French guidelines on the use of systemic treatments for moderatetosevere psoriasis in adults

These guidelines were developed by the psoriasis research group of the French Society of Dermatology with the aim of providing updated decision-making algorithms for the systemic treatment of adult patients with moderate-to-severe psoriasis.Our algorithms were generated after rigorous evaluation of existing guidelines on the treatment of psoriasis and of publications concerning new systemic treatments, not yet incorporated into existing guidelines. A total of nine existing guidelines and 53 publications related to new systemic treatments were found to meet our criteria for use in the generation of the algorithms. We have proposed two new algorithms to assess therapeutic responses, both of which incorporate emerging criteria for evaluating treatment goals. Updated therapeutic strategy algorithms, incorporating both established and new systemic therapies, were also generated for the treatment of plaque psoriasis and psoriatic arthritis, together with recommendations for the treatment of particular forms of psoriasis and treatment of patients with comorbidities.The aim of these guidelines on the management of psoriasis in clinical practice was to propose updated decision-making algorithms to practitioners involved in the treatment of patients with moderate-to-severe psoriasis. The new algorithms were developed to take into account new scientific data and the emergence of highly effective new drugs for the treatment of psoriasis. Our recommendations concern adult patients with moderate-to-severe psoriasis warranting systemic therapy. Patients with psoriasis are primarily managed by dermatologists, but rheumatologists, general practitioners, nurses, and pharmacists are also involved in their treatment. These guidelines are targeted towards all health professionals involved in the management of patients with psoriasis.The initial working group was made up of three dermatologists (FA, AV, MT), without any conflict of interest with the pharmaceutical industry. Relevant papers were selected using two different methods, depending on the therapeutic agent studied. The systematic approach to assessing and adapting existing These authors contributed equally to this work.
guidelines (ADAPTE) method 1 was used for therapeutic agents already incorporated into existing guidelines, such as cyclosporin, methotrexate, acitretin, phototherapy, tumour necrosis factor (TNF) inhibitors, and ustekinumab. Published guidelines concerning the treatment of psoriasis were evaluated using the Appraisal of Guidelines, REsearch and Evaluation II (AGREE II) scale. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref] Guidelines published between January 2012 and July 2017, for which the total AGREE score was above or equal to 90 after two independent evaluations, were considered for the elaboration of the present guidelines. To identify relevant papers about apremilast, secukinumab and ixekizumab, we performed a literature search through MEDLINE database between January 2014 and October 2017 using terms from the Medical Subject Heading (MeSH):  apremilast ,  secukinumab ,  ixekizumab  and  psoriasis . The articles were all selected through Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method. [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] We focused on large and/or prospective cohorts and/or controlled randomized studies, limited to English papers. Recommendations were elaborated according to the French national authority for health (Haute Autorit e de Sant e, HAS) guidelines for clinical practice recommendations.A total of nine existing guidelines [bib_ref] Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations..., Armstrong [/bib_ref] [bib_ref] Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment..., Coates [/bib_ref] [bib_ref] The 2012 BSR and BHPR guideline for the treatment of psoriatic arthritis..., Coates [/bib_ref] [bib_ref] Treatment of nail psoriasis: best practice recommendations from the Medical Board of..., Crowley [/bib_ref] [bib_ref] European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] Recommendations for the treatment of nail psoriasis in patients with moderate to..., Langley [/bib_ref] [bib_ref] S3-guidelines on the treatment of psoriasis vulgaris (short version), Nast [/bib_ref] [bib_ref] European S3-Guidelines on the systemic treatment of psoriasis vulgaris-Update 2015-Short version-EDF in..., Nast [/bib_ref] [bib_ref] Assessment and management of psoriasis: summary of NICE guidance, Samarasekera [/bib_ref] [bib_ref] British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017, Smith [/bib_ref] and 53 publications relating to new drugs were found to meet the criteria for use in the generation of our current guidelines. Details of the keywords used in the literature search and a flowchart of our analysis of selected guidelines and publications are available as supplementary material (Appendix S1 and S2).
The first version of the manuscript was reviewed by nine dermatologists, all of whom were experts in the field of psoriasis management. If a consensus was not achieved for a recommendation, a vote was performed, and participants were asked to agree or disagree with the recommendation. The initial working group then produced a document detailing the conclusions generated by this process, indicating whether a consensus had been reached or whether there was no consensus for each recommendation. This final document was then reviewed by public and private practice practitioners involved in psoriasis treatment. These reviewers were mainly dermatologists or practitioners involved in the management of associated comorbidities, e.g. gastroenterologists, rheumatologists and endocrinologists. Thirty-four practitioners were initially solicited, out of whom 30 reviewed the guidelines. Two patients suffering from psoriasis also reviewed the document.

## When should a systemic treatment be initiated?
Our guidelines recommend that systemic therapy, including phototherapy, should be proposed to patients with any form of psoriasis meeting one of the following criteria:
- the disease is considered to be moderate-to-severe, defined as psoriasis covering over 10% of the body surface area (BSA), or resulting in a psoriasis area severity index (PASI) score >10 and/or a dermatology life quality index (DLQI) score >10;
- the disease has a significant impact on physical and social well-being, or on psychological well-being resulting in disease-related clinically relevant depression or anxiety;
- the disease is localized but cannot be controlled with topical therapy and is associated with significant functional impairment and/or high levels of distress, e.g. severe nail disease or involvement at high-impact sites (such as the palms and soles, genitals, scalp, face and flexures).

