Focus on Psoriasis

A report from the 2018 European Academy of Dermatology and Venereology Congress in Paris, France

By Thomas Scharnitz, MD

The European Academy of Dermatology and Venereology (EADV) was founded in 1987 to unite European Dermato-Venereologists, with the aim of advancing excellence in clinical care, research, education, and training. The EADV, which now consists of nearly 7,000 members from more than 100 countries, held its 27th meeting Sept. 12-16 in Paris, France. This annual congress featured numerous distinguished psoriasis investigators and included several psoriasis lectures from IPC councilors. Encompassing clinical manifestations, pathogenesis, diagnostic acumen, therapeutic advances, and late-breaking outcomes of ongoing research, the 27th EADV Congress provided a comprehensive summary of the emerging advances in psoriasis.

On opening day, the IPC presented a symposium based on the theme “Personalized psoriasis treatments: Real world practice approaches and key global insights.” Serving as faculty for the symposium were IPC Chief Medical Officer Dr. Peter CM van de Kerkhof, emeritus professor at Radboud University, Nijmegen, the Netherlands, who also was symposium chair, and IPC Councilors Murlidhar Rajagopalan, MD, Apollo Hospitals, Chennai, India, and Dr. Claus Zachariae, MD, Gentofte Hospital, Copenhagen, Denmark. Summaries of the lectures made at the symposium are presented here along with additional summaries of psoriasis-related lectures presented throughout the congress.

IPC Sister Society Day Symposium

• Treatment-resistant psoriasis in a limited-access country
• Active early intervention
• Palmoplantar psoriasis

EADV Congress | Psoriasis: Review and updates

• Clinical manifestations and pitfalls
• Pathogenic insights, treatment decisions in paradoxical reactions
• Diagnosis, management of palmoplantar psoriasis
• Scalp and nail psoriasis: Diagnosis and treatment
• Topical and phototherapies
• Classic systemic therapies and combinations
• TNF antagonists
• Advance in systemic therapies: IL-17 and IL-23 antagonists

Late Breaking Updates

• Psoriasis and pregnancy: GESTA-PSO study results
• Generalized pustular psoriasis and BI 655130
• BMS-986165 improves biomarkers
• Tight-controlled dose reduction of biologics
• Long-term efficacy, safety of tildrakizumab

IPC Symposium: “Personalized psoriasis treatments: Real world practice approaches and key global insights”

Treatment-resistant psoriasis in a limited-access country

In a captivating lecture, Dr. Rajagopalan detailed the therapeutic challenges in his home country of India. Low per capita income ($1,900 per year), drastic limited access in non-urban areas, and disparity of government funding in psoriasis (compared to tuberculosis and leprosy) present unique inequities and barriers to care.

Topical treatments and phototherapy are a mainstay for limited disease (comprising 80% of Indian patients), but the general population still largely views psoriasis as an exclusively external condition. Though topical therapies are available and affordable, the hot climate, steroid atrophy (to which Indian skin appears more susceptible) and ensuing phobia, and patient-physician communication gaps contribute to poor topical adherence (nearing 50%). Phototherapy remains equally available and affordable. Indian dermatologists frequently prefer PUVA (ultraviolet light A therapy with the light-sensitive drug psoralen) and reserve narrowband-ultraviolet light B (UVB) treatment for those with lighter skin (types 1-3) contraindications. Major barriers also include $5-10 cost per session (relatively expensive) and affordable government-run centers that are clustered in urban areas and reach only 20% of patients, due to suboptimal organization and lack of transportation.

Approximately 30% of patients require systemic drugs, but the diagnosis of severe disease varies widely, and psoriatic arthritis is often not easily identified. Dr. Rajagopalan attempts to combat omnipresent compliance and access issues through telemedicine, but equipped centers are sparse. Public health registries do not exist, nurse visits are reserved for conditions such as tuberculosis, and many patients procure systemics directly from pharmacies (without prescriptions), frequently underdosing with inadequate response. Lab monitoring requires relatively expensive office and lab visits. A uniform module and standard for all Indian dermatologists does not yet exist despite intrastate efforts.

Methotrexate, cyclosporine, and acitretin are commonly used systemics. Methotrexate presents unique challenges. A 2015 joint-specialty position paper suggests that metabolic risk factors in India are rapidly increasing and that nearly 25% of systemic-naïve Indian patients are prone to nonalcoholic fatty liver disease (NAFLD). Supporting data demonstrate nearly 2-fold elevated hepatic triglyceride and plasma IL-6 levels when compared to Caucasians in the United States. Without treatment consensus for NAFLD or data to predict methotrexate impact, even small transaminase elevations can lead to discontinuation. Therefore, Dr. Rajagopalan uses 5-day methotrexate troughs to avoid post-dose spikes. Acetretin use is limited due to slow onset and monotherapy failure rate nearing 50%. Cyclosporine is used nearly exclusively as short-term bridge therapy. Biologics present a problematic prescribing course, as 25% of the Indian population is exposed to tuberculosis and hepatitis B, no clear tuberculosis screening/monitoring consensus exists, and extensive use of biologics can decrease herd immunity. Insurance and cost also preclude most biologics. Biologic fatigue further limits use, and the aforementioned issues with methotrexate complicate its use to combat immunogenicity.

