Focus on Psoriasis

A report from the 2019 Annual Meeting of the World Congress of Dermatology, Milan, Italy

By Rebecca Nguyen, MB, BS, FACD 

With more than 15,000 registrants, the 2019 24th World Congress of Dermatology was a resounding success as hosted in June by the Italian Society of Dermatology at the MiCo Milano Convention Centre in Milan, Italy. The international conference was organized through the auspices of the International League of Dermatological Societies, which holds a meeting every 4 years. The wealth of psoriasis-focused sessions during the congress demonstrated the innovative advancements in understanding the pathogenesis of the disease, as well as in its diagnosis and treatment. Well-attended sessions discussed the epidemiology, pathogenesis, comorbidities, treatment efficacy, and emerging therapies associated with psoriasis.

Contents and quick links

• Psoriasis epidemiology
• Psoriasis pathogenesis
• Psoriasis comorbidities
• Plenary session
• Psoriasis treatment
• Controversies
• References 

pSORIASIS EPIDEMIOLOGY

IPC Board Member Professor Chris Griffiths, Salford Royal NHS University Trust and University of Manchester, United Kingdom, discussed the latest BADBIR (British Association of Dermatologists Biologic and Immunomodulators Register) data. The registry showed no increased risk of death, infection requiring hospitalization, malignancy, or serious adverse events in patients who used biologic agents versus conventional systemic agents to treat their psoriasis. Data from a recent study found no significant increased risk of MACE (major adverse cardiovascular events) in those with first-line use of ustekinumab versus TNF-α inhibitor agents.¹ There was no increased risk of cutaneous squamous cell carcinomas or basal cell carcinomas in those who are biologic-exposed versus those receiving conventional systemic therapy.²

Patients who responded to first-line use of adalimumab were more likely in those who were female or had psoriatic arthritis and less likely if they weighed more than 100 kg or were unemployed. Those who responded to first-line use of ustekinumab had a higher baseline PASI (Psoriasis Area Severity Index) score, weighed more than 100kg, or were unemployed and retired. Those less likely to respond were female or had psoriatic arthritis. Compared to those on adalimumab, patients who were on etanercept or infliximab were more likely to discontinue their treatment; patients on ustekinumab were less likely to discontinue. Predictors of discontinuation included being female, a smoker, having psoriatic arthritis, or being previously treated with methotrexate or cyclosporine. Up to 25% of patients switched biologic agents during the first year of exposure and those who had were switched to a second biologic therapy.

In the era of stratified medicine, at least one study showed that measuring adalimumab levels early in treatment predicts response at 6 months.³ Patients who are HLA-cw6 positive have a faster and greater response to ustekinumab and have a superior PASI 90 response compared to those who are HLA-cw6 negative.⁴

IPC Board Member Dr. Claudia de Cruz, ClinicaDermacross, Santiago, Chile, discussed the barriers to treatment of psoriasis in Latin America, including significant out-of-pocket costs; reimbursement issues due to restriction; delayed or denied access; poor geographical spread of dermatologists across Latin America; and variable expert knowledge. Among ways to overcome these barriers, she said, are access to biosimilars, telemedicine to reduce geographical isolation, and educating and mentoring local physicians.

Dr. Alexander Egeberg, Copenhagen University Hospital, Denmark. discussed the impact of biologic treatment on cardiovascular comorbidities. Young patients with severe psoriasis have an increased risk of cardiovascular disease.⁵ The impact of treatment with canakinumab, an IL-1β inhibitor, versus placebo in a randomized controlled trial with 10,061 patients (who did not have psoriasis) showed a statistically significant reduction in acute myocardial infarction but with a large number needed to treat (NNT).⁶ A 2019 randomized, double-blind study of 5,000 patients (who did not have psoriasis) treated with methotrexate versus placebo showed no clinical benefit and the trial was stopped after a median follow up of 2.3 years.⁷ Dr. Egeberg discussed how bias and confounding factors are issues with many currently-published psoriasis and cardiovascular risk studies. Even if there is a benefit of immunomodulation treatment of psoriasis, the number needed to treat is high and the risk-benefit ratio favors established cardiovascular risk-reduction strategies. 

