab have been shown to achieve high levels of skin clearance in PSO [ 47 , 48 , 49 ]. However, IL-23 inhibition does not result in a complete blockage of IL-17, which is also produced via non-Th17 cells [ 50 , 51 ]. The direct downstream inhibition of IL-17A cytokines has been also shown to be a clinically effective strategy, as demonstrated by the therapeutic benefit of secukinumab and ixekizumab in moderate to severe PSO [ 39 , 52 ]. However, given the abundance of IL-17F in psoriatic lesions [ 53 , 54 ], it has been postulated that the simultaneous selective inhibition of both IL-17A and IL-17F cytokines may provide an additional benefit compared to inhibiting IL-17A only [ 18 ]. This has been corroborated in the phase III BE RADIANT trial that demonstrated a greater clinical benefit for the selective dual IL-17A and IL-17F inhibition with bimekizumab compared to IL-17A inhibition only with secukinumab [ 21 ].
A key finding of this NMA was the superiority of bimekizumab 320 mg in achieving PASI 90 and PASI 100 at 10 to 16 weeks compared with all treatment options and superiority in achieving PASI 75 at 10 to 16 weeks compared with all treatment options, except ixekizumab 80 mg and risankizumab 150 mg. These findings were consistent when tested using the available binomial RE models, whereby bimekizumab had significantly higher odds of achieving PASI 75 and PASI 90 response levels versus all comparators (except PASI 75 versus risankizumab 150 mg). The magnitude of difference consistently increased with higher PASI responses. Bimekizumab, with its selective inhibition of both IL-17A and IL-17F, offered the additional benefit in achieving complete skin clearance within 10 to 16 weeks of treatment. While Sbidian et al. [ 55 ] found that bimekizumab ranked fourth behind infliximab, ixekizumab and risankizumab in achieving PASI 90, their NMA included only a single RCT assessing the efficacy of bimekizumab (BE ABLE 1, a phase 2 dose-finding study, with only 40 patients receiving the licensed dose strength of 320 mg) [ 19 ], and estimates of relative effects between treatments were more imprecise than in the current study, which used data from four bimekizumab phase 3/3b trials (BE READY, BE SURE, BE VIVID, and BE RADIANT) [ 25 , 26 , 27 , 28 ]. They also included trials investigating non-approved therapies and assessed PASI within a wider time frame (8 to 24 weeks). Although these methodologic differences limit direct comparability, our findings showed that with the inclusion of additional evidence, bimekizumab had a substantial advantage in achieving higher PASI response rates compared with other biologic and non-biologic therapies at 10 to 16 weeks.
The results of our NMA were consistent with the recently published NMA conducted by Armstrong et al. [ 43 ] and Shear et al. [ 56 ]. Both NMAs demonstrated that biologic treatments were superior over non-biologic treatments in improving short-term PASI outcomes. Among biologics, both NMAs showed that IL inhibitors had better efficacy compared with TNF inhibitors. However, unlike our NMA, none of the aforementioned NMAs included trials that evaluated the efficacy of bimekizumab in PSO. The scope of this NMA differed from several other previously published NMAs; for example, some evaluated unlicensed dosages of available therapies (Jabbar-Lopez et al. [ 57 ] and Sbidian et al. [ 55 ]) restricted analysis to comparisons of specific treatment classes (Bai et al. [ 58 ] and Xu et al. [ 59 ]), included paediatric patients (Jabbar-Lopez et al. [ 57 ]) or had a different follow-up time (Xu et al. [ 59 ] and Sbidian et al. [ 55 ]). Our NMA employed distinct methodologic approaches at the level of evidence generation, which aimed to provide clinically meaningful comparative effect estimates among the biologics. For example, the protocol was limited to approved treatments with licensed dosages and restricted the follow-up period (10–16 weeks), which facilitated the interpretation of results in a healthcare decision-making setting.
This study employed the REZ model—an enhancement to the standard multinomial analysis model—to study the comparative efficacy of non-biologic and biologic interventions in achieving improvement in PASI outcomes [ 35 ]. The REZ model addresses the inherent drawbacks of both the binomial and standard multinomial models. For instance, in a binomial model, treatments with missing data for certain thresholds are excluded entirely from the corresponding NMA, and these models do not account for the dependence between the ordinal PASI thresholds. In addition, for PASI thresholds with very rare events, binomial models often fail to converge. While these drawbacks are addressed in standard multinomial models, which allow “borrowed strength” across PASI levels, they also assume that treatments have the exact same relative efficacy versus one another for each PASI level. The enhanced REZ multinomial model simultaneously addresses the drawbacks of both the binomial and standard multinomial models by adding a random effects component that allows for variability in relative effects across PASI levels, while still ‘borrowing strength’ through modelling a mean effect between each threshold. Fahrbach et al. [ 35 ] demonstrated that the REZ model was associated with considerably better model fit for both the FE versus RE in another NMA conducted in patients with moderate to severe PSO. A multinomial model was employed because of the advantage given by such a model of synthesizing data across dependent outcomes (e.g., PASI 50/75/90/100) simultaneously. Wright et al. [ 60 ] concluded that although the choice of multinomial versus binomial models minimally impacted the efficacy and safety estimates, they led to different results at the level of relative ranking of therapies. Baseline risk was simultaneously adjusted for, where possible. Although the unadjusted models were associated with slightly better overall fit compared to the adjusted models in our NMA, there are multiple factors that support the notion of adjusting for placebo response. Slight absolute differences in placebo response rates across trials (e.g., 3% vs 6%) greatly impact unadjusted relative treatment effects. The estimate of the slope of baseline risk was highly significant, and previous considerations of response in autoimmune disorders have also found that adjustment for baseline risk is useful [ 34 ].