In closing, Dr. Rajagopalan re-emphasized the dire need for a national registry, increased prescriber education, and real-world biologic studies. He is working to elicit change by stressing the crucial systemic sequalae and costly comorbidities of psoriasis. He expressed his pride in the IPC and offered sincere thanks for its committed collaboration to improve care in India through IPC’s outreach efforts, including its 2017 Master Class in Mumbai, which presented psoriasis-related lectures for dermatologists wanting to expand their expertise in managing the disease.

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Active early intervention

Is it time to reassess the use of systemic or biologic drugs early in the course of psoriasis? Dr. van de Kerkhof made a powerful case for early intervention by focusing on two dynamics in psoriasis: the “immunologic scar” and the systemic continuum.

Evidence of lesional memory, or immunologic scar, is quickly mounting. Clark et al (Invest. Dermatol, 2011) found upregulated inflammatory cytokines such as Interleukin (IL)-17, IL-22, and IFN-γ in biopsies of clinically healed lesions. Park et al (Nature Med, 2015) discussed the emerging role of tissue-resident memory T-cells that play an integral role in the chronic relapsing course. The systemic continuum, coined “the psoriatic march,” begins early and continues near indefinitely. Both adaptive immunity, characteristic of stable disease and innate immunity, dominant in active and reactive disease, initiate systemic inflammation and introduce the risk to well-described metabolic, cardiovascular, arthritic, renal, and psychiatric comorbidities. Dr. van de Kerkhof suggested that practitioners consider interceding in the early immunologic psoriatic process to halt this march and stunt immunologic scar development. An early investment would provide lasting effects and serious impact in long-term disease modification.

The value of early intervention is demonstrated in many immunologic diseases, with quintessential examples in rheumatoid arthritis and Crohn’s disease. Descriptions in psoriasis have comparatively lagged, but recent literature suggests both reduction in major adverse cardiac events (Gottlieb, AAD, 2015 PB 8512) and diabetes (Solomon et al, JAMA, 2011) with active systemic/biologic therapy. Despite growing interest and mounting evidence, dedicated early-intervention studies with long-term follow-up are needed. One such randomized multicenter study, “STEPin,” by Iversen et al (J Eur Acad Dermatol Venereol, 2018, in press) evaluating secukinumab vs narrowband-UVB in treatment-naïve patients, will assess reduction in Psoriasis Area and Severity Index (PASI) scores, immunological changes, and pathogenic tissue-resident memory T cells in skin biopsies, with long-term follow-up.

With compelling, rapidly evolving data supporting the systemic sequelae in psoriasis, Dr. van de Kerkhof concluded that it is time to re-examine the time-honored treatment algorithms to actively reduce comorbidities and improve quality of life. He posited that, though practitioners need dedicated studies and prescribing freedom, they also possess the necessary treatments and should, therefore, remain ambitious.

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Palmoplantar psoriasis

Palmoplantar psoriasis is an uncommon but particularly difficult diagnostic and therapeutic variant. Dr. Zachariae provided a comprehensive review of this condition and summarized current and developing management strategies. Diagnosing palmoplantar psoriasis can be difficult, specifically when considering the similarities of conditions such as hyperkeratotic dermatitis and palmoplantar pustulosis. Recognition of this condition is vital, though, as patients exhibit striking quality of life (QOL) disruption. Pettey et al (J Am Acad Dermatol, 2003) found patients with palmoplantar disease reported significantly more burning, soreness, and higher Psoriasis Disability Index scores. Similarly, Chung et al (J Am Acad Dermatol, 2014) found palmoplantar patents were more likely to report significantly altered Dermatology Life Quality Index (DLQI) scores.

Clearance of palmoplantar psoriasis remains notoriously challenging. Topicals are often limited due to the thick stratum corneum and contact hypersensitivity. PUVA phototherapy can improve symptoms significantly. In one trial, 63% achieved Physician’s Global Assessment (PGA) of 0-1 (Carrascosa et al, Actas Dermosifiliogr, 2013). Systemic therapies vary in efficacy. Raposo et al (Am. J. Clin. Dermatol, 2016) observed 48% of patients receiving acitretin achieved Palmoplantar Pustular Psoriasis Area Severity Index (ppPASI) 50 to 75 response, and erythema, scaling, induration, and fissuring scores improved in both methotrexate (61% of patients) and cyclosporine (50%).

Though few dedicated palmoplantar psoriasis studies exist, Dr. Zachariae highlighted two recent trials by IPC Founding President Alan Menter and IPC Councilor Alice Gottlieb. Menter et al (J Eur Acad Dermatol Venereol, 2017), which measured ppPASI-50/-75/-100 at 12 weeks, found that ixekizumab (~80%, ~70%, ~50% of patients) significantly outperformed both etanercept (67.8%, 44.1%, 32.2%) and placebo (32.9%, 18.8%, 8.2%). The phase-3b GESTURE trial (Gottlieb et al, J Am Acad Dermatol, 2015) studying secukinumab displayed similar efficacy. In both Palmoplantar Investigator's Global Assessment (ppIGA) and ppPASI scores, secukinumab 300 mg (ppIGA score 0-1 in 33.3% and ppPASI 54.6%) and secukinumab 150 mg (22.1% and 35.2%) significantly outperformed placebo (1.5% and 4.1%).