## Therapeutic objectives
Treatment goals in both the current and previously published guidelines were established with the aim of avoiding suboptimal or unnecessary treatment. Several factors should be taken into account when establishing treatment goals for systemic therapy in patients with moderate-to-severe psoriasis, including the disease severity, measured as either an absolute value or by comparison with baseline values; the coexistence of psoriatic arthritis (PsA) or any other comorbidities; the impact of the disease on the physical, psychological and social well-being of the patient; the risk-benefit ratio of continuous systemic treatment, and the patient's point of view and level of satisfaction.
A European consensus meeting of expert physicians and use of a collaborative Delphi procedure led to the generation of a decision algorithm for plaque psoriasis in 2011. [bib_ref] Definition of treatment goals for moderate to severe psoriasis: a European consensus, Mrowietz [/bib_ref] In this algorithm, a treatment response in plaque psoriasis was considered as adequate if it resulted either in a 75% reduction in the PASI (PASI 75) from baseline, or in a 50% reduction in the PASI (PASI 50) and a DLQI score of less or equal to five. Primary treatment failure was defined as not achieving a PASI 50 response.
All experts except one agreed to reject the 2011 algorithm. There is currently no consensus about treatment goals in plaque psoriasis, mainly resulting from a lack of correlative data concerning available criteria and patient satisfaction, e.g. the physical and psychological impacts of the disease need to be evaluated. Ongoing investigations of patient-reported outcomes and their correlation with absolute residual PASI scores, such as a visual analogue scale for pruritus or pain, will need to be integrated into the algorithm in the near future. Shared decision-making with patients, incorporating the safety aspects of drug interventions emerging from patient surveys, should also be incorporated.
The highly beneficial therapeutic response observed with some newly available biological agents for psoriasis treatment has led some authors to consider that certain criteria (i.e. PASI 50 and PASI 75) are outdated. [bib_ref] PASI90 response: the new standard in therapeutic efficacy for psoriasis, Puig [/bib_ref] [bib_ref] Treatment goals for psoriasis: should PASI 90 become the standard of care, Torres [/bib_ref] New criteria have emerged such as those listed below.
- Absolute PASI 3: this parameter is easier to calculate than the PASI 75 response, is independent of variations in baseline severity and better reflects the clear or almost clear status (or a physician global assessment (PGA) score of 0-1) of the patient (Expert opinion).
- DLQI 0 or 1: have been proposed as scores indicating the absence of an impact of psoriasis on quality of life (Expert opinion).
- PASI 90 and PASI 100 responses: these criteria have emerged as a result of the high efficacy of some of the most recent biological agents. However, several authors question their clinical relevance compared to other criteria, such as PASI 75 (Expert opinion).
In the absence of strong evidence from the literature and given the lack of consensus for a unique algorithm within our working group and among the interviewed experts, we have generated two updated decision algorithms for treatment goals in plaque psoriasis [fig_ref] Figure 1: Treatment goals in plaque psoriasis [/fig_ref] ; Expert opinion). Out of a total of five proposals stemming from our study, only these two algorithms were considered as acceptable by the study participants. Both algorithms use the new criteria for evaluating therapeutic response. There is no difference in therapeutic strategy between the two algorithms and it therefore remains a matter of choice as to which algorithm is used by healthcare professionals on a daily basis.
When should the treatment response be evaluated?
We found that there was no consensus regarding the optimal timing for efficacy assessments in the existing guidelines and publications that we reviewed. As a result of the specificity of each therapeutic agent, details of our recommendations for the timing of efficacy assessments are listed in the description for each molecule provided in [fig_ref] Table 1: Summary of the systemic treatment options for psoriasis  [/fig_ref] (a-k). In contrast, our study revealed that there is a consensus about the need to assess treatment efficacy and safety at regular intervals (ideally twice a year) during maintenance therapy. We recommend that the assessment frequency is managed jointly by the general practitioner and the dermatologist, and is primarily driven by the safety monitoring recommendations (Expert opinion).