The strengths of this review include its rigorous methodology, which is adherent to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and its thorough assessment and inclusion of all eligible evidence base. However, our study had some limitations. This review only captured publications available in English and published before July 2020. As a result, more recent, relevant publications may not have been included. Nevertheless, each of the IL inhibitors was represented in at least five trials in the base case network (except for tildrakizumab, which was assessed in three trials). While the inclusion of newer evidence will further improve the robustness of the NMA estimates, it is unlikely to have a substantial impact on our SLR and NMA conclusions. While no major differences in the patient characteristics were found across included trials, a degree of heterogeneity was evident in the prevalence of PsA, time since PSO diagnosis and previous use of systemic therapies. However, the adjustment of baseline risk via placebo rates adjusted for some of the potential heterogeneity in patient characteristics across the trials. Finally, our NMA only evaluated short-term PASI responses and did not investigate the comparative safety among the different treatments, as the assessment of safety end points requires longer term studies that follow substantially higher number of patients.
Conclusions
This NMA demonstrated that IL-17 and IL-23 inhibitors were highly effective in short-term improvement of PSO symptoms among patients with moderate to severe disease. With bimekizumab and its selective inhibition of both IL-17A and IL-17F, patients were significantly more likely to achieve PASI 90 or PASI 100 within 10–16 weeks of the first injection than with all other biologics. Patients with moderate to severe PSO receive lifelong therapy; therefore, future studies should evaluate the risk–benefit balance of available therapies by studying the long-term effectiveness and safety data in open-label extensions and in real-world settings.
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Acknowledgements
This study and the Rapid Service Fee was funded by UCB Pharma. Richard B. Warren is supported by the Manchester NIHR Biomedical Research Centre.
Medical Writing, Editorial, and Other Assistance
Medical writing and editorial assistance in the preparation of this article was provided by Sean Smith, Colleen Dumont, and Lauren Randall from Evidera and was funded by UCB Pharma. Samantha Martel and Grammati Sarri contributed to the design and execution of the original systematic literature review and meta-analysis, upon which this work is based. The authors also acknowledge Susanne Wiegratz from UCB Pharma for publication coordination.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Author Contributions
Substantial contributions to study conception and design: KF, MB, BN; substantial contributions to analysis and interpretation of the data: KF, MB, BN, AF, PK, SK, MS, VT; drafting the article or revising it critically for important intellectual content: KF, MB, BN, AF, PK, SK, MS, VT, AA, RW, CM, CL, MA; final approval of the version of the article to be published: KF, MB, BN, AF, PK, SK, MS, VT, AA, RW, CM, CL, MA.
Disclosures
April Armstrong: Has served as a research investigator and/or scientific advisor to AbbVie, Almirall, Arcutis, ASLAN, BI, Bristol Myers Squibb, EPI, Incyte, LEO Pharma, UCB Pharma, Janssen, Lilly, Nimbus, Novartis, Ortho Dermatologics, Sun Pharma, Dermavant, Dermira, Sanofi, Regeneron, and Pfizer. Kyle Fahrbach , Marissa Betts , Binod Neupane , Paulina Kazmierska , Mahmoud Slim : Employees by Evidera, Inc., by PPD. Craig Leonardi : Speaker (honoraria) for AbbVie, Celgene, Eli Lilly and Novartis; served as an investigator for AbbVie, Actavis, Amgen, Boehringer Ingelheim, Celgene, Coherus, Corrona, Dermira, Eli Lilly, Galderma, Glenmark, Janssen, LEO Pharma, Merck (MSD), Novartis, Novella, Pfizer, Sandoz, Stiefel and Wyeth; served on scientific advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Dermira, Eli Lilly, Janssen, LEO Pharma, Pfizer, Sandoz, UCB Pharma and Vitae. President of the International Psoriasis Council Fellow of the American Academy of Dermatology Member of the American Dermatological Association Adjunct Professor of Dermatology at St. Louis University School of Medicine. Private practice in St. Louis, MO. Matthias Augustin : Consulting fees from AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, GSK, Hexal, Janssen, LEO Pharma, Medac, Merck, MSD, Mundipharma, Novartis, Pfizer, Sandoz, UCB Pharma, and Xenoport. Andreas Freitag : Employee of Evidera at the time the research was conducted. AF is currently an employee at Cytel. Sandeep Kiri : Employee of UCB Pharma, stockholder of GSK and UCB Pharma. Vanessa Taieb : Employee of UCB Pharma. Natalie Nunez Gomez : Employee and shareholder of UCB Pharma. Richard B. Warren : Consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, and UCB Pharma; research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis, and UCB Pharma; honoraria from Astellas, DiCE, GSK, and Union.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Armstrong, A., Fahrbach, K., Leonardi, C. et al. Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis. Dermatol Ther (Heidelb) 12 , 1777–1792 (2022). https://doi.org/10.1007/s13555-022-00760-8
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Received : 16 May 2022
Accepted : 08 June 2022
Published : 07 July 2022
Issue Date : August 2022
DOI : https://doi.org/10.1007/s13555-022-00760-8
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