Non-IL-17 biologics trials in palmoplantar psoriasis also displayed efficacy. Bissonnette et al (J Eur Acad Dermatol Venereol, 2011) found patients receiving infliximab achieved ppPASI-75 in 33.3% vs 8.3% on placebo at 14 weeks (p = 0.03). Patients receiving adalimumab in the REACH trial (Leonardi et al, Arch Dermatol, 2011) achieved Physician’s Global Assessment (PGA) scores of clear/almost clear in 31% vs 4% for placebo at 16 weeks (p = 0.01). For ustekinumab, Au SC et al (J Dermatol Treat, 2013) found 12 patients (60%) improved PGA score by ≥ 2 points by week 16, but only 7 (35%) achieved remission. In the ESTEEM 2 Trial (Paul et al, Br J Dermatol, 2015) apremilast 30mg BID demonstrated 65.4% ppPGA score of 0-1 vs 31.3% on placebo. Bissonnette et al (J Eur Acad Dermatol Venereol. 2018) found no significant difference in the proportion of patients achieving ppPGA of 0-1 at 6 weeks with apremilast (14% vs. placebo 4%; p =0.16) but did find superiority in achieving ppPASI ≥ 75 (22% vs placebo 8%, p = 0.049).

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EADV Reviews and Updates

The second day of the EADV conference featured exceptional psoriasis-related lectures in two “Review and Updates” sessions.

Lectures in the first session – which was co-chaired by Drs. Bertrand Richert, Brugmann and Children's University Hospitals, Brussels, Belgium, and Professor Lajos Kemény, Albert Szent-Györgyi Health Center, Szeged, Hungary – concentrated largely on the diagnosis and management of difficult psoriasis manifestations. The second session – co-chaired by IPC President Dr. Jonathan Barker, St John's Institute of Dermatology, King's College London, United Kingdom, and Dr. Rolland Gyulai, University of Pécs, Hungary – addressed the optimal strategies of using both standard and emerging therapeutic modalities.

Clinical manifestations and pitfalls

In this lecture, Jan Simon, MD, Universität Leipzig, Germany, provided an extensive review of the manifestations and pitfalls of challenging and atypical psoriasis variants, which often pose significant diagnostic frustration. He advocated that practitioners obtain detailed personal and family history and perform astute whole-body examination, paying special attention to frequently subtle concomitant findings.

One such type of psoriasis, guttate, is rare in adults, but not uncommon in children. The classic “droplike” plaques typically follow pharyngitis or an upper respiratory infection, and differential diagnoses include tinea, erythema annulare centrifugum, and pityriasis lichenoides. When diagnosis is questionable, antistreptolysin-O titer and anti-DNAse-B antibodies can support diagnosis, and tonsillectomy can occasionally improve the condition.

For inverse psoriasis, given the distribution and absence of significant scaling, differentiating this condition from both common (intertrigo, candidiasis, dermatitis) and rare (Hailey-Hailey) conditions can be problematic. When psoriasis involves the groin and genitals, the differential expands, as the disease often mimics nutritional deficiencies, lichen planus, extramammary Paget’s, and the inflammatory phase of lichen sclerosus.

Scalp and nail psoriasis are both highly common. Helpful findings to differentiate scalp psoriasis from other inflammatory dermatoses include sharp demarcation, silvery adherent scale, and conchal bowl involvement. The diffuse pitting, oil spots, distal onycholysis, subungual hyperkeratosis, and preferential hand involvement seen in nail psoriasis help delineate it from dystrophic nail conditions. A rare pustular psoriasis variant, acrodermatitis continua of Hallopeau, presents as distal digit erythema and subungual pustules with subsequent scaling, crusting, and nail plate shedding.

Prompt diagnosis is critical for optimal treatment in the rare, severe pustular and erythrodermic variants. Pustular psoriasis is usually triggered by drugs and infections, as are its common pitfalls, acute generalized exanthematous pustulosis (AGEP) and Sneddon-Wilkinson disease. The annular variant often has centrifugal expansion with the palisading pustules the advancing edge. The von Zumbusch (generalized) variant presents with systemic symptoms and painful, abrupt erythema preceding pustulation and scaling. Distinguishing erythrodermic psoriasis from drug exanthems, Sezary syndrome, and erythrodermic dermatitis remains challenging.

Though up to 30% of patients with psoriasis will develop psoriatic arthritis, 10-15% of all patients lack cutaneous involvement. Recognizing this inflammatory disease early is vital to providing swift therapy to prevent sequelae. The 5 manifestations of the disease in order of prevalence are mono- or oligo-arthritis, asymmetric distal involvement, RA-like symptoms, arthritis mutilans, and spondylitis/sacroiletitis, though overlap may exist. Psoriatic onycho-pachy-dermoperiostitis (POPP) is an exceedingly rare variant with painful distal interphalangeal (DIP) joint swelling, nail changes, periosteal inflammation, and hyperostosis.

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Pathogenic insights, treatment decisions in paradoxical reactions

Paradoxical psoriasis is increasingly documented, given the pervasive use of TNF-α inhibitors (TNFi). In his presentation, IPC Councilor Michel Gilliet, MD, University of Lausanne, Switzerland, provided an in-depth review of this condition. Paradoxical psoriasis never relapses, TNFi-induced lesions develop independent of the condition (ulcerative colitis or Crohn’s disease, for example) despite improvement. All TNF-α inhibitors can cause such lesions, and 5% of all patients are affected. Four distinct histopathologic phenotypes of paradoxical psoriasis exist: typical psoriasiform, spongiform, interface, and pustular.