## Systemic treatments for plaque psoriasis in patients without comorbidities
Our algorithm for the therapeutic strategy in patients suffering from plaque psoriasis without comorbidities is presented in [fig_ref] Figure 2: Treatment algorithm for patients suffering from plaque psoriasis without comorbidities [/fig_ref]. Treatments were classified by taking into account the following parameters: efficacy, safety, real-time follow-up data, drug survival and global price evaluation. We recommend that if the patient meets one of the criteria for initiating a systemic treatment, then methotrexate should be proposed as the preferred therapeutic option (Expert opinion). Exceptions to this recommendation include:
- patients for which there is a contraindication to the use of methotrexate (Expert opinion);
- patients that are pregnant, breastfeeding, or plan to have child in the near future (men and women); we recommend that cyclosporin is used instead of methotrexate for treatment of these patients (Grade A);
- patients for whom there is a need for short-term disease control; we recommend that cyclosporin is used instead of methotrexate for treatment of these patients (Grade B).
Narrowband UVB phototherapy (NBUVB) can also be prescribed as a first-line treatment (Grade A). Home-based NBUVB is not currently available for use in France; however, where it is available we recommend that it is offered to compliant and adherent patients who are unable to follow a clinic-based phototherapy schedule (Grade B). For patients with large thick plaques, we recommend the use of psoralen UVA phototherapy (PUVA) or re-PUVA therapy rather than NBUVB, except in young female patients (Grade C). The addition of acitretin to PUVA therapy is an option in case of failure to respond to PUVA alone (Grade A).
As a result of its lower efficacy compared to other available treatments, acitretin should not be recommended as a monotherapy in the systemic treatment strategy for plaque psoriasis. However, we concluded that it may be beneficial to propose acitretin as a treatment option for some patients with methotrexate and cyclosporin contraindications (Expert opinion).
Biologic agents are not labelled in France as first line therapies, but as a treatment options for adults with moderate-tosevere psoriasis who have not responded to at least two standard systemic therapies, or if the patient is intolerant or has a contraindication to these treatments. Thus, biologic agents could not be proposed as first line therapies in the present algorithm.
We recommend that biological agents and apremilast are prescribed only after the contraindication of, intolerance to or failure of two systemic treatments, such as methotrexate, cyclosporin, or phototherapy. No consensus was reached as to whether or not acitretin should be included with methotrexate, cyclosporin and phototherapy in the list of the two failed or contraindicated systemic treatments.
Given the low efficacy of apremilast compared to biological agents and the risk of some potentially severe adverse events associated with apremilast therapy, we recommend that therapeutic strategies using biological agents are explored prior to initiating systemic treatment with apremilast (Expert opinion). Further studies are required to establish a place for apremilast in the therapeutic armamentarium.
Taking into consideration the short-term and long-term efficacies, the long-term safety and tolerability assessments, the administration regimens and the drug survival rates of the available biological agents, we suggest that adalimumab or ustekinumab should be the preferred first-line biological agents (Expert opinion). If treatment goals are not achieved, switching between these agents (i.e. from ustekinumab to adalimumab or another TNF inhibitor, or vice versa) or initiation of IL-17 inhibitor therapy should be considered (Expert opinion).
It should be noted that the initiation of a biosimilar should be based on existing national guidelines, such as those published in France on the status of biosimilar medicines. 18

## Details on systemic treatments for psoriasis
A short description of the systemic treatments for psoriasis is provided in [fig_ref] Table 1: Summary of the systemic treatment options for psoriasis  [/fig_ref] (a-k). The clinical and paraclinical assessments associated with each treatment are described in Tables 2(a,b) and 3, respectively.

## Treatment options for patients with comorbidities or those with special circumstances
Our recommendations for patients with comorbidities or special circumstances, such as patients with an alcohol addiction or breastfeeding mothers, were generated after an exhaustive literature review of these topics. A summary of the recommendations Refer to protocol regimens of the French society of photodermatology (2016). The initial dose and increase modalities depend on the Fitzpatrick skin type and tolerance scale.
- NBUVB (outpatient or at home when available): 3 sessions/week (Grade A), 20-30 sessions (Grade A).
- PUVA: use oral psoralen at 0.6 mg/kg followed 2-3 h later by exposure to UVA irradiation: 2-3 sessions per week, for 20-30 sessions (Grade A).
- A lack of improvement after 20 sessions is considered as a failure (Grade D). - Bath PUVA: prepare the bath by diluting a 0.75% solution of psoralen in 80-100 L of water to obtain a concentration of 2.6 mg of psoralen per litre (Grade C). The bath should last 15 min and be followed by irradiation immediately after drying. The recommended doses of UVA are lower than those used for oral PUVA. Number of cumulative sessions of phototherapy during a lifetime should not exceed 200 (Grade C).

## Efficacy (monotherapy)
Onset of clinical effect: after 1 or 2 weeks. Efficacy assessment: after 20 sessions.

## Precautions
See Tables 2(a,b) and 3 on clinical and biological pre-treatment procedures and surveillance.

## Vaccination
No specific recommendation. Follow French immunization schedule. Live vaccines are permitted during treatment.

## Surgery
Phototherapy can be maintained in patients undergoing surgery if the patient's condition allows it. (2017 Optional combination therapy

## Cost in france
[formula] - Grade A with ETA, - Grade B with NBUVB, - Grade B with INFLI, - Grade C with ADA. [/formula]
Main adverse events Fatigue, nausea, vomiting, moderate hair loss, transaminase increase, bone marrow suppression, gastrointestinal and mucosal ulcerations, infections, liver fibrosis, interstitial pneumonia. [fig_ref] Table 1: Summary of the systemic treatment options for psoriasis  [/fig_ref] Continued
[formula] (b) Methotrexate (MTX) [/formula]

## Main contraindications
Severe infections, serious kidney and liver dysfunction, bone marrow suppression, men and women currently trying to conceive children, pregnancy, breastfeeding, pulmonary fibrosis or poor lung function, alcohol abuse, active peptic ulcer.

## Precautions
See Tables 2(a,b) and 3 on clinical and biological pre-treatment procedures and surveillance. Inform the patient on how to take the drug (only once a week). If liver ultrasound is abnormal at baseline: check PIIIP or Fibroscana. Fibroscana should be performed at baseline in obese patients if long-term treatment is planned. Adequate contraception for men and women is mandatory. After the end of treatment, contraception is recommended for 3 months in men and only 1 day in women (contraception should be continued until the end of treatment and conception is possible as soon as contraception is stopped).

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination. Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of MTX required prior to minor surgery (Grade B).
- Discuss interruption of MTX (30 h) prior to major surgery in patients with a history of healing disorders or wound infections (Grade C). Cost in France (2017) For 20 mg/week: between 84/year (oral form) and 1 080/year (s.c. form).