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Psoriasis pathogenesis

IPC Board Member Professor Lars Iversen, Aarhus University Hospital, Denmark, discussed the theory of the psoriatic march, in which potential irreversible long-term changes are associated with disease longevity. It is postulated that IL-17A-producing T cells are promoted by IL-6 and IL-1B to produce IL17-A. This induces chemokines that, in turn, recruit more IL-17A-producing T cells, which bear a CCR6 chemokine receptor. This leads to increased T cell penetration into the skin and possible transformation into tissue-resident memory T cells. This cycle continues and untreated psoriasis leads to a large resident memory T cell population, which induces chronicity.⁸

IPC Councilor Dr. Andrew Blauvelt, Oregon Medical Research Center, United States, postulated that tissue-resident T memory cells may be dependent on IL-23 for survival and that treatment with IL-23 inhibitors may give long-lasting remission; however, this is an unstudied area. In instances of both Crohn’s disease and rheumatoid arthritis, intensive early intervention improves outcomes.^9,10 No evidence exists suggesting that early treatment of psoriasis improves outcomes. Further research is needed.

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Psoriasis comorbidities

IPC Councilor Associate Professor Peter Foley, University of Melbourne, Australia, discussed how the risk of obesity is significantly increased in patients with psoriasis.¹¹ Other health issues related to obesity include the prevalence of nonalcoholic fatty liver disease in 48–59% of patients with psoriasis compared to 20-30% in the general population.¹² Weight loss has been associated with improvement of psoriasis, including improving response to treatment with cyclosporine.¹³ However, weight loss alone may not be enough to maintain disease remission.¹⁴

Treatment with agents such as adalimumab, secukinumab, ixekizumab, ustekinumab, guselkumab and rizukizumab has shown a drop-off in efficacy at higher body weight compared to lower body weight. Infliximab dosing is based on a patient’s weight, so does not have this issue. Anti-TNF agents as a class may cause weight gain.¹⁵

IPC Councilor Professor Alice Gottlieb, Icahn School of Medicine at Mount Sinai, New York, United States, discussed the importace of recognizing and treating psoriatic arthritis and psoriasis to inhibit progression. Recognizing psoriatic arthritis and measuring response criteria have been described using the Psoriatic Arthritis Responder Criteria (PsARC), American College of Rheumatology (ACR) 20 score, and the European League Against Rheumatism (EULAR) 28. The 2018 American College of Rheumatology/National Psoriasis Foundation guidelines describe TNF-inhibitor and IL-17 inhibitor agents as more effective than IL-12/23 inhibitor agents for psoriatic arthritis. Methotrexate is superior to nonsteroidal anti-inflammatory agents as adjunct oral agents.¹⁶

Dr. Alessandro Giunta, University of Rome, Italy, presented challenging psoriasis-related cases in which treatment of patients’ comorbidities such as hepatitis C, periodontitis, HIV, diabetes, and obesity improved their psoriasis.

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Plenary session

IPC Board President Jonathan Barker, who was invited to speak at the conference plenary session, discussed “Psoriasis 2019.” He briefly covered the genetics of psoriasis, which has about 60 known genetic loci. The most well known is HLA-C*06:02, which is involved in antigen presentation to CD8 and natural killer T cells. Another well-known association is IL-36RN loss-of-function mutations, which are associated with generalized pustular psoriasis. The biologic revolution has enabled almost total or total clearance to be a goal. However, challenges include cost, access, and long-term safety data, which are not yet available. Rationalizing of treatments may ensure improved access, with biosimilars becoming increasingly available and genetic biomarkers’ response to biologics playing a potential role.