Dr. Gilliet’s team studied 25 patients with various conditions who received TNF-α inhibitors and consequently developed paradoxical psoriasis. Analyzing the paradoxical skin lesions, they found cytokines and interleukins (TNF-α, IL-23/8/12, IL-1b) expressed at the same level as in classic psoriasis, but, remarkably, found that type-1 interferons (IFNs), IFN-α2 and IFN-β1 were highly overexpressed in paradoxical psoriasis patients. Accordingly, they detected much higher levels of IFN-producing plasmacytic dendritic cells (pDCs) in the dermis of these paradoxical lesions than in classic psoriasis.

Mechanistically, TNFi interferes with the natural differentiation of pDCs. Normally, TNF-α produced by pDCs promotes self-differentiation into non-IFN producing dendritic cells (DCs). TNFi drugs inhibit this self-differentiation, thus prolonging IFN-α production (by pDCs). To prove this hypothesis, Dr. Gilliet’s team injured mice skin in vivo, inducing production of pDCs and, subsequently, IFN-α. They found the relative expression of IFN-α in mice treated with TNFi was prolonged over the subsequent 2-3 days. By day 7, the TNFi-treated mice showed IFN-dependent thickening of the dermis, with subsequent amelioration after administration of an IFN-blocking antibody. Dr. Gilliet’s work suggests the principal difference from classic psoriasis is that paradoxical psoriasis does not expand the T-cell population that produces Th17. In summary, TNFi-induced paradoxical psoriasis is IFN-driven and T-cell independent, lacks pDC differentiation, and lacks disease memory.

With this novel data, Dr. Gilliet proposed that “paradoxical psoriasis” is a misnomer, as this condition is strikingly immunologically different from classic psoriasis. He suggested it may instead be considered “interferon-itis.” In management, Dr. Gilliet strongly recommended immediate discontinuation of the causative TNFi and appropriate change in therapeutic course. Many early-phase trials investigating medications targeting pDC, TLR-7/9, and IFN signaling are currently underway, and Dr. Gilliet’s team plans to conduct future genetic studies to identify at-risk patients.

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Diagnosis, management of palmoplantar psoriasis

Dr. Kemény discussed the diagnosis and management of palmoplantar psoriasis, a rare but frustrating variant. Although broadly characterized as hyperkeratotic or pustular, much overlap exists. Purely hyperkeratotic disease accounts for 50% of cases, purely pustular 16%, mixed 12%; 22% do not classify neatly into any category. Diagnosis is often elusive given this wide phenotypic variability, but common differential diagnoses for hyperkeratotic lesions include hyperkeratotic hand dermatitis, tinea, and pityriasis rubra pilaris (PRP), and, for pustular lesions, acute dermatitis, acrodermatitis continua of Hallopeau, and palmoplantar pustulosis (PPP). Controversy exists regarding whether PPP and palmoplantar psoriasis are distinct or related entities; however, recent genetic expression microarray by Bissonnette et al (PLOS One, 2016) suggests these conditions are largely related, yet distinct from psoriasis vulgaris. Differentiating palmoplantar psoriasis from other conditions is vital, given the emerging disease-specific therapeutic advances. Meticulous full-body examination is paramount, as 82% of patients have concomitant psoriatic plaques, but 1/3 of all psoriatic arthritis patients have less than 10% body surface area (BSA) involvement. Treatment of palmoplantar psoriasis follows an algorithm comparable to chronic plaque psoriasis. PUVA (ultraviolet light A therapy with the light-sensitive drug psoralen), acitretin, methotrexate, and cyclosporine remain the most efficacious medications for pustular disease, as topical therapy is often unsatisfactory. Biologics appear promising despite few dedicated randomized controlled trials. A recent systematic review by Sanchez et al (Dermatol Ther, 2017) found that adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab all demonstrated > 80% efficacy for hyperkeratotic palmoplantar psoriasis. Pustular disease remained more recalcitrant, and only infliximab and ustekinumab appeared to provide moderate efficacy. In closing, Dr. Kemény referenced 2 recent palmoplantar-specific trials by IPC Councilors Takashi Terui and Alice Gottlieb. Terui et al (JAMA Derm, 2018) found palmoplantar pustulosis severity index scores improved significantly with the Interleukin (IL)-23 antagonist gesulkumab, and Gottlieb et al (GESTURE trial, J Am Acad Dermatol, 2017) found significant improvements in Palmoplantar Psoriasis Area and Severity Index (ppPASI) and Dermatology Life Quality Index (DLQI) with the IL-17A antagonist secukinumab.

