Comparison of Management Guidelines for Moderate-to-Severe Plaque Psoriasis: A Review of Phototherapy,Systemic Therapies,and Biologic Agents

Abstract

Introduction:

Many international guidelines for management of psoriasis exist and most have variations in grading evidence quality, strength of recommendations, and dosing. The objective of our review is to compare international guidelines published in the United Kingdom, Canada, Europe, and the United States for the management of moderate-to-severe plaque psoriasis.

Methods:

We conducted a literature review on systemic therapies and phototherapy for moderate-to-severe plaque psoriasis in adult patients. The British, Canadian, European, and American guidelines served as the key comparators in our review. To identify relevant supporting clinical trials not referenced in the guidelines, we conducted literature searches in PubMed and EMBASE. Two authors independently extracted data on indications, dosing, efficacy, evidence grade, and strength of clinical recommendation for each therapy.

Results:

Monoclonal antibodies directed toward tumour necrosis factor and interleukin (IL)-12/23 received the strongest recommendations for treatment of moderate-to-severe plaque psoriasis, supported by robust, high-quality randomized controlled trials (RCTs). Newer agents such as IL-17 and IL-23 inhibitors are not referenced in most guidelines. There are fewer RCTs for conventional therapies and few head-to-head comparisons with biologics, making it difficult to draw direct comparisons. Among older agents, methotrexate is most strongly recommended for long-term maintenance and cyclosporine is recommended for short-term control of flares.

Conclusion:

Physicians should individualize psoriasis-management strategies based on medication tolerance, efficacy, safety, patient comorbidities, availability of the medication, and patient preference.

Keywords

acitretin biologics cyclosporine guidelines IL-12/23 IL-17 IL-23 methotrexate phototherapy psoriasis TNF

Introduction

Psoriasis is a chronic, immune-mediated cutaneous disorder characterized by well-defined, scaly, erythematous plaques and systemic features.¹ It affects approximately 2% to 3% of the global adult population and is caused by a complex interaction of environmental and genetic factors.^1,2 The physical and psychosocial burden of psoriasis results in reduced quality of life and comorbidities such as cardiovascular disease,³ psoriatic arthritis,⁴ obesity,^5,6 and anxiety/depression.^7,8 Given the chronic nature of psoriasis, long-term management is required to control disease manifestations.^1,9

Psoriasis is managed with topical and/or systemic therapies based on disease severity, treatment efficacy, side effects, patient preference, and individual patient response.^9,10 First-line treatment for mild-to-moderate plaque psoriasis consists of topical corticosteroids, topical vitamin D analogues, and combination therapies.^9,11–13 Moderate-to-severe plaque psoriasis is treated primarily using phototherapy, conventional systemic agents (methotrexate, oral retinoids, and cyclosporine), novel small molecules (apremilast), and biologics.^14–16 Targeted therapies for specific immune mediators have been approved, including monoclonal antibodies and fusion proteins inhibiting tumour necrosis factor (TNF)-alpha (etanercept, adalimumab, infliximab, and certolizumab pegol), interleukin (IL)-12/23 (ustekinumab), IL-23 (guselkumab), and IL-17A (secukinumab, ixekizumab, and brodalumab). These biologic therapies have demonstrated long-term efficacy and acceptable safety profiles,.^15,17,18

There are several international guidelines for the management of psoriasis based on best evidence and, where evidence is lacking, expert opinion.^19,20 Clinical practice guidelines increase the quality of patient care by reducing gaps between research evidence and clinical practice, and can be useful in the evaluation and management of psoriasis.^21,22 Noteworthy guidelines include those from the National Institute for Health and Care Excellence (NICE) in the United Kingdom,²³ the European S3 in Europe,^24–26 the American Academy of Dermatology (AAD),^1,27,28 and the Canadian guidelines endorsed by the Canadian Dermatology Association.^29,30 However, there is some variability between these guidelines and some do not include newer agents. Furthermore, applicability of these guidelines may be affected by treatment availability, type and quality of evidence incorporated, author biases, industry bias, lack of stakeholder involvement, and jurisdictional realities in regions where each guideline was produced.^21,31

To assess recommendations for systemic therapies in treating moderate-to-severe plaque psoriasis in adult patients, we completed a review of the British, European, American, and Canadian clinical guidelines.

Methods

We compared the literature on systemic therapies for moderate-to-severe plaque psoriasis in adult patients by analyzing the British NICE, European S3, American AAD, and Canadian guidelines for our review. Although other guidelines exist, we selected these countries because based on our experience they are the most widely referenced among Canadian dermatologists. To identify relevant supporting studies not referenced in guidelines, we conducted structured literature searches in PubMed and EMBASE for randomized controlled trials, systematic reviews, and meta-analyses, and purposively sampled relevant studies published in English. No date limits were set. We developed unique search strings for each database for psoriasis and all known conventional systemic therapies, phototherapies, and biologic agents used to treat psoriasis, capturing all relevant literature using Boolean operators. To ensure our search was comprehensive, we searched for gray literature using Google Scholar and clinicaltrials.gov. Supporting studies were selected using a purposive sampling schema that sought to draw on articles that allowed for comparison and critical appraisal of the 4 included guidelines.

Two authors (AI and ACRP) extracted and tabulated data from the 4 guidelines. Data were extracted on indications, dosing, evidence grade, and strength of clinical recommendation for each therapy. Both authors purposively sampled relevant literature from the literature searches, extracting and tabulating data accordingly. All data were validated by 3 authors (AI, ARCP, and PF), and any disagreements that arose were adjudicated through consensus. Dosing was further verified by an accredited hospital pharmacist and dermatologist (CS). Narrative synthesis methodologies were used to synthesize data, describe trends, and contrast recommendations among included studies.

Results

Guidelines for phototherapy are presented in Table 1, guidelines for conventional systemic therapies and apremilast are presented in Table 2, guidelines for other nonbiologic systemic therapies are presented in Table 3, and guidelines for biologic therapies are presented in Table 4.^1,23–29,32 Dosing recommendations were generally not discussed in the Canadian guidelines; as such, dosing was included only where available. Levels of evidence and recommendation grades used by the various guidelines are summarized in Appendix 1. The year of publication, funding considerations, and methodology for development of recommendations are summarized in Appendix 2.

Table 1.

Phototherapy for Treatment of Psoriasis.