## (c) cyclosporin (csa)
Dosing scheme Starting dose - 2.5 mg/kg/day by oral delivery, divided in half and taken morning and evening (Grade A).
In the absence of comorbidity, start with 5 mg/kg for faster action (Grade B).
- If there is no adequate response to the starting dose at W4-W8, or when rapid disease control is necessary, increase the dose to a maximum of 5 mg/kg (Grade B).
- Use the ideal weight for obese patients (Grade B).

## Maintenance dosage
- Intermittent therapy (2-4 months of treatment) or continuous therapy with minimal effective dose, depending on the clinical situation (Grade B).
- Slow tapering of CSA offers a slight delay in psoriasis relapse (Grade B). - Consider other treatment options when disease relapses rapidly (Expert opinion).
- Avoid using CSA continuously for more than 2 years unless disease is severe and other treatment options cannot be used, and collaborate with a nephrologist (Grade C). Half-life 7 h.

## Efficacy (monotherapy)
Onset of clinical effect: 4 weeks. Efficacy assessment: W8.
- Short-term efficacy: PASI 75: 60-88.6% at W8-W12/PASI 90: 29% at W12/DLQI: 9.3-point reduction at W12. - Median drug survival 23.3% at 1 year.

## Optional combination therapy
Given the lack of robust data on CSA therapy in combination, we recommend not to use CSA with any other systemic treatment, including phototherapy.

## Adverse events
Renal impairment, arterial hypertension nausea, diarrhoea, liver dysfunction, gingival hyperplasia, paraesthesia, muscle pain, headache tremors, hypertrichosis, increased blood lipids.

## Main contraindications
Impaired renal function, uncontrolled arterial hypertension, severe infectious disease, history of malignancy (possible exceptions: cured basal cell carcinoma, history of in situ squamous carcinoma) or current malignancy, concomitant PUVA therapy.

## Precautions
See Tables 2(a,b) and 3 on clinical and biological pre-treatment procedures and surveillance. Be aware that CSA increases the risk of nonmelanoma skin cancers in patients already treated with phototherapy.

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination (especially the elderly). Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of CSA required prior to minor surgery (Grade B).
- Discuss interruption of CSA (35 h) prior to major surgery in patients with a medical history of healing disorders or wound infections (Grade C). Cost in France (2017) For a dose of 3 mg/kg/day in a 70 kg patient: 3 144/year.

## (d) acitretin
Dosing scheme Starting dose
- Use incremental dosing starting from 10 mg/day to achieve a target dose of 0.3-0.5 mg/kg daily (Grade B).

## Maintenance dose
- To be adapted to the clinical response and tolerance, usually between 0.5 and 0.8 mg/kg daily, with a maximum dose of 50 mg daily (Grade C). The degree of lip dryness may help to determine the maximum tolerated dose (Expert opinion). - Long-term therapy must be discussed on a case-by-case basis according to clinical and biological tolerance.
- Treatment must be initiated by a dermatologist.
Half-life 2-5 days.

## Efficacy (monotherapy)
Onset of clinical effect: 4-8 weeks. Efficacy assessment: after 3 or 4 months at the optimum dose; discontinue the treatment if response is inadequate (Expert opinion). Response rate is difficult to assess because of the low quality of published trials. PASI 75: 30% at W12-24 with a dose of 0.4 mg/kg. Drug survival at first year: 42.3%.
Optional combination therapy Level A with PUVA therapy, Level B with NBUVB,
[formula] Level B with ETA, Level C with INFLI. [/formula]
Adverse events Teratogenicity, hypervitaminosis A (cheilitis, xerosis), conjunctivitis (contact lenses may become unbearable), hair loss, photosensitivity, hyperlipidaemia, muscle, joint and bone pain, idiopathic intracranial hypertension, decreased colour vision and impaired night vision.

## Main contraindications
Severe renal or hepatic impairment. Women of child-bearing age: pregnancy, breastfeeding, desire to have children or insufficient guarantee of effective contraceptive measures up to 3 years after discontinuation of therapy. Alcohol abuse. Blood donation.

## Precautions
See Tables 2(a,b) and 3 on clinical and biological pre-treatment procedures and surveillance. Start treatment on the second or third day of the menstrual cycle, after satisfactory contraception for at least 1 month prior to treatment. Double contraception is recommended. Emphasize the need for reliable contraception in women of child-bearing age for up to 3 years after therapy. Check pregnancy test before starting treatment, then every month during treatment, and then every month for 2 months after treatment discontinuation.
There is no need for contraception in men.

## Vaccination
No specific recommendations. Follow the French immunization schedule. Live vaccines are permitted during treatment.

## Surgery
Acitretin can be safely continued in patients undergoing surgery.
Cost in France (2017

## Main adverse events
Injection-site reactions, headache and muscle/bone pain, viral, bacterial or fungal infections (including tuberculosis), weight gain, allergic reactions, anaphylactic and anaphylactic-like reactions, serum sickness or serum sickness-like reactions, autoimmune processes, worsening of congestive heart failure, neurological disorders, nonmelanoma skin cancers.

## Main contraindications
Cardiac insufficiency (NYHA grade III or IV), active tuberculosis or other serious infections, active malignancy, pregnancy, breastfeeding, demyelinating disease, hypersensitivity.