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psoriasis treatment

IPC Board Member Professor Bruce Strober, University of Connecticut, United States, presented data showing that risankizumab, a humanized IgG1 monoclonal antibody against the p19 subunit of IL-23, was well tolerated in phases 1, 2, and 3 trials, including Trial 1311.1, UltIMMa-1, UltIMMa-2, IMMhance, IMMvent,SustalMM, M16-178, M16-007, M16-009, and LIMMITLESS. It is associated with low and consistent infectious rates in patients with moderate to severe plaque psoriasis in short-term and long-term pooled clinical data. Overall adverse events were low and did not increase with long-term therapy. Long-term data are currently available for up to 47 months and comprised 2,471 patients with a total of 3,404 patient years. There was an average of 16.5 months of dosing.

At week 16, infection rates were slightly higher than placebo, mostly consisting of upper respiratory tract infections and rare episodes of fungal infections including tinea. Serious infections were uncommon though slightly higher than ustekinumab, including a patient with cellulitis and dermatomal herpes zoster infection with no discontinuation required. In long-term data, most common infections included upper respiratory tract infections. Serious infections were rare but included sepsis, cellulitis, and pneumonia. There were cases of tinea and oral candida but no systemic candidiasis and 2 cases of herpes zoster in a dermatomal distribution which did not require discontinuation. There were 9 cases of latent tuberculosis, which were treated with standard prophylaxis therapy with no active tuberculosis. There was no reactivation of tuberculosis after 77 weeks of follow-up.

Professor Iversen, Aarhus University Hospital, discussed tildrakizumab, a new monoclonal antibody against the p19 subunit of IL-23, and the rates of extended MACE in the phase 3 clinical trials reSURFACE 1 and 2 with up to three years of data. Incident rates were reported as events per 100 patient years of exposure (EAIR). Of the patients participating in the trials, 25% had a prior history of cardiovascular disease and 20% had hypertension. There were more than 2,000 patient years of exposure for tildrakizumab, 153 patient years for etanercept, and 205 for placebo. The EAIR for the tildrakizumab 200 mg group was 0.54, 0.4 for the tildrakizumab 10 mg group, 0.65 for the etanercept group, and 0.49 for placebo, which was comparable across all groups. It confirmed there were low rates of extended MACE events, and tildrakizumab had a favorable long-term cardiovascular risk profile.¹⁷

Adjunct Professor Phoebe Rich of Oregon Health and Science University, United States, discussed mirikizumab, a new monoclonal antibody that binds to the p19 subunit, causing IL-23 inhibition, and its effects on scalp psoriasis. This was a phase 2 study, AMAF, which compared mirikizumab 30 mg, 100 mg, 300 mg, and placebo. At week 16, those who did not achieve PASI 90 were re-randomized to mirikizumab 300 mg given every 8 weeks. They used the PSSI (Psoriasis Scalp Severity Index) score to rate scalp psoriasis improvement up to week 52 in those who did not achieve PASI 90 at week 16. The number of patients who achieved a PSSI score of 0 (clearance of scalp psoriasis) increased from week 16 to week 52. Clearance of scalp psoriasis was maintained throughout week 16 to week 52 with maintenance dosing.

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Controversies

There was a lively discussion between IPC Councilor Associate Professor Paolo Gisondi, University of Verona, Italy, and Professor Phyllis Spuls, University of Amsterdam, the Netherlands, of intermittent versus continuous use of biologic treatments in psoriasis.

In a recent study, patients treated with etanercept who had reached a PASI score of 0 for at least 12 months were randomized to either stopping or continuing treatment. A PASI >5 score was defined as having psoriasis relapse. Study results showed that 65% of those who discontinued etanercept experienced relapse compared to 9% of those who continued taking the drug. Median time to relapse was 6 months with a mean score of PASI 8 for relapse.¹⁸

The presenters also discussed STOP, a multicenter retrospective study of suspension of TNF inhibitors in patients with psoriasis. At 6 months of follow-up, 35.9% of etanercept, 25% of adalimumab, and 39% of infliximab patients had to be re-treated due to relapse of their disease.¹⁹

It was discussed whether biologic therapy should be stopped in certain scenarios such as clinically relevant adverse events, patient refusing to continue therapy, loss of efficacy, vaccinations, pregnancy, and major surgery. At this stage, it is not possible to identify which patient can successfully cease therapy without experiencing recurrence. Biologics are all labeled for continuous use except for etanercept.²⁰

The presenters did not give a definitive answer as to whether biologic therapy should be continuous or intermittent. Further research is needed and, currently, it is up to the individual practitioner to decide.