Therapy	American²⁸	Canadian^29,30	British²³	European^24-26
Phototherapy, ultraviolet B	• Indication: generalized psoriasis unresponsive to topicals • Dosing ○ BB: initial dosing according to skin type (20-60 mJ/cm²) or MED (50% of MED); subsequent dosage increased by 5-30 mJ/cm² or ≤25% of initial MED; tx 3-5×/wk; single course is 20-25 tx ○ Narrowband: initial dosing according to skin type (130-400 mJ/cm²) or MED (50% of MED); subsequent dosage increased by 15-65 mJ/cm² or ≤10% of initial MED; tx 3-5×/wk; single course is 15-20 tx • Recommendation ○ BB-UVB: C ○ NB-UVB: B • Evidence ○ BB-UVB: III ○ NB-UVB: II	• NB-UVB recommended over BB-UVB • Efficacy: NB-UVB can lead to full clearance, although 3-mo efficacy depends on frequency of tx; less durable remission than PUVA but safer ○ LoE: 2++ • UVB phototherapy should be conducted to minimize cumulative UV light exposure; use UV-sparing combination therapies if appropriate ○ LoE: 4 ○ Recommendation: D • Efficacy: NB-UVB 2×/wk ○ Short-term efficacy (NB-UVB 2×/wk): Patients may achieve clearance within 4-15 wk (LoE: 1+) ○ Long-term efficacy: remission after tx cessation can be maintained for 6 mo (LoE: 2++) • Efficacy: NB-UVB 3×/wk ○ Short-term efficacy: patients may achieve clearance within 4-15 wk (LoE: 1+) ○ Long-term efficacy: remission following tx may be maintained for 6 mo and up to 12 mo in other patients (LoE: 2++)	• First-line phototherapy: NB-UVB ○ Tx given 2-3×/wk based on patient preference ○ Response may be achieved more quickly with tx 3×/wk ○ Offer alternate tx if: (1) results unsatisfactory; (2) rapid relapse after tx; (3) difficult access to tx; (4) person is at high risk of skin cancer • Do not routinely use phototherapy as maintenance therapy	• Dosing: based on skin type; BB-UVB ranges from 20 to 60 mJ/cm² and NB-UVB ranges from 200 to 600 mJ/cm² • Phototherapy recommended as induction therapy for moderate-to-severe psoriasis • NB-UVB recommended as first-choice • Phototherapy not suitable for long-term tx because of long-term side effects with cumulative tx and being somewhat impractical
Evidence and recommendation	• Recommendation: BB-UVB: C • Recommendation: NB-UVB: B • LoE: BB-UVB: III • LoE: NB-UVB: II	• Recommendation: See above. • LoE: See above.	• Not described.	• Not described.
Phototherapy, topical targeted therapy (excimer laser)	• Indications: mild-severe psoriasis with <10% BSA involvement • Dosing: initial dose dictated by patient skin type, plaque characteristics, and induration (500-900 mJ/cm² for XTRAC); subsequent doses adjusted according to clinical response and side effects; dosed 2-3×/wk until patient clear (usually 10-12 tx for clearance)	• N/A	• N/A	• Use of excimer lasers should be limited to targeted tx of individual plaques
Evidence and recommendation	• Recommendation: B • LoE: II	• Not described.	• Not described.	• Not described.
Phototherapy, systemic PUVA	• Indications: generalized psoriasis and resistant to topical therapy • Dosing: 8-methoxypsoralen, 0.4-0.6 mg/kg, taken 1-2 h before exposure to UVA; tx 2-3×/wk; single course is 20-25 tx and repeated as indicated	• Indication: moderate-to-severe plaque psoriasis • Efficacy: highly effective, leading to clearance within 4-6 wk at 4 tx sessions/wk, or over longer periods with less-frequent sessions • Lifetime exposure should be capped at 200 PUVA sessions; use UV-sparing combination therapies if appropriate ○ LoE: 2++ ○ Recommendation grade: B • Patients with history of PUVA should be wary of using an immunomodulatory agent, such as cyclosporine, after use because of potential emergence of SCC or NMSC • Short-term (3 mo) efficacy: LoE 1+ • Long-term (6 mo) efficacy: LoE 2++ • Combination therapy efficacy: LoE 1+	• Second-line phototherapy: PUVA ○ Do not routinely offer co-therapy with acitretin ○ Increased risk of skin cancer association and subsequent use of cyclosporine may increase risk of cancer • Do not routinely use phototherapy as maintenance therapy	• PUVA recommended if UVB fails
Evidence and recommendation	• Recommendation: A • LoE: I
Phototherapy – topical and bath PUVA	• Indications: topical PUVA for palmoplantar psoriasis; bath PUVA for generalized psoriasis • Dosing ○ Topical: 0.1% 8-methoxypsoralen in emollient and treat 2-3×/wk; apply 30 min before UVA; start at 0.25-0.5 J/cm², increase by 0.25-0.5 J/cm²; 30-40 tx for single course and repeat as needed • Bath: 50 mg of 8-methoxypsoralen in 100 L of water; 20-30 min pre-exposure; schedule similar to systemic PUVA; 30-40 tx for single course and repeat as needed
Evidence and recommendation	• Recommendation: B • LoE: II	• Recommendation: See above. • LoE: See above.	• Not described.	• Not described.

Abbreviations: BB, broadband; BSA, body surface area; LoE, level of evidence; MED, minimal erythema dose; min, minutes; mo, month; NB, narrowband; NMSC, non-melanoma skin cancer; PUVA, psoralen and ultraviolet A; SCC, squamous cell carcinoma; tx, treatment; UVA, ultraviolet A; UVB, ultraviolet B, wk, week.

Please refer to Appendix 1 for guideline definitions of recommendations and evidence grading.

Table 2.

Conventional Nonbiologic Systemic Therapies and Apremilast for Treatment of Psoriasis.