## Precautions
See Tables 2(a,b) and 3 for clinical and biological pre-treatment procedures and surveillance.

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination (especially the elderly).
Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of INFLI is required prior to minor surgery (Grade C).
- Discuss interruption of INFLI prior to major surgery in patients with a medical history of healing disorders or wound infections (Grade C). Surgery may be placed between two infusions (Expert opinion).

## Main adverse events
Injection-site reactions, headache and muscle/bone pain, viral, bacterial or fungal infections (including tuberculosis), weight gain, allergic reactions, autoimmune processes, worsening of congestive heart failure, neurological disorders, nonmelanoma skin cancers.

## Main contraindications
Cardiac insufficiency (NYHA grade III or IV), active tuberculosis or other serious infection, active malignancy, pregnancy, breastfeeding, demyelinating disease, hypersensitivity.

## Precautions
See Tables 2(a,b) and 3 for clinical and biological pre-treatment procedures and surveillance.

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination (especially the elderly).
Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of ADA required prior to minor surgery (Grade C).
- Discuss interruption of ADA prior to major surgery (3-5 half-lives = 6-10 weeks) in patients with a past medical history of healing disorders or wound infections (Grade C). Cost in France (2017) Around 11 400 for the first year for Humiraa (80 mg loading dose and 40 mg every other week, starting W1).
No biosimilar available in France in 2017.

## (g) etanercept (eta)
Dosing scheme s.c. administration.
- 50 mg BIW for up to 12 weeks, followed by 50 mg QW is a more effective strategy than 50 mg QW from the beginning of treatment (Grade A).
- Possibility of intermittent therapy (grade C).
- No weight-dose adjustment for obese patients.

## Half-life 70 h (3 days).
Efficacy ( Treatment of moderate-to-severe psoriasis

## Precautions
See Tables 2(a,b) and 3 for clinical and biological pre-treatment procedures and surveillance. The needle cover on the prefilled syringe contains dry natural rubber and should not be handled by patients allergic to latex.

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination (especially the elderly).
Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of ETA required prior to minor surgery (Grade C).
- Discuss interruption of ETA prior to major surgery (3-5 half-lives = 9-15 days) in patients with a past medical history of healing disorders or wound infections (Grade C). Cost in France (2017) Around 12

## Main adverse events
Injection-site erythema, fatigue and muscle/bone pain, diarrhoea, viral, bacterial or fungal infections (no reactivation or new onset of tuberculosis), allergic reactions, exfoliative dermatitis, MACE.

## Main contraindications
Active tuberculosis or other serious infection, pregnancy, breastfeeding, active malignancy, hypersensitivity.

## Precautions
See Tables 2(a,b) and 3 for clinical and biological pre-treatment procedures and surveillance. In patients with increased cardiovascular risk, initiate the treatment in collaboration with a cardiologist and control risk factors. The needle cover on the prefilled syringe contains dry natural rubber and should not be handled by patients allergic to latex.

## Vaccination
Follow the French immunization schedule Primary vaccination and/or boosters for HBV/annual influenza/pneumococcal vaccination (especially the elderly). Live-attenuated vaccines are contraindicated during treatment.

## Surgery
- No systematic interruption of USTK required prior to minor surgery (Grade C) - Discuss interruption of USTK prior to major surgery (3-5 half-lives = 9-15 weeks) in patients with a past medical history of healing disorders or wound infections (Grade C). Cost in France (2017) Around 14

## Adverse events
Infections (upper respiratory tract, candida), diarrhoea, neutropenia, inflammatory bowel disease onset and flare.

## Main contraindications
Hypersensitivity, active infection, pregnancy, breastfeeding, active malignancy.

## Precautions
Avoid if possible in patients with a history of inflammatory bowel disease (Grade C).
Close monitoring of patients with psychiatric disorders and/or a history of suicide attempts and/or severe depression (possible class effect -Expert opinion).
In patients with increased cardiovascular risk, initiate in collaboration with a cardiologist and control risk factors (no long-term safety assessment in patients at high cardiovascular risk -Expert opinion).

## Vaccination
Follow the French immunization schedule Primary vaccination and/or boosters for HBV and HAV/annual influenza/pneumococcal vaccination (especially the elderly). Live-attenuated vaccines are contraindicated during treatment.

## Surgery
No data available about surgery. We recommend interrupting SEC 4 weeks before performing scheduled surgery. Resume medication after healing (American College of Rheumatology and American Association of Hip and Knee Surgeons recommendations).

## Cost in france (2017) cosentyxa
- Intermittent dosing: treatment can be stopped in patients who achieve PGA 0/1 at week 12 and then reintroduced in case of relapse (80 mg every 4 weeks) (Grade C).

## Optional combination therapy no
Adverse events Infections (upper respiratory tract, candida), injection site reactions, neutropenia, inflammatory bowel disease onset and flare.

## Main contraindications
Hypersensitivity, active infection, pregnancy, breastfeeding, active malignancy.

## Precautions
Avoid if possible in patients with a history of inflammatory bowel disease (Grade C). Close monitoring of patients with psychiatric disorders and/or a history of suicide attempts and/or severe depression (possible class effect -Expert opinion).
In patients with increased cardiovascular risk, initiate in collaboration with a cardiologist and control risk factors (no long-term safety assessment in patients at high cardiovascular risk -Expert opinion).

## Vaccination
Follow the French immunization schedule. Primary vaccination and/or boosters for HBV and HAV/annual influenza/pneumococcal vaccination (especially the elderly). Live-attenuated vaccines are contraindicated during treatment.