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References

1. Rungapiromnan W et al. J Eur Acad Dermatol Venereol. 2019, accepted, pending publication.
2. Mason KJ, Barker J, Burden DJ, et al. The risk of keratinocyte carcinoma in psoriasis patients receiving biologic therapy compared to conventional systemic therapy: Results from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2018; 138:Supplement PS41.
3. Wilkinson N, Tsakok T, Dand N, et al. Defining the therapeutic range for adalimumab and predicting response in psoriasis: A multicentre prospective observational cohort study. J Invest Dermatol. 2019;139:115-23.
4. Li K, Huang CC, Randazzo B, et al. HLA-C*06:02 allele and response to Il-12/23 inhibition: Results from the ustekinumabphase 3 psoriasis program. J Invest Dermatol. 2016;136:2364-71.
5. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006; 296:1735-41.
6. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-31.
   
7. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019; 380:752-62. 
8. Iversen L, Eidsmo L, Austad J, et al.Secukinumab treatment in new-onset psoriasis: aiming to understand the potential for disease modification – rationale and design of the randomized, multicentre STEPin study. J Eur Acad Dermatol Venereol. 2018;32:1930-9.
9. Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: The eleven-year results of the Finnish rheumatoid arthritis combination therapy trial. ArthritisRheum. 2009;60:1222-31.
10. D'Haens G, Baert F, van Assche G, et al.Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;23:660-7.
11. Prey S, Paul C, Bronsard V, et al. Cardiovascular risk factors in patients with plaque psoriasis: a systematic review of epidemiological studies. J Eur Acad Dermatol Venereol. 2010;24:(suppl 2):23–30.
12. Gisondi P, Tessari G, Conti A, et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital based case-control study. Br J Dermatol. 2007;157:68-73.
13. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G. Weight loss improves the response of obese patients with moderate-to-severe chronic plaque psoriasis to low-dose cyclosporine therapy: a randomized, controlled, investigator-blinded clinical trial. Am J Clin Nutr. 2008;88(5):1242-7.
14. Del Giglio M, Gisondi P, Tessari G, Girolomoni G. Weight reduction alone may not be sufficient to maintain disease remission in obese patients with psoriasis: a randomized, investigator-blinded study. Dermatology. 2012;224:31-7.
15. Tan E, Baker C, Foley P. Weight gain and tumour necrosis factor-alpha inhibitors in patients with psoriasis. Australas J Dermatol. 2013;54:259-63.
16. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation guideline for treatment of psoriatic arthritis. Arthritis Care Res. 2019; 71:2-29.
17. Reich K, Warren RB, Iversen L, et al. Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomised phase III clinical trials (reSURFACE1 and reSURFACE2) through 148 weeks. Br J Dermatol. 2019 Jun 19. [Epub ahead of print]
18. Bellinato F, Girolomoni G, Gisondi P. Relapse of psoriasis in patients who asked to discontinue etanercept after achieving a stable clinical remission. Letter to Editor. Br J Dermatol. 2019 Jun 18. [Epub ahead of print]
19. Stinco G, Balato N, Buligan C, et al. A multicenter retrospective case-control study on suspension of TNF-inhibitors and outcomes in psoriatic patients (STOP study). G Ital Dermatol Venereol. 2019 Aug;154(4):392-399. [Epub 2018 Sep 24]
20. Smith CH, Jabbar-Lopez ZK, Yiu ZZ, et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis. Br J Dermatol. 2017;177:628–36.
    
    

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