Therapy	American²⁷	Canadian^29,30	British²³	European^24-26
Methotrexate	• Indication: severe, recalcitrant, disabling psoriasis that is not adequately response to other tx • Dosing: administered as a wkly single oral dose; test dose of 2.5-5 mg is recommended; total dose should not exceed 30 mg/wk PO; SC or IM dosing may also be used for compliance, mitigating adverse events, or if NPO, but PO first line; folic acid supplementation 1-5 mg/day PO (except for day of methotrexate dosing) • Baseline monitoring: CBC and platelet count; BUN, creatinine, LFTs; liver biopsy if significant liver disease, pregnancy test and HIV test; consider testing for purified protein derivative; consider CXR if pulmonary disease • Ongoing monitoring: CBC and platelet count initially every 2-4 wk for first few months then every 1-3 mo depending on dose adjustments, symptoms, previous CBC; pregnancy test when indicated; LFTs monthly, BUN and creatinine every 2-3 mo depending on dose adjustments, symptoms, previous bloodwork; consider repeat liver biopsy if high risk, cumulative doses more than 3.5-4 g, or after each 1.5 g dose based on LFTs, risk factors	• Indication: moderate-to-severe plaque psoriasis • Dosing: use with folate; 25 mg/wk is more effective than 10 mg/wk over 12 wk in patients with severe psoriasis • Modest and inconsistent effect compared to cyclosporine over a 12-wk period; however, better for long-term use over years or decades • Use limited by risk of liver toxicity and monitoring of liver function • Monitoring: pre-treatment liver biopsies with repeat biopsies at intervals based on cumulative consumption (ie, after 1.5 g taken); monitor bloodwork for liver and kidney function; screen for pregnancy prior to starting; monitor for other effects including pancytopenias, pulmonary toxicity, lymphoma, acute myelosuppression, Epstein-Barr virus-associated lymphoproliferative disease, osteoporosis	• Offer as first-choice systemic agent • Dosing: incremental dosing starting at 5-10 mg/wk and increase up to 25 mg/wk; assess after 3 mo; use lowest possible dose to maintain remission • Monitoring: evaluate for risk of hepatotoxicity at baseline and throughout treatment using standard LFTs, serial serum procollagen III levels, and assessing pre-existing risk factors	• Dosing: administered once wkly (PO, IM, or SC); for PO administration, you can wkly dose on one occasion or divide them into 3 separate doses to reduce toxicity (up to 30 mg/wk); initial dose at 5-10 mg then increase if needed; initial dose in the elderly should be 2.5 mg • Some guideline members recommend methotrexate (15-22.5 mg/wk) based on clinical experience while others recommend it based on limited evidence available • Recommended for long-term tx and induction^a • Can be given by oral or SC delivery; in general, a starting dose of 15 mg/wk is used, but individual dosages can range from 5 to 25 mg/wk • Baseline monitoring: laboratory controls (CBC, LFTs, creatinine, urine sediment, urine pregnancy test, HBV/HCV, serum albumin, serum procollagen III); CXR • Ongoing monitoring: check concomitant medication; repeat laboratory controls at predefined intervals (CBC after first week; CBC, LFTs, serum creatinine, urine sediment, serum albumin every 2 wk during first 2 mo and every 2-3 mo thereafter); procollagen III every 3 mo
Evidence and recommendation	• Recommendation: B • LoE: II	• Recommendation: Not described. • LoE: 1+	• Not described.	• Recommendation: See legend. • LoE: 2
Cyclosporine	• Indication: non-immunocompromised patients with severe, recalcitrant psoriasis • Dosing: 2.5-5.0 mg/kg/d PO in 2 divided doses/d; downward dose adjustments (by 0.5-1.0 mg/kg) when patient achieves clearance or major side effects like hypertension or decreasing kidney function; optimally used as interventional therapy for a maximum of 1 y (US approval)	• Indication: moderate-to-severe plaque psoriasis • Dosing: intermittent use in periods up to 12 wk • Efficacy: effective in severe plaque psoriasis, but best employed intermittently, rather than for long-term use • Avoid use in patients with hypertension and hypertriglyceridemia • Should be reserved for intermittent control and ordinarily should not be used for >12 wk, unless indicated	• Offer if need rapid or short-term disease control or are considering conception and require systemic agent • Dosing: 2.5-3.0 mg/kg/d PO of cyclosporine and escalate to 5.0 mg/kg/d after 4 wk if no response to lower dose or if rapid control necessary; assess after 3 mo; use lowest possible dose to maintain remission for up to 1 y	• Dosing: initial dosage of 2.5-3.0 mg/kg/d PO; daily dose administered in 2 divided doses (morning and evening); dose can be scaled up to 5 mg/kg/d after 4-6 wk if unsatisfactory response and lab parameters unaffected; after up-dosing, if patient sees response after another 4 wk, discontinue tx; for rapid response, use initial dose of 5 mg/kg/d • Cyclosporine suggested primarily for induction therapy in adults with moderate-to-severe psoriasis not controlled with topicals or phototherapy^a • Cyclosporine can be used up to 2 y in long-term therapy in individual cases, but renal function and toxicity must be carefully monitored; suggest consultation with nephrologist^b
Evidence and recommendation	• Recommendation: B • LoE: II	• Recommendation: B • LoE: 1++	• Not described.	• Recommendation: See legend. • LoE: 1
Acitretin	• Indication: severe plaque psoriasis • Dosing: 10-50 mg/d given as a single dose; lower doses (≤25 mg/d) may be used to reduce side effects, particularly in combination therapy; reduce phototherapy light dose by 30%-50% when combining with acitretin	• Indication: moderate-to-severe plaque psoriasis; rarely used as monotherapy • Dosing: low-dose acitretin (25 mg/day) is safer and better tolerated than high-dose (50 mg/day) • Efficacy: little evidence of benefit as monotherapy; better used in combination therapy • Not to be used in women of childbearing age unless they are willing to use contraception for 3 y after discontinuation	• Indication: consider if methotrexate and cyclosporine have failed or are inappropriate • Dosing: incremental dosing up to 25 mg/d; consider escalation up to 50 mg/d if no other tx options available; assess after 4 mo	• Based on evidence, cannot make a recommendation for or against the use of acitretin as monotherapy^c • Based on clinical experience and individual patient, they suggest low dose (20-30 mg/d) based on tolerability and high dose (>30 mg/d) based on efficacy^b • Acitretin not suggested as first choice monotherapy among conventional systemic tx • Tx of women of child-bearing age strongly discouraged because of teratogenicity
Evidence and recommendation	• Recommendation: B • LoE: II	• Recommendation: Not described. • LoE: 1-	• Not described.	• Recommendation: See legend. • LoE: Not described.
Apremilast	• N/A	• N/A	• Indication: use when patient failed other conventional systemic agents and phototherapy • Efficacy: patients should achieve PASI-75 or PASI-50 with 5-point reduction in DLQI by wk 16 of tx; if not, stop tx	• Suggested as a second-line medication for the induction and long-term treatment of psoriasis^b
Evidence and recommendation	• Not described.	• Not described.	• Not described.	• Recommendation: See legend. • LoE: Not described.

Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; CXR, chest x-ray; DLQI, Dermatology Quality of Life Index; HBV, hepatitis B virus; HCV, hepatitis C virus; IM, intramuscular; LFT, liver function test; LoE, level of evidence; mo, month; NPO, non per os (nothing by mouth); PASI, Psoriasis Area Severity Index; PO, per os (by mouth); SC, subcutaneous; tx, treatment; US, United States; wk, week; wkly, weekly; y, year.

Please refer to Appendix 1 for guideline definitions of recommendations and evidence grading.

Table 3.

Other Nonbiologic Systemic Therapies for Treatment of Psoriasis.

Therapy	American²⁷	Canadian^29,30	British²³	European^24-26
Azathioprine	• Indication: no FDA approval for psoriasis • Dosing: once-daily dosing guided by TPMT levels ○ TPMT <5.0 U: do not use azathioprine ○ TPMT 5-13.7 U: 0.5 mg/kg max dose ○ TPMT 13.7-19 U: 1.5 mg/kg max dose ○ TPMT >19.0 U: 2.5 mg/kg max dose ○ Alternate non-TPMT dosing: start at 0.5 mg/kg, check for cytopenia; if no cytopenia, can increase dose by 0.5 mg/kg/d after 6-8 wk if necessary and increase by 0.5 mg/kg/d every 4 wk thereafter as needed • Efficacy: only small studies exist evaluating efficacy ○ Study 1: 19/29 patients achieved >75% improvement ○ Study 2: 5/10 patients achieved >25% improvement • Recommendation: C • LoE: III	N/A	N/A	N/A
Fumaric acid esters (Fumaderm)	• Indication: no FDA approval for psoriasis • Dosing: one tablet of Fumaderm (starting dose) increased to max 6 tablets per day over 8 wk • Efficacy: ○ Study 1: mean PASI-50 achieved at 16 wk; ○ Study 2: fumarate alone for 9 wk led to PASI-50; fumarate plus calcipotriol for 3 wk led to PASI-50 • Recommendation: B • LoE: I	N/A	N/A	• Dosing: highest recommended dose is 1.2 g/d • Recommendations ○ Recommended for induction tx and long-term tx (up-up) ○ Recommended with slow increase dosing regimen (up-up) ○ Combine with topical tx recommended ○ Tx limited by gastrointestinal adverse effects and flush symptoms ○ Efficacy: after 16 wk, 50%-70% of patients achieved PASI-75 (LoE 2)
Hydroxyurea	• Indication: no FDA approval for psoriasis • Dosing: start dose at 500 mg PO BID and increase up to 4 g/d as tolerated; alternate dosing used is 3-4.5 g/wk • Efficacy: varies widely ○ Study 1: PASI-70 in 55% of patients with mean tx time of 36 wk ○ Study 2: 48% reduction in PASI score after 12 wk ○ Long-term efficacy: 60% of patients achieved clearance or almost clearance after 16 mo • Recommendation: B Evidence: III	• Indication: not approved in Canada for psoriasis • Little evidence of superior efficacy compared to standard systemic tx (methotrexate, cyclosporine)	N/A	N/A
Leflunomide	• Indication: no FDA approval for psoriasis • Dosing: initial 3 d loading dose of 100 mg/d followed by 20 mg/d long term • Efficacy: 17% achieved PASI-75 after 24 wk of tx • Recommendation: B • LoE: II	N/A	N/A	N/A
Mycophenolate mofetil	• Indication: no FDA approval for psoriasis • Dosing: 1.0-1.5 g orally 2×/d • Efficacy: 47% mean PASI reduction at 12 wk when treated with 1.0-1.5 g BID; 47% mean PASI reduction at 6 wk when treated with 1.0 g BID for 3 wk, then 0.5 g BID for 3 more wk • Recommendation: C LoE: III	• Indication: not approved in Canada for psoriasis • Little evidence of superior efficacy compared to standard systemic tx (methotrexate, cyclosporine)	N/A	N/A
Sulfasalazine	• Indication: no FDA approval for psoriasis • Dosing: 500 mg PO BID initial dose, increased up to 3-4 g/d as tolerated • Efficacy: global improvement of 30%-59% of patients treated with 3-4 g/d of sulfasalazine after 8 wk • Recommendation: B • Evidence: II	N/A	N/A	N/A
Tacrolimus	• Indication: no FDA approval for psoriasis • Dosing: 0.05-0.15 mg/kg • Efficacy: poorly characterized; patients treated with 0.10-0.15 mg/kg achieved statistically significant improvement in PASI compared with placebo by 9 wk • Recommendation: B • LoE: II	N/A	N/A	N/A
6-thioguanine	• Indication: no FDA approval for psoriasis • Dosing: 80 mg 2×/wk initial dose and increase by 20 mg every 2-4 wk, up to 160 mg 3×/wk • Efficacy ○ Short-term study: 6/11 patients showed response after 2-4 wk ○ Long-term study: 58% of patients effectively maintained at 24 mo and tx safely used up to 145 mo; another study showed 14/18 patients had 90% improvement • Recommendation: C • LoE: III	N/A	N/A	N/A

Abbreviations: BID, twice a day; FDA, United States Food and Drug Administration; LoE, level of evidence; max, maximum; mo, month; PASI, Psoriasis Area Severity Index; PO, per os (by mouth); TPMT, thiopurine methyltransferase; tx, treatment; wk, week.

Please refer to Appendix 1 for guideline definitions of recommendations and evidence grading.

Table 4.

TNF Inhibitors, IL-12/23 Inhibitors, and IL-17A Inhibitors for Treatment of Psoriasis.