## Surgery
No data available about surgery. We recommend interrupting IXE 4 weeks before performing scheduled surgery. Resume medication after healing (American College of Rheumatology and American Association of Hip and Knee Surgeons recommendations).

## Cost in france (2017) taltza
- 

## Optional combination therapy
No data for skin psoriasis. Can be used in combination with DMARDs in PsA (Grade C).

## Adverse events
Diarrhoea (at onset, long-term persistence possible), nausea, asthenia, insomnia, upper respiratory tract infections, headaches, depression, weight loss.

## Main contraindications
Hypersensitivity, pregnancy.

## Precautions
Avoid in patients with psychiatric disorders and/or a history of suicide attempts and/or severe depression (Expert opinion).

## Vaccination
No specific recommendation was given in the SmPC. Follow the French immuniation schedule.
No data available about live-attenuated vaccines.

## Surgery
No data available about surgery. (2017) First year (including titration) = 7061, then 7368/year Molecules are categorized into three groups: classical systemic therapies, biologic agents and apremilast. The order of presentation of molecules within each group was chosen randomly. ACR, American College of Rheumatology; ADA, adalimumab; APR, apremilast; BIW, twice weekly; CHF, chronic heart failure; CSA, cyclosporin; DLQI, dermatology life quality index; DMARDS, disease-modifying anti-rheumatic drugs; ETA, etanercept; HAV, hepatitis A virus; HBV, hepatitis B virus; INFLI, infliximab; IXE, ixekizumab; MACE, major adverse cardiovascular event; MTX, methotrexate; NBUVB, narrowband UVB phototherapy; NYHA, New York heart association; PASI, psoriasis area severity index; PIIIP, procollagen III peptide; PsA, psoriatic arthritis; PUVA, psoralen UVB phototherapy; QW, once weekly; RCT, randomised controlled trial; s.c., subcutaneous; SEC, secukinumab; SmPC, summary of product characteristics; TNFi, tumour necrosis factor inhibitors; USTK, ustekinumab; W, weight. - Make sure that the patient wears goggles and protection for chronic sun-exposed areas (face, neck) and genital regions during the session.

## Cost in france
- Adequate contraception for men and women. After the end of treatment, continued contraception is recommended for 3 months in men and for only 1 day in women (contraception should be continued until the end of treatment and conception is possible as soon as contraception is stopped).
- Inform the patient on how to take the drug (QW) and about early symptoms of AE.
- CSA is permitted during pregnancy but may increase the probability of pregnancy-related complications.
Reliable contraception is advised (note that the efficacy of progesterone-containing contraceptives can be reduced). Avoidance of excessive sun exposure.
- Follow national cancer screening recommendations (breast, cervix, colon)
- Teratogenic risk and necessity of long-term effective contraception (at least 3 years after discontinuation). Provide written information.
- Alcohol avoidance.
- Blood donation is forbidden during treatment and for up to 3 years after cessation of treatment.
- Start treatment on the second or third day of the menstrual cycle, after satisfactory contraception for at least 1 month prior to treatment.
Clinical examination before treatment Objective assessment of the disease (PASI/PGA/BSA/arthritis/DLQI) - Preneoplastic skin lesions and malignant skin lesions.
- Dysplastic nevi.
- Concomitant medication (phototoxic and immunosuppressive drugs).
- Past or active infection.
- Signs of liver cirrhosis and respiratory failure.
- Concomitant medication.
- Vaccination status.
- Medical history of arterial hypertension, malignancies, renal and liver diseases.
- Past or active infection.
- Malignancies.
- Blood pressure measurement on two separate occasions.
- Concomitant medication.
- Vaccination status.
- Concomitant medication.
- Signs of liver cirrhosis and metabolic syndrome.
Clinical examination during treatment Objective assessment of the disease (PASI/PGA/BSA/arthritis/DLQI) and evaluation of patient satisfaction - Control erythema before dosage and increase and record UV dose.
- Record the cumulative UV dose and the number of sessions.
- Lifelong screening of skin cancer is mandatory.
- AE: fatigue, nausea, vomiting, gastro-intestinal and mucosal ulcerations, signs of liver cirrhosis and respiratory failure, persistent cough.
- AE: signs of renal impairment, nausea, diarrhoea, hypertrichosis, gingival hyperplasia, paraesthesia.
- Blood pressure measurement.
- Skin cancer screening.
- Regular gynaecologic screening for papillomavirus infection. - Rare cases of hypoglycaemia during treatment in diabetic patients.
- Increased risk of infection.
- Need for contraception.
- Follow national cancer screening recommendations (breast, cervix, colon).
- Increased risk of infection, notably fungal infections.
- Need for contraception.
- Follow national cancer screening recommendations (breast, cervix, colon).
- Risk of diarrhoea and nausea after treatment initiation.
- Increased risk of infection.
- Risk of depression.
- Need of contraception.
Clinical examination before treatment Objective assessment of the disease (PASI/PGA/BSA/arthritis/DLQI) - Known chronic heart failure or heart failure symptoms.
- Adenopathy.
- Active/latent/exposure to tuberculosis.
- Active or chronic infection. - Cancer.
- Multiple Sclerosis.
- Lupus erythematosus.
- Live vaccine: recent? In the future?
- Cardiovascular risk factors.
- Adenopathy.
- Active/latent/exposure to tuberculosis.
- Active or chronic infection.
- Cancer.
- Live vaccine: recent? In the future?
- Inflammatory bowel disease (personal or familial history).
- Candidiasis.
- Cardiovascular risk factors.
- Adenopathy.
- Active/latent/exposure to tuberculosis.
- Active or chronic infection.
- Cancer.
- Live vaccine: recent? In the future? - Psychiatric disorders.
- Suicide attempts.
- Chronic infection.
- Adenopathy.
- Psychiatric disorder.
- Suicide attempts.
- Cancer.
Clinical examination during treatment Objective assessment of the disease (PASI/PGA/BSA/arthritis/DLQI) and evaluation of patient satisfaction - Weight gain.
- Injection-site reactions.
- Infections.
- Cancer (particularly nonmelanoma skin cancer).
- Cardiovascular risk factors and events (MACE).
- Injection-site reactions.
- Infections.
- Cancer (particularly nonmelanoma skin cancer).
- Cardiovascular risk factors and events (MACE).
- 