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Scalp and nail psoriasis: Diagnosis and treatment

In this lecture, Dr. Richert, a trustee of the Council for Nail Disorders, discussed scalp and nail psoriasis, two of the most common clinical findings in psoriasis, affecting nearly 80% and 50-90% of all patients with psoriasis, respectively. Scalp involvement is the presenting sign in approximately 25% of patients and nearly always involves significant pruritus, which can occasionally generate late-stage cicatricial alopecia. Trichoscopy reveals glomerular-shaped perifollicular capillary dilatation, contrasted with the reticular capillary pattern of seborrheic dermatitis. Although keratolytics are classically employed, literature suggests descaling is of marginal benefit (Shokeen et al, Dermatol Online J, 2014); simplifying the regimen improves adherence and satisfaction. Combination topical steroids and vitamin D analogues outperform either monotherapy (Schlager et al, Cochrane Database of Systematic Reviews, 2016.). A main drawback to topical therapy is self-discontinuation following clinical and symptomatic improvement. Maintenance therapy is crucial, though only 40% of patients continue past 8 weeks.

Nail disease is stubborn and exceedingly agonizing to patients; 93% describe cosmetic distress, 58% experience vocational interference, and 52% report pain (de Jong et al, Dermatology, 1996). Given the wide spectrum of clinical findings, nail psoriasis is commonly misdiagnosed as paronychia or onychomycosis. Importantly, psoriatic arthritis is strongly associated with distal nail onycholysis with odds ratio of 3.42 (Love et al, Scand J Rheumatol, 2010). Inflammation migrating along the extensor tendon can produce onycholysis, as the nail unit is part of the enthesis (Tan et al, Ann Rheum Dis, 2006). X-ray can miss early disease; therefore, MRI and rheumatology referral are crucial for early systemic intervention. Conservative therapies (lacquer, trauma avoidance, topical and intralesional steroids) may help, but systemics and biologics are often required. Cyclosporine clears nails rapidly (Sanchez-Regana et al, J Eur Acad Dermatol Venereol, 2011) and transition to methotrexate or low-dose acitretin (0.3 mg/kg) can provide some patients with stability. Biologics are increasingly recognized as superior therapies.

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Topical and phototherapY

With highly effective systemics and biologics in psoriasis, Wolfram Hoetznecker, MD, PhD, of Universität Tübingen, Germany, discussed the steadfast value of topical- and photo- therapies, specifically in patients with limited disease, significant comorbidities, or financial limitations.

Topical therapies remain a cornerstone for nearly all patients with psoriasis. Dr. Hoetznecker first highlighted the rapid efficacy of dianthrol (anthralin) which provides swift Psoriasis Area and Severity Index (PASI) 75 response in 50% of patients. Holstein et al (J Dermatol Sci, 2017) demonstrated significant decrease in epidermal thickness and Ki-67 staining and normalized cytokeratin-16 expression early in anthralin therapy. Topical corticosteroids and vitamin D analogues remain widely used. Combination therapy provides significant synergistic effects and appears superior to either monotherapy, as demonstrated in a Cochrane review by Mason et al (J Am Acad Dermatol, 2013) and in a study by Menter et al (J Drugs Dermatol, 2013). Many active trials studying novel topicals in psoriasis are currently in various phases, including JAK-kinase inhibitors (tofacitinib), PDE-4 inhibitors (crisaborole), and novel tropomyosin-receptor kinase A (Trk-A) antagonists. The TrkA-antagonists show promise in reducing psoriatic pruritus, first demonstrated with topical CT327 by Roblin et al (Acta Derm Venereol, 2015). Additional phase 2 studies on the TrkA-antagonist SNA-120 are active. Results are pending.

Phototherapy provides PASI reductions of 50-75% for ultraviolet light B and 50-100% for PUVA at 4-6 weeks, and remains an important therapy, given relatively few and mild side effects. The most substantial adverse effect is increased risk of nonmelanoma skin cancer (NMSC) with PUVA, favoring squamous cell carcinoma (SCC) over basal cell carcinoma (BCC). As reported by Stern et al (J Invest Dermatol. 2003) and supported by many long-term studies, SCC risk becomes significant around 200 therapeutic sessions, typically after years of therapy. Although NMSC risk with narrowband-ultraviolet light B (nb-UVB) therapy was demonstrated in animal trials, currently no convincing data exist for humans. Despite studies demonstrating increased efficacy of PUVA, a review of 13 randomized controlled trials by Chen et al (Cochrane Database Syst Rev, 2013) revealed heterogenous results, and many dermatologists favor nb-UVB to reduce NMSC risk. Regardless, Dr. Hoetzenecker concluded that phototherapy of any form is a highly effective, but advised caution with long-term use of either modality.

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Classic systemic therapies and combinations

In this lecture, Dr. Gyulai focused on the use of “classic” oral psoriasis medications in the realm of new, highly effective biologics, namely methotrexate, acitretin, cyclosporine, and fumaric acid.

The relatively new apremilast and arthritis-specific medications were omitted. These remain important due to an established safety profile and are very cost effective. Additionally, many biologics and TNFi (TNF inhibitors) are listed only as second-line therapies, and subsets/ of patients cannot tolerate subcutaneous or IV dosing.