Therapy	American¹	Canadian^29,30	British²³	European^24-26
Anti-TNF
Adalimumab	• Indication: moderate-to-severe psoriasis • Dosing: 80 mg SC first wk, 40 mg SC second wk, follow by 40 mg SC every other wk	• Dosing: 40 mg SC every other wk, following 80 mg loading dose; more frequent dosing also explored • Appears to be appropriate for long-term continuous use • Short-term (3 mo) LoE: 1++ • Long-term (6 mo) LoE: 2++ • Long-term (1 y) LoE: 2+	• Indication: recommended for adults with plaque psoriasis who are considering anti-TNF tx and who meet the following criteria: ○ Disease is severe as defined by a total PASI of 10 or more and DLQI of 10 or more ○ Psoriasis has not responded to standard systemic tx including cyclosporine, methotrexate, and PUVA; or contraindicated or intolerant of these tx • Adalimumab should be discontinued in people whose psoriasis has not responded within 16 wk; adequate response defined as either: ○ PASI-75 at wk 16 or • PASI-50 and 5-point reduction in DLQI at wk 16	• Dosing: 80 mg SC at wk 0, follow by 40 mg SC every other wk for maintenance tx (started 1 wk after induction dose)^b • Recommended for induction therapy of moderate-to-severe psoriasis if phototherapy and conventional systemic agents yield inadequate response (or contraindicated or not tolerated)^a • After 10-16 wk, patient should be evaluated and maintenance therapy can be considered with lowest effective dose
Evidence and recommendation	• Recommendation: A • LoE: I	• Recommendation: Not described. • LoE: See above.	• Not described.	• Recommendation: See legend. • LoE: 1
Etanercept	• Indication: moderate-to-severe psoriasis • Dosing: 50 mg 2×/wk given SC for 3 mo, followed by 50 mg once/wk	• Appears to be appropriate for long-term continuous use • Dosing: 50 mg BIW, stepped down to 25 mg BIW after first 12 wk of tx; best evidence for clearance or near clearance seen with constant dose of 50 mg BIW • Short-term (3 mo) LoE: 1++ • Long-term (6 mo) LoE: 2++ • Long-term (1 y) LoE: 2++	• Indication: dosing not exceeding 25 mg 2× wk is recommended for adults with plaque psoriasis who meet the following criteria: ○ Disease is severe, defined by total PASI of 10 or more and DLQI of 10 or more ○ Psoriasis has not responded to standard systemic tx including cyclosporine, methotrexate, and PUVA; or contraindicated or intolerant of these tx • Discontinue in people whose psoriasis has not responded within 12 wk; adequate response defined as either: ○ PASI-75 at wk 12 or ○ PASI-50 and 5-point reduction in DLQI at wk 12	• Dosing: initial dose recommendation 2 × 25 mg/wk or 2 × 50 mg/wk (wk 0-12) ○ After 10-16 wk, if induction is successful, maintenance tx should be continued at lowest effective dose ○ Suggested for induction therapy (25 mg or 50 mg BIW) for moderate-to-severe psoriasis if phototherapy or conventional systemic agents inadequate, contraindicated, or not tolerated^a • For maintenance therapy, 50 mg 1×/wk is commonly used dose
Evidence and recommendation	• Recommendation: A • LoE: I	• Recommendation: Not described. • LoE: See above.	• Not described.	• Recommendation: See legend. • LoE: 1
Infliximab	• Indications: severe psoriasis • Dosing: 5mg/kg dose infusion at wk 0, 2, and 6; then q 6-8 wk; adjust dose and interval of infusions as needed for optimal efficacy	• Highly effective on initial exposure, even in acute, severe flares • Variable efficacy beyond first tx or follow re-initiation; seen in some patients who maintain control or clearance through 1 y of tx may develop resistance to infliximab tx • Short-term (3 mo) LoE: 1+ • Long-term (6 mo) LoE: 1+ • Long-term (1 y) LoE: 2++	• Indication: recommended for treating plaque psoriasis in adults, only if: ○ PASI of ≥20, DLQI >18 ○ Disease has not responded to standard systemic therapies, PUVA or patients is contraindicated or intolerant of these • Stop tx if adequate response not seen by 10 wk. Adequate response defined as either: ○ PASI-75 or • PASI-50 with 5-point reduction in DLQI	• Advantage: rapid clinical efficacy • If after 10-16 wk induction therapy is successful, maintenance therapy can be considered • Recommended as second-line medication for induction and long-term tx^a • Dosing: 5 mg/kg bodyweight IV every 8 wk during long-term tx^a
Evidence and recommendation	• Recommendation: A • LoE: I	• Recommendation: Not described. • LoE: See above.	• Not described.	• Recommendation: See legend. • LoE: 1
Anti-IL12/23
Ustekinumab	• Not covered	• Intended for long-term continuous therapy • Dose: 45 mg SC at wk 0, 4, and then q12 wk thereafter (for patients ≤100 kg) or 90 mg following the same regimen (for patients >100 kg); up-dosing from 45 mg q12 wk to 90 mg q8 wk results in improved response for patients with loss of response • Efficacy • Short-term (3 mo) LoE: 1+ • Long-term (6 mo) LoE: 1+ • Long-term (1 y) LoE: 1+	• Indication: recommended for treating plaque psoriasis in adults, only if: ○ PASI of ≥10, DLQI ≥10 ○ Disease has not responded to standard systemic therapies, PUVA or patients is contraindicated or intolerant of these • If psoriasis has not responded adequately, stop at 16 wk if either: ○ Patient has not achieved PASI-75 or ○ Patient has not achieved PASI-50 with a 5-point reduction in DLQI	• Recommended as second-line medication for induction and long-term management^a • Suggested dosing: 45 mg SC for patients ≤100 kg and 90 mg for patients >100 kg^b
Evidence and recommendation	• Not described.	• Recommendation: Not described. • LoE: See above.	• Not described.	• Recommendation: See legend. • LoE: Not described.
Anti-IL 17A
Secukinumab	• Not covered	• Not covered	• Indication: recommended for treating plaque psoriasis in adults, only if: ○ PASI of ≥10, DLQI ≥10 ○ Disease has not responded to standard systemic therapies, PUVA or patients is contraindicated or intolerant of these ○ Company provides drug with discount agreed to in patient-access scheme • If psoriasis has not responded adequately, further tx cycles are not recommended. Stop at 12 wk if either: ○ Patient has not achieved PASI-75 or ○ Patient has not achieved PASI-50 with a 5-point reduction in DLQI	• Recommended for the induction and long-term treatment of psoriasis^a • Use as first- or second-line medication should be performed taking into account individual factors and regional regulations
Evidence and recommendation	• Not described.	• Not described.	• Not described.	• Recommendation: See legend. • LoE: Not described.
Ixekizumab	• Not covered.	• Not covered.	• Indication: recommended for treating plaque psoriasis in adults, only if: ○ PASI of ≥10, DLQI ≥10 ○ Disease has not responded to standard systemic therapies, PUVA or patients is contraindicated or intolerant of these ○ Company provides drug with discount agreed to in patient-access scheme • If psoriasis has not responded adequately, stop at 12 wk if either: ○ Patient has not achieved PASI-75 or ○ Patient has not achieved PASI-50 with a 5-point reduction in DLQI	• Not covered.
Evidence and recommendation	• Not described.	• Not described.	• Not described.	• Not described.
Brodalumab	• Not covered.	• Not covered.	• Indication: recommended for treating plaque psoriasis in adults, only if: ○ PASI of ≥10, DLQI ≥10 ○ Disease has not responded to standard systemic therapies, PUVA, or patient is contraindicated or intolerant of these ○ Company provides drug with discount agreed to in patient-access scheme • If psoriasis has not responded adequately, stop at 12 wk if either: ○ Patient has not achieved PASI-75 or ○ Patient has not achieved PASI-50 with a 5-point reduction in DLQI	• Not covered.
Evidence and recommendation	• Not described.	• Not described.	• Not described.	• Not described.