## Table 2
Continued to be considered in these patients is provided in [fig_ref] Table 4: Summary of the recommendations for systemic treatments in patients with comorbidities or... [/fig_ref]. Details of the findings are available in the full version of the manuscript (Appendix S4). - Avoid PUVA (insufficient data) (Expert opinion). - Absolute contraindication: Acitretin (Grade A).
- Consider start or maintenance of TNFi if there is no alternative (Expert Opinion).
- Avoid USTK, anti-IL17 and APR (Expert opinion): not enough available data.

## Cancer (cured)
Close collaboration with oncologist and/or multidisciplinary cancer care team.
- Prefer MTX or phototherapy (except in cases of skin cancer) or acitretin (Grade C).
- Avoid CSA (Grade A).
- Case-by-case decision (Grade C).
- The initiation of a biological agent has to be discussed with the oncologist and depends on the stage and prognosis of the tumour (Grade C).
- If no alternative, consider USTK or TNFi (prefer ETA or ADA) (Grade C).
- Not enough follow-up data for APR and anti-IL17.

## Demyelinating disease
Involve a neurologist.
- Prefer MTX (Grade C). - Consider phototherapy (Grade C).
- No data available for acitretin and CSA (be aware of the neurotoxic effects of CSA, Expert opinion).
- Prefer USTK (Grade Clonger follow-up data compared to anti-IL17).
- Consider anti-IL17 (Grade Cno negative effect of SEC on multiple sclerosis in phase II).
- Avoid TNFi (Grade C).
- No data available for APR.

## Diabetes
- Involve a diabetologist in case of uncontrolled diabetes.
- If possible, delay treatment initiation in patients with a glycosylated haemoglobin >8%. - Refer to major cardiovascular risk section below. - Not enough data but no negative feedback for anti-IL17 and APR.

## Heart failure
Involve a consultant cardiologist.

## - prefer nbuvb (grade c) or acitretin (expert opinion)
or MTX (Expert opinion).
- Avoid CSA because of the associated increase in blood pressure (Grade A).
- NYHA I or II CHF: consider TNFi (prefer ETA) or USTK (Grade C).
- NYHA III or IV CHF: prefer USTK (Expert opinion). - Avoid TNFi in NYHA class III or IV CHF (deleterious) (Grade A).
- Not enough data but no negative feedback for anti-IL17 and APR. Hepatitis B or C Involve a consultant hepatologist. - In case of active HBV infection (HBV DNA >2000 IU/ mL), TNFi must be deferred until the infection is controlled with an adequate antiviral treatment (Grade C).
- Consider TNFi (prefer ETA, Grade C) before USTK (less data available, Grade C) in cases with inactive HBV (HBV DNA <2000 IU/mL, normal transaminases, HbsAg+), in association with antiviral prophylaxis and regular liver tests and close HBV DNA load monitoring. - or resolved (anti-HBs+) HBV or in chronic HCV patients, in association with regular liver tests and close HBsAg/HCV RNA monitoring (Grade C).
- No sufficient data available for anti-IL17 or APR.

## Hiv infection
- Involve a relevant specialist.
- Optimise effective antiretroviral treatment (Grade C).
- Close monitoring of bacterial and mycobacterial infections.
- Prefer NBUVB (Grade C) rather than PUVA. - Insufficient data available for anti-IL17 and APR.

## Inflammatory bowel disease
Close collaboration with a gastroenterologist.
- Prefer MTX (Grade A).
- Consider CSA (Grade B) or NBUVB (Grade C).
- No data available for acitretin.
- Prefer ADA, INFLI or USTK (Grade A).
- Avoid Anti-IL17 (Grade C).
- No data available for APR.

## Liver disease (cirrhosis, fibrosis)
Involve a consultant hepatologist.
- Prefer NBUVB (Grade C) rather than PUVA.
- Acitretin and CSA should not be considered as first-line treatments (Grade C).
- Avoid MTX (Grade C).
- Consider TNFi or USTK in patients with steatosis or compensated cirrhosis (Grade C).
- No data are available for APR and anti-IL17.

## Major cardiovascular risk
Involve a consultant cardiologist. - Prefer TNFi or USTK (Grade B).
- Avoid APR (Grade B) and anti-IL17 (Expert opinion, possible class effect).

## Renal impairment 
Close collaboration with a nephrologist.
- Prefer NBUVB (Grade C) rather than PUVA. - Idem plaque psoriasis.