First used 60 years ago, methotrexate (MTX) remains the most common classic medication in psoriasis. MTX’s high affinity inhibition for DHF-reductase primarily suppresses Interleukin (IL)-2 and subsequently T-cells. Recently, Yan et al (Br J Dermatol, 2018) suggested MTX is also capable of upregulating CD-73 expression in regulatory T cells (Tregs), restoring suppressor function. MTX achieves ~35-40% PASI 75, but Warren et al (Lancet, 2017) suggests intensified dosing results in even higher efficacy rates, with PASI 75 at 24 weeks in 50% of patients, nearing the range of anti-TNFs. Adherence is approximately 50% at 1 year (Dommasch et al, J Am Acad Dermatol, 2018). Interestingly, pre-treatment serum calcium levels may serve as predictors of methotrexate success (Zhai et al, J Am Acad Dermatol, 2015) and MTX is nearly 3 times more efficacious in the HLA-Cw6 population. Known liver toxicity sometimes precludes therapy, but Shetty et al (Am J Med Sci, 2017) reported that MTX alone does not cause liver toxicity; the risk becomes apparent only with comorbidities such as obesity or diabetes. Tang et al (J Am Acad Dermatol, 2018) reported MTX in psoriasis does not increase cirrhosis risk with chronic viral hepatitis and found no difference in liver cirrhosis-free survival during 12-year follow-up. Accurate, non-invasive elastography provides favorable monitoring.

Acitretin binds to retinoic acid receptors, regulating gene expression by altering nuclear transcription. Dermatologists have likely been underdosing acitretin, attaining diminished efficacy. Lee et al (BMC Dermatol, 2016) found PASI 75 in only ~20% of patients by 24 weeks on acitretin 10 mg BID. Conversely, Borghi et al (Acta Derm Venereol, 2015) found that approximately 67% of patients achieve PASI 75 by week 16, with 10 mg increments every 2 weeks until lowest effective dose. Chen et al (Sci Rep, 2018 and Per Med, 2018) found polymorphisms that may predict acitretin responders, which could individualize future prescribing. Cyclosporine, a calcineurin inhibitor that downregulates IL-2 and T-cell activity, has been used in psoriasis since 1979. The well-known side effects limit its use, but CSA remains important in severe flares, for rapid response (58% achieve PASI 75 by week 12), in re-introduction of therapy with retained effectiveness (Ho et al, Br J Dermatol, 1999), and in special circumstances such as pregnancy. Fumaric acid, though not available in many countries, demonstrates efficacy comparable to methotrexate, with ~ 40% achieving PASI 75 with relatively few side effects.

Combination therapy in both psoriasis and other systemic inflammatory conditions classically pairs drugs with different targets, attacking different elements of the pathogenic pathway. Methotrexate and etanercept combined are more effective than either alone (Gottlieb et al, Br J Dermatol, 2012). Methotrexate reduces drug clearance of adalimumab by 44% and infliximab by 30%, and reduces immunogenicity when paired with many anti-TNFs (adalimumab with methotrexate 1% vs 12% without, etanercept < 2% vs 3% without, IFX 0-15% vs 7-53% without, depending on dose). The relative risk of serious adverse effects is low in combination therapy of anti-TNFs and methotrexate or acitretin.

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TNF antagonists

TNF-α antagonists (anti-TNFs) revolutionized psoriasis treatment in the early 2000s, but recently, targeted biologics have shown unparalleled clinical response. In this session, IPC Councilor Curdin Conrad, MD, PhD, investigator at Lausanne University Hospital, Switzerland, summarized the importance of anti-TNFs despite this shift to newer agents.

Novel biologics have demonstrated escalating efficacy. Reich et al (Br J Dermatol, 2011) found superiority with ustekinumab, Mrowietz et al (J Am Acad Dermatol, 2015) with secukinumab, and Blauvelt et aI (J Am Acad Dermatol, 2017) with ixekizumab. Recently, Papp et al (N Engl J Med, 2017) demonstrated that the IL-23 antagonist rizankizumab achieves a PASI 100 score in 50-60% of patients. Equal safety data accompanies this efficacy. Various meta-analyses (Nast et al, J Invest Dermatol, 2015; Ryan et al, JAMA, 2015; Jabbar-Lopez et a, J Infect Dis, 2017) found no difference in safety between the novel biologics and anti-TNFs, and the PSOLAR longitudinal registry suggests ustekinumab causes less serious infections than anti-TNFs. Long-term drug survival also appears superior with ustekinumab, supported by van den Reek et al (Br J Dermatol, 2014) and Gniadecki et al, (Br J Dermatol, 2015). Compounding the above, anti-TNFs carry drug-specific adverse effects such as lupuslike syndrome, paradoxical psoriasis, increased tuberculosis risk, and possibly demyelinating disorders.

The above information begs the question, why choose anti-TNFs to treat psoriasis? Anti-TNFs remain the gold standard in many systemic inflammatory conditions. In psoriasis, the benefits extend beyond cutaneous disease, specifically regarding cardiovascular disease. Gelfand et al (JAMA, 2006) found that risk of myocardial infarction and mortality correlate with psoriasis severity. Boehncke et al (BMJ, 2010) described how psoriatic inflammation increases future MI risk. More recently, the reduction in major adverse cardiovascular events (MACE) with anti-TNF therapy has been elucidated. Wu et al (J Am Acad Dermatol, 2018) demonstrated 50% reduced relative risk in a phototherapy cohort only when paired with anti-TNF. Ahlehoff et al (J Eur Acad Dermatol Venereol, 2015), though not a random controlled trial, found that anti-TNFs significantly reduce mortality and MACE when compared to ustekinumab. Anti-TNFs also remain preferred in treating children, given their established safety, and we are learning how to predict which patients will be anti-TNF responders. Wilkinson et al (J Invest Dermatol, 2018) of the PSORT Consortium demonstrated PASI 75 probability of 81% in adalimumab at serum levels of 7 ug/ml. The ability to predict responders may influence future prescribing habits.