Abbreviations: BIW, biweekly; DLQI, Dermatology Quality of Life Index; IL, interleukin; IM, intramuscular; IV, intravenous; LoE, level of evidence; mo, month; PASI, Psoriasis Area Severity Index; PUVA, psoralen and ultraviolet A; q, every; SC, subcutaneous; TNF, tumour necrosis factor; tx, treatment; wk, week; y, year.

Please refer to Appendix 1 for guideline definitions of recommendations and evidence grading.

Section 1: Phototherapy

Phototherapy, Ultraviolet B (Narrowband and Broadband)

Narrowband-ultraviolet B (NB-UVB) is universally recommended as the first-choice UVB phototherapy, before broadband-UVB (BB-UVB), for moderate-to-severe plaque psoriasis.^{23–25,28,29} Phototherapy should not routinely be used as maintenance therapy because of theoretical carcinogenesis with long-term use. Recommended treatment regimens vary from 2-3 times per week (Canadian^29,30 and British²³) to 3-5 times per week (American²⁸), with skin type consideration used to optimize dosing.

Phototherapy, Topical Targeted Therapy (Excimer Laser)

Excimer lasers should be limited to targeted treatment of plaques. The AAD guidelines specifically indicate its use only if there is <10% body surface area involvement.²⁸ Specific guidelines for topical targeted therapy are not overtly covered in the Canadian, British, or European guidelines.

Phototherapy, Psoralen Plus Ultraviolet A (PUVA)

PUVA is typically recommended for patients who have failed NB phototherapy.²⁸ It carries an increased risk of adverse effects compared to UVB therapy, and may be associated with an increased risk of cutaneous malignancy. Concurrent use with cyclosporine is contraindicated. The American guidelines recommend 2-3 treatment sessions per week, whereas the Canadian guidelines recommend 4 treatment sessions per week.^28–30 PUVA is not suitable for maintenance therapy, and lifetime cumulative sessions should be limited to 200 treatments, as per the Canadian guidelines, to reduce the risk of cutaneous malignancy.^29,30

Section 2: Conventional Nonbiologic Systemic Therapies and Apremilast

Methotrexate

Methotrexate is the first-line long-term treatment for moderate-to-severe plaque psoriasis in patients who are not adequately controlled with topical agents.^{23–25,27,29,30} Guidelines recommend follow-up assessment of methotrexate between 12 and 16 weeks after initiating treatment.^{23–25,27,29,30} Dosing recommendations vary slightly among guidelines. The American guidelines recommend incremental dosing starting at 2.5-5.0 mg per week with a maximum oral dose of 30 mg/week,²⁷ while the British guidelines recommend a starting dose of 5-10 mg/week, with a maximum dose of 25 mg per week.²³ European guidelines state that a starting dose of 5-15 mg per week can be used, with up to 30 mg per week orally for maintenance therapy.^24,25 All guidelines suggest baseline and ongoing monitoring of liver function (serum albumin) and liver transaminases (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) collectively referred to as LFTs when prescribing methotrexate, as hepatotoxicity is a well-documented adverse event. The European, Canadian, and American guidelines also recommend monitoring kidney function, pregnancy status, and complete blood counts (CBCs) throughout treatment.^24,27,29,30 The American guidelines specifically advise monitoring CBC every 2-4 weeks for the first few months, then every 1-3 months thereafter.²⁷ In addition, they suggest monitoring LFTs monthly and blood urea nitrogen with creatinine every 2-3 months.²⁷ Similarly, the European guidelines recommend monitoring CBCs, LFTs, creatinine, urine sediment, and serum albumin every 2 weeks during the first 2 months, then every 2-3 months thereafter.²⁴ According to the AAD guidelines, high-risk patients should have a delayed baseline liver biopsy, then a repeat biopsy may be indicated after a cumulative dose of 1.5 g. Low-risk patients should have a liver biopsy after 3.5-4 g.^27,29,30 An in-depth guideline on methotrexate published by Carretero et al recommends using a cumulative threshold dose of 3.5-4 g for liver biopsy.³³

Cyclosporine

Cyclosporine is indicated for short-term induction therapy for flares of moderate-to-severe psoriasis, but is not intended for long-term maintenance therapy.^{23,24,27,29,30} Patients using cyclosporine require close monitoring for hypertension and kidney injury, and therefore should be followed up approximately 4 weeks after treatment initiation.^24,27,29,30 Given the relatively high risk of severe adverse events, guidelines recommend different maximum lengths of treatment: 1 year (American),²⁷ 12 weeks (Canadian),^29,30 1 year (British),²³ and 2 years (European).^24,25 Oral dosing regimens between 2.5 and 5.0 mg per kg per day, subdivided into 2 doses per day, are universally recommended.^{23–25,27,29}