## Figure 3
Psoriatic arthritis treatment algorithmadapted from the EULAR, GRAPPA and UK NICE guidelines. [bib_ref] Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment..., Coates [/bib_ref] [bib_ref] European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] European League Against Rheumatism recommendations for the management of psoriatic arthritis with..., Gossec [/bib_ref] [bib_ref] Pharmacological treatment of psoriatic arthritis: a systematic literature review for the 2015..., Ramiro [/bib_ref] APR, apremilast; ADA, adalimumab; CSA, cyclosporin; DMARD, disease-modifying anti-rheumatic drugs; MTX, methotrexate; NSAIDs, nonsteroidal antiinflammatory drugs; PsA, psoriatic arthritis; TNFi, tumour necrosis factor inhibitors; updated in 2015 to include newly approved therapies such as IL-17 inhibitors, IL-12/23 inhibitors and anti-PDE4 agents. [bib_ref] European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis..., Gossec [/bib_ref] [bib_ref] Pharmacological treatment of psoriatic arthritis: a systematic literature review for the 2015..., Ramiro [/bib_ref] The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have also published PsA treatment recommendations. [bib_ref] Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment..., Coates [/bib_ref] Gossec et al. [bib_ref] Management of psoriatic arthritis in 2016: a comparison of EULAR and GRAPPA..., Gossec [/bib_ref] compared the EULAR and GRAPPA recommendations and concluded that the recommendations of the EULAR were primarily rheumatological, whereas those of the GRAPPA were balanced between the rheumatological and dermatological aspects of psoriasis. The British society of dermatology has also published guidelines regarding the treatment of psoriasis and PsA. 14 Given the available data and the recent UK guidelines, we have modified the EULAR PsA algorithm to include apremilast and ixekizumab . The main difference between our algorithm and that of the EULAR concerns phase III of the treatment strategy and the introduction of a biological agent. We propose categorizing patients according to two major clinical profiles. The first clinical profile would include psoriasis patients for whom skin involvement predominates over PsA. In such patients, we recommend that adalimumab or ustekinumab are used as first-line biological agents, similarly to patients with plaque psoriasis. The second clinical profile would include patients for whom PsA predominates over cutaneous involvement. In such patients, we recommend that a TNF inhibitor is used as a first-line biological agent. In case of failure, switching to a second TNF inhibitor or to another class of inhibitors (anti-IL17 or anti-IL12/23) should be considered. At present, secukinumab is the only anti-IL17 treatment approved for PsA but efficacy data are available for both ixekizumab and secukinumab. Anti-IL12/23 should be considered in case of peripheral PsA.
We recommend that apremilast, the therapeutic effect of which appears to be limited with no available data on its impact on peripheral bone structural damage, should only be used in PsA when there are contraindications to biotherapy, or in non-severe and non-active forms of the disease.
In the absence of published data and available tools for comparing the criteria for the degrees of severity of cutaneous and articular involvement, it appears that it is the patient who chooses which form of psoriasis (articular or cutaneous) affects them the most. In case of patient-reported predominant rheumatological involvement, the overall management of the patient should be ensured by the rheumatologist in collaboration with the dermatologist, and vice versa in case of predominant skin involvement.

## Unmet needs in the french psoriasis guidelines
Several questions could not be addressed in the present recommendations as a result of a lack of evidence-based data. Notably, we were not able to provide satisfactory answers to the following questions.
- What is the exact place of apremilast in the therapeutic armamentarium?
- How long before and after surgery should apremilast be tapered?
- Should methotrexate be prescribed in association with biologic agents?
- In patients treated with biological agents who experience complete clearing, is it possible to adjust or stop the treatment? What would be the best strategy; a gradual or immediate stop?
Further studies are necessary to provide clear answers to these questions.

## Planned update of the french psoriasis guidelines
An update of the present guidelines will be necessary by 2020.
[fig] Figure 1: Treatment goals in plaque psoriasis. (a, b) Updated decision algorithms considered as acceptable by the current working group. DLQI, dermatology life quality index; PASI, psoriasis area severity index; PGA, physician global assessment. [/fig]
[fig] Figure 2: Treatment algorithm for patients suffering from plaque psoriasis without comorbidities. CSA, cyclosporin; MTX, methotrexate; NBUVB, Narrowband UVB; PUVA, psoralen UVA; re-PUVA, retinoid psoralen UVA. [/fig]
[fig] : Prefer phototherapy (Grade C). Consider acitretin (Grade C) except in patients with dyslipidaemia. Consider MTX in case of phototherapy and acitretin contraindications (Grade B). Apply caution because of the increased risk of infection and hepatic fibrosis. Avoid CSA (Grade B). Prefer biological agents with a short half-life or those with fewer associations with an increased infectious risk (Avoid INFLI) (Expert opinion). [/fig]
[table] Table 1: Summary of the systemic treatment options for psoriasis  (a) Phototherapy (NBUVB, home-based NBUVB, PUVA, bath PUVA) [/table]
[table] Table 2: Summary of the clinical assessments associated with first-line (a) and second-line (b) systemic treatments for psoriasis. Adverse events are listed in order of frequency [/table]
[table] Table 4: Summary of the recommendations for systemic treatments in patients with comorbidities or with special circumstances [/table]
[table] Table 5: Summary of the management recommendations for particular forms of psoriasis Management of particular forms of psoriasis First-line systemic treatments: phototherapy, MTX, CSA, acitretin Second-line systemic treatments: TNFi, USTK, anti-IL17, APR Nonpustular palmoplantar psoriasis  Idem plaque psoriasis. [/table]