Despite the advent of new and exciting targeted biologics, Dr. Conrad asserted that use of anti-TNFs remains indispensable when treating psoriasis and its comorbidities. Therapy should remain individualized to treat the entire condition, not just cutaneous disease.

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Advance in systemic therapies: IL-17 and IL-23 antagonists

In his presentation, IPC President Dr. Barker provided a brief summary of systemic therapies ranging from methotrexate in the 1960s and retinoids in the 1980s to the present-day booming generation of T-cell-targeting biologics. He referenced the serendipitous clearance of psoriatic plaques in rheumatoid patients receiving cyclosporine reported by Mueller and Herrmann in 1979, with subsequent dedicated studies by Voorhees, Valdimarsson, and Jónsdóttir validating the use of cyclosporine in psoriasis and supporting a T-cell-driven pathogenesis. Ensuing research on alefacept (CD2 pathway) and efalizumab (CD11a pathway) by Lebwohl, Nestle, and Ellis in the early 2000s further promoted the importance of T-cell-directed therapies. Continuing this trend in 2009, Nestle, Kaplan, and Barker highlighted the crucial role of IL-23 on Th17 cells in psoriasis pathogenesis, and Strange and Tso elucidated psoriasis genetics of HLA-CW6 and the IL-23 signaling pathways.

Referencing exceptional diagrams in papers by Girolomoni et al (J Eur Acad Dermatol Venereol, 2017) and Baker and Isaacs (Ann. Rheum Dis, 2018), Dr. Barker analyzed the current and emerging, highly specific biologics that target the paramount IL-23, IL-17, TNF-α, and IL-12 pathways. Dr. Barker’s principal focus in this discussion was the recognition that, although these biologics target similar IL-17 and IL-23 pathways, precise differences in their mechanisms and downstream effects exist. Additionally, each drug varies in efficacy, safety profile, tolerability, issues with comorbidities, and drug acquisition costs. Therefore, dermatologists must remain diligent when prescribing individual medications. Importantly, random controlled trials often exclude large subsets of patients and are not powered to detect rare or serious adverse events. Trials often do not reflect real-life data or prescribing practice. Dr. Barker closed by remarking that, to date, very few sequential studies have been performed, so the optimal use of biologics requires judicious, ongoing investigation.

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Late Breaking Updates

Psoriasis remains perhaps the most compelling, dynamic, and innovative area of dermatology research. From the French GESTA-PSO study of psoriasis in pregnancy to many studies on biologics, 5 distinguished psoriasis investigators presented early results from both ongoing and recently completed trials addressing psoriasis care and management. 

Psoriasis and pregnancy: GESTA-PSO study results

Although much literature exists regarding psoriasis therapies in pregnancy, little has been studied regarding patient-physician communication. Dr. Anne-Claire Fougerousse, Bégin Military Teaching Hospital, Saint-Mandé, France, presented preliminary results of the GESTA-PSO trial, a 6-month national (France) observational multicenter survey of 361 mixed dermatology practitioners, focused on “biologic agent generation” dermatologists (dermatologists who obtained diplomas in or after 2004). Survey response rate was 42.2%, mean percentage of females aged 18-45 was 28.6%, with significant difference between hospital (25.3%) vs private/mixed (31.9%) practice. Results demonstrated that, although 75% of dermatologists discussed the impact of psoriasis on sexual function and pregnancy, only 20% of dermatologists initiate this discussion and 12% never discuss this topic. The most common issues initiated by patients included compatibility of psoriasis with pregnancy (64%), disease transmission to the fetus (54%), and fetal risks (49%). In total, 45% of male dermatologists and 26% of female dermatologists have been confronted with a patient’s unplanned pregnancy during psoriasis treatment (p = 0.0022), and only 28% were familiar with existing recommendations for treatment in women of childbearing potential. Although the sample population was not representative of all practitioners, this study highlights the necessity to approach this difficult topic and the need for psoriasis-specific pharmacovigilance registries for biologics in pregnancy.

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Generalized pustular psoriasis and BI 655130

Generalized pustular psoriasis (GPP) is a rare, debilitating systemic condition characterized by acute intermittent flares with many triggers. Previous studies established strong links between IL-36 signaling hyperactivation and GPP (DITRA IL-36 trials). To date, interventions have proven suboptimal, with no approved biologics in Europe or the United States for treating the condition. In this lecture, IPC Board Member Hervé Bachelez, MD, PhD, Saint-Louis Hospital, Paris, France, reported early data from a phase 1, proof-of-concept trial, a 20-week study of 7 patients receiving one 10 mg/kg dose of BI 655130, an anti-interleukin-36 receptor antibody.

Inclusion criteria included 2+ documented flares of GPP and moderate to severe generalized pustular psoriasis Physician Global Assessment (gpPGA) score ≥ 3. Primary endpoints were safety and durability, and secondary endpoints included PGA of 0, 1, and percent change of generalized pustular psoriasis Psoriasis Area and Severity Index (gpPASI) score by week 2. Early data suggested no severe adverse events and no infections, with rapid sustained improvements in gpPGA (PGA = 0,1 in all patients at 4 weeks, sustained in 5 patients at 20 weeks) and gpPASI (mean change 73.2% [SD = 16.2] by week 2). Initial data suggested safety and efficacy, which notably was independent of severe IL-36RN mutation status seen in 3 of the patients. Preparations are underway for pivotal follow-up trials.