Acitretin

Across all guidelines, there are weak recommendations for the use of acitretin as a first-line systemic monotherapy in the treatment of psoriasis.^23,24,27,29 The American guidelines recommend using acitretin at 25 mg or lower per day to mitigate side effects, but note that its efficacy is poorly defined and it is better suited in combination with phototherapy.²⁷ The Canadian guidelines also recommend a dose of 25 mg per day, but state its benefit is limited when used alone.^29,30 British guidelines recommend consideration of acitretin only if methotrexate and cyclosporine are intolerable, contraindicated, or failed first.²³ The British Association of Dermatologists recommends a daily dose of 25-50 mg, with liver enzyme, fasting serum cholesterol, and triglyceride monitoring every 2-4 weeks for the first 2 months, then every 3 months thereafter.³⁴ Similarly, the European guidelines “cannot make a recommendation for or against acitretin as a monotherapy” and, among systemic therapies, it should be a second-line or third-line consideration.^24,25

Apremilast

Because apremilast is a relatively new agent, only the British and European guidelines have recommendations^23,26 based closely on data from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and ESTEEM 2 phase III trials.^35,36 In the British guidelines, it is indicated for patients who have failed other conventional systemic therapies and phototherapy.²³ In the European guidelines, apremilast is suggested as a dual-purpose second-line therapy for primary induction and long-term management of psoriasis.²⁶

Section 3: Other Nonbiologic Systemic Therapies

Recommendations for other nonbiologic systemic therapies are thoroughly covered only in the American guidelines.²⁷ As such, these recommendations have been summarized in Table 3, but not compared because of the lack of available data from other guidelines. Therapies in this table include azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil/sodium, sulfasalazine, tacrolimus, and 6-thioguanine.

Section 4: Biologic Therapies

In general, biologic therapies should be considered in moderate-to-severe psoriasis that is not responding to topical therapies, phototherapy, or conventional systemic therapies (eg, methotrexate, cyclosporine, acitretin).^1,23,24 The Canadian guidelines specifically recommend systemic or biologic agents for patients with moderate-to-severe psoriasis, as defined by psoriasis that is refractory to topical treatment.^29,30 Alefacept and efalizumab are mentioned in older guidelines; however, they have been withdrawn from the market.^27,29

Adalimumab

All guidelines recommend a subcutaneous (SC) loading dose of 80 mg adalimumab for the first week, followed by 40 mg SC the second week, and 40 mg SC every second week thereafter.^{1,24,25,29,30} Follow-up should generally be scheduled at 16 weeks, while the European guidelines recommend follow-up between 10 and 16 weeks.^24,25 If there is no significant clinical response by the recommended follow-up time, the treatment should be discontinued. The British guidelines suggest that adalimumab should be considered as a treatment option if the Psoriasis Area Severity Index (PASI) is ≥10, Dermatology Quality of Life Index (DLQI) is ≥10, and systemic therapies are not tolerated or are contraindicated or ineffective.²³ The British guidelines also recommend discontinuation of adalimumab if the patient does not achieve PASI-75 or PASI-50 with a 5-point decrease in DLQI by week 16.²³

Etanercept

The Canadian guidelines recommend dosing etanercept at 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly thereafter.^29,30 European guidelines recommend dosing at 25 mg or 50 mg twice weekly for 12 weeks and 50 mg once weekly thereafter.^24,25 Similarly, the American guidelines suggest 50 mg twice weekly for 3 months, followed by 50 mg once weekly thereafter.¹ The British guidelines recommend a maximum dosing of 25 mg 2 times per week and suggest that etanercept should be considered as a treatment option if PASI is ≥10, DLQI is ≥10, and systemic therapies are not tolerated or are contraindicated or ineffective.²³ The British guidelines also recommend discontinuation of etanercept if the patient does not achieve PASI-75 or PASI-50 with a 5-point decrease in DLQI by week 12.²³

Infliximab

The American guidelines recommend a loading dose of infliximab 5 mg/kg at weeks 0, 2, and 6, followed by a maintenance dose of 5 mg per kg every 6-8 weeks.¹ European guidelines recommend a maintenance dose of 5 mg per kg every 8 weeks.^24,25 Canadian and European guidelines state that the advantage of infliximab is its rapid efficacy for severe flares.^24,25,29,30 In general, 10-week follow-up is recommended to assess patient response. The British guidelines suggest consideration of infliximab in patients with PASI ≥20, DLQI ≥18, and if systemic therapies are not tolerated or are contraindicated or ineffective.²³ The British guidelines recommend discontinuation of infliximab if there is a poor response by week 10 (inability to achieve PASI-75 or achieve PASI-50 with a 5-point decrease in DLQI).

Ustekinumab (Interleukin-12/23 Inhibitor)

This drug is not yet included in the American guidelines.²³ In patients weighing 100 kg or less, suggested dosing is 45 mg SC at weeks 0 and 4, followed by maintenance dosing of 45 mg SC every 12 weeks thereafter.^24,25,29,30 In patients weighing more than 100 kg, suggested dosing is 90 mg SC, following the same schedule and regimen previously stated.^24,25,29,30 In patients with poor response using the standard dosing regimen, Canadian guidelines recommend up-dosing from 45 mg every 12 weeks to 90 mg every 8 weeks.^29,30 In general, clinical response should be seen by week 12.^29,30 The British guidelines suggest consideration of ustekinumab in patients with PASI ≥10, DLQI ≥10, and if systemic therapies are not tolerated or are contraindicated or ineffective.²³ Although the pivotal ustekinumab studies measured efficacy at week 12, the British guidelines recommend that ustekinumab should be discontinued if adequate response (PASI-75 or PASI-50 with 5-point decrease in DLQI) is not achieved by week 16.²³

Secukinumab (Interleukin-17A Inhibitor)

This drug is not yet included in the American or Canadian guidelines. The British guidelines suggest consideration of secukinumab in patients with PASI ≥10 and DLQI ≥10, who are contraindicated, fail, or cannot tolerate systemic therapies. In all cases, the drug company must provide the secukinumab “with the discount agreed in the patient access scheme.”²³ British guidelines recommend that secukinumab should be discontinued if significant response (PASI-75 or PASI-50 with 5-point decrease in DLQI) is not achieved by week 12.²³ The European guidelines recommend secukinumab for the initial management or long-term treatment of psoriasis, while taking into account “individual patient factors and regional regulations.”²⁶

Ixekizumab (Interleukin-17A inhibitor)

Ixekizumab is not yet included in the American, Canadian, or European guidelines. The British guidelines suggest consideration of ixekizumab in patients with PASI ≥10 and DLQI ≥10, who are contraindicated, fail, or cannot tolerate systemic therapies. In all cases, the drug company must provide the ixekizumab “with the discount agreed in the patient access scheme.”²³ British guidelines recommend that ixekizumab should be discontinued if significant response (PASI-75 or PASI-50 with 5-point decrease in DLQI) is not achieved by week 12.²³

Brodalumab (Interleukin-17A inhibitor)

Brodalumab is not yet included in the American, Canadian, or European guidelines. The British guidelines suggest consideration of brodalumab in patients with PASI ≥10 and DLQI ≥10, who are contraindicated, fail, or cannot tolerate systemic therapies. In all cases, the drug company must provide the brodalumab “with the discount agreed in the patient access scheme.”²³ British guidelines recommend that brodalumab should be discontinued if significant response (PASI-75 or PASI-50 with 5-point decrease in DLQI) is not achieved by week 12.²³

Discussion

Our review summarizes and compares the major international treatment guidelines for moderate-to-severe plaque psoriasis. Overall, TNF inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors have the strongest recommendation for treatment of moderate-to-severe plaque psoriasis, supported by high-quality RCTs.^{1,23,24,29,30} Guselkumab,³⁷ an IL-23 inhibitor, recently received Health Canada approval for the treatment of psoriasis but has not yet been included in any guidelines. Similarly, the TNF inhibitor certolizumab pegol was approved by the United States Food and Drug Administration in May 2018 for plaque psoriasis but is not yet included in any guidelines.

Many patients face barriers accessing biologics directly because of restrictions in government and some private insurance plans. Although exact requirements differ, individuals generally need to fail or have contraindication to at least 2 or more systemic therapies to obtain coverage. Of the conventional systemic agents, methotrexate is most strongly recommended for long-term maintenance, while cyclosporine is recommended for short-term use for psoriatic flares.²³ NB-UVB appears to be the most strongly preferred form of phototherapy among expert groups.^24,28–30

Conclusion

Our review compares the current Canadian, European, British, and American recommendations for management of moderate-to-severe plaque psoriasis in adults and recapitulates the level of evidence in these guidelines. Biologics received the strongest recommendations for treatment of moderate-to-severe plaque psoriasis, supported by robust, high-quality RCTs. However, there are fewer RCTs for older agents and few head-to-head comparisons with biologics, making it difficult to draw direct comparisons. Based on the expert consensus in these guidelines, health care professionals should individualize psoriasis-management strategies based on medication tolerance, efficacy, safety, patient comorbidities, availability of the medication, and patient preference.

Footnotes

Appendix

Appendix 2.

Year of Publication, Funding Details, and Methodology for Determining Recommendations for Each Guideline.

	American^1,27,28	Canadian^29,30	British²³	European^24-26
Year of publication	• Original publication: May 2008 to September 2009 • Latest update: None	• Original publication: June 2009 • Latest update: September 2016	• Original publication: October 2012 • Latest update: September 2017	• Original publication: October 2009 • Latest update: September 2017
Funding considerations	• None.	• Financial assistance provided by Abbott Laboratories Limited, Amgen Canada Inc, Astellas Pharma Canada Inc, EMD Serono Canada Inc, Galderma Canada Inc; Isotechnika Inc, Janssen- Ortho Inc, LEO Pharma Inc, Schering-Plough Canada Inc, and Wyeth. • Sponsors were permitted to submit unpublished manuscripts for consideration by the Guidelines Committee provided the article was accepted for peer-reviewed publication by cutoff date. • Sponsors not involved in any other aspect of guideline development nor informed of makeup of Guidelines Committee.	• Full list of stakeholders published on the NICE website.	• Guidelines funded by a grant from EDF. • EADV and IPC supported the guidelines by covering travel costs for its members. • Publication of guidelines supported by educational grants from Abbott International, Essex Pharma GmbH, and Wyeth Pharma GmbH.
Methodology for developing recommendations	• Work group of recognized psoriasis experts used an evidence-based model to determine recommendations. • Where evidence-based data were not available, expert opinion was used to generate clinical recommendations.	• Guidelines originally created by a Guidelines Committee consisting of 16 Canadian dermatologists. • Guidelines subsequently reviewed by wider medical community and Therapeutics Committee of the Canadian Dermatology Association. • Guidelines developed primarily from systematically graded evidence from extensive literature review and clinical judgment.	• Recommendations based on GDG interpretation of available evidence, considering the balance of benefits, harms, and costs. • When clinical and economic evidence was of poor quality, conflicting, or absent, GDG made recommendations based on expert opinion. • Consensus recommendations reached through discussions by GDG.	• Three existing evidence-based national guidelines (GB, NL, DE) used as bases for new evidence-based European guidelines. • Therapeutic recommendations made based on available evidence. • Guidelines group designated important sections as those requiring consensus. • Vonsensus process consisted of a nominal group process and a Delphi procedure. • External review by European national dermatological societies and experts outside of guidelines group.

Abbreviations: BAD, British Association of Dermatologists; DE, Germany; EADV, European Academy of Dermatology and Venerology; EDF, European Dermatology Forum; GB, Great Britain; GDG, Guideline Development Group; IPC, International Psoriasis Council; NICE, National Institute for Health and Care Excellence; NL, Netherlands.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mr Ighani, Mr Partridge, and Dr Sibbald have nothing to declare.

Dr Shear has acted as a consultant and/or speaker for AbbVie, Actelion, Amgen, Celgene, Hospira, Janssen, Janssen Biotech, Lilly, Novartis, Sanofi, Genzyme, and Takeda.

Dr Lynde has acted as a principal investigator, speaker, and/or consultant for AbbVie, Amgen, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, Pfizer, and Valeant.

Dr Gulliver has received honoraria from AbbVie, Amgen, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo, Novartis, Pfizer, Roche, and Valeant for participation on advisory boards, consultant services, and speaker engagements. He has also received grant or research support for clinical trials from AbbVie, Amgen, Astellas, Celgene, Lilly, Novartis, Pfizer, and Regeneron.

Dr Fleming has received honoraria and/or consultant fees from AbbVie, Galderma, and Eli Lilly.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Neil H. Shear

Patrick Fleming

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