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BMS-986165 improves biomarkers

Broad inhibition of the Janus kinase enzyme (JAK) with medications such as apremilast provides established improvement in psoriasis but carries undesirable immunosuppression risk. Through associations with the JAK-2 enzyme, tyrosine kinase 2 (TYK2) mediates IL-17, IL-23, the IL-20 family, and innate interferons (IFN) and keratinocytes (KCs). In this lecture, IPC Councilor James Krueger, MD, PhD, Rockefeller University, New York, United States, presented results from a double-blind, placebo-controlled phase 2 study of 267 patients with moderate to severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥ 12, Body Surface Area [BSA] ≥ 10, static Physicians Global Assessment [sPGA] ≥ 3). The patients received various doses of the oral agent BMS-986165, a highly selective TYK2 inhibitor. Primary endpoint of PASI 75 reduction at 12 weeks closely matched data for IL-23 antagonists and outperformed apremilast. PASI 75 reductions were 69% for 3mg BID, 67% for 6mg BID, and 75% for 12 mg daily (all P < 0.001 vs. placebo). Reductions in the histopathologic hallmarks of psoriasis also mirrored anti-IL-23 biologics. Additionally, doses > 3 mg BID markedly reduced IL-17 and IL-22 expression, cytokines associated with KC activation, and β-defensin and S-100A9 inflammatory genes, and inhibited IFN-regulated gene expression. Importantly, no effects of broad JAK inhibition were demonstrated on biomarkers; no aberrancies were observed in T-/NK-/B-cell or neutrophil counts, hemoglobin, or cholesterol. BMS-986165 was generally well tolerated, with few (2%) nondrug-related serious adverse effects, identical to placebo rate (2%). (Papp, et al, NEJM, September 2018.)

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Tight-controlled dose reduction of biologics

Many psoriasis patients remain on biologics indefinitely, but there is a paucity of data regarding the safety and efficacy of dose reductions. Juul van den Reek, MD, PhD, and postdoctoral fellow PhD candidate Selma Atalay, both of Radboud University, Nijmegen, the Netherlands, presented the findings from the multicenter, open-label, non-inferiority CONDOR trial studying tight-controlled dose reductions in 120 psoriasis patients with low, stable disease activity (PASI ≤ 5, Dermatology life Quality Index [DLQI] ≤ 5) on biologics (etanercept, adalimumab, or ustekinumab). Primary endpoint was a strict a priori noninferiority (NI) margin of 0.5 in PASI difference over 12 months. Sixty patients were randomized to both control group (usual care) and intervention group (dose reductions), with 111 included in analysis (58 control, 53 intervention). Dose reductions occurred every 3 months, initially by 33% then subsequently 50%, with patients returning to previous effective dose if flare occurred. The endpoint PASI difference between groups was 1.1 (95% CI 0.6-1.5), suggesting inferiority, as this exceeded the set NI margin of 0.5. However, Dr. van den Reek questioned the clinical relevance of such a minor increase, as both median PASI and DLQI remained well-below 5 in both groups and previously reported “minimal clinical important difference” in PASI is 3.2 (Mattei et al, J Eur Acad Dermatol Venereol, 2014]. Overall, sustained dose reduction was possible in 70% of patients, no serious adverse events occurred, and no significant difference in persistent flares between groups was observed. Long-term follow-up continues (CONDOR-X) and future analyses will include cost-effectiveness, serum drug levels, and antibody formation.

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Long-term efficacy, safety of tildrakizumab

IPC Councilor Diamant Thaci, MD, University of Lübeck, Germany, presented 3-year (148 weeks) safety and efficacy results regarding the anti-IL23p19 monoclonal antibody tildrakizumab from the reSURFACE1 (tildrakizumab vs placebo) and reSURFACE2 (tildrakizumab vs etanercept) trials, which demonstrated significant PASI ≥ 75 response and PASI ≥ 90 response for both tildrakizumab 100 mg and 200 mg (Reich et a, Lancet, 2017). The 3-year extension study results included patients who initially achieved PASI ≥ 75 response at 28 weeks and continued the same tildrakizumab dose. Some PASI 75 responders were randomized to receive placebo after 16 weeks in part 3 studies. Regarding 3-year efficacy, the primary endpoint maintenance of PASI 75 response was observed in 91% (tildrakizumab 100 mg) and 92% (tildrakizumab 200 mg) at 148 weeks. PASI 90 for both doses exhibited similar overall stability. Additionally, at 148 weeks, approximately 50% of PASI 75 responders did not relapse when switched to placebo, and median time to relapse was 226 days (tildrakizumab 100 mg) and 258 days (tildrakizumab 200mg), suggesting durability. Adverse events were rare overall for both tildrakizumab doses during this 3-year period. Regarding adjusted adverse events (per 100 patient years), there were no substantial differences between tildrakizumab and placebo, and no significant differences between tildrakizumab and etanercept. Tildrakizumab also has low injection-site adverse events, which may translate to improved compliance in tildrakizumab-treated patients. Dr. Thaci’s group plans to follow and report on 4- and 5-year data.

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