MEETING HIGHLIGHT

IL-17 Summit 2018: Advances in the management of psoriasis

28 Feb 2019
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Prof. Deng Lie Hua

Vice chairman of China Medicine Education Association,

Professor and Physician,
Department of Dermatology,
The First Affiliated Hospital of Jinan University,
China

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Prof. Sun Le Dong

Vice-director and Secretary-general,
Dermatology Committee,
China Medicine Education Association;  


Professor and Physician,
Zhujiang Hospital of Southern Medical University,
China

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Prof. Huang, Zheng-Ming

Chairman of China Medicine Education Association,
Professor in Medicine,
302 Military Hospital of China,
China

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Prof. Guo, Qian

Professor and Physician,
Department of Dermatology,
Sun Yat-Sen Memorial Hospital,
Sun Yat-Sen University,
China

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Dr. Ho, Ka-Keung

Specialist in Dermatology,
Hong Kong SAR

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Dr. Huang, Yu-Huei

Assistant Professor and Physician,
Department of Dermatology,
Taipei Chang Gung Memorial Hospital,
Taiwan

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Prof. Lai, Ching-Lung

Chair of Medicine and Hepatology,
The University of Hong Kong,
Hong Kong SAR

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Dr. Lai,Sik-To

Senior Consultant in Gastroenterology and Hepatology,
Union Hospital, Shatin,
Hong Kong SAR;
Clinical Associate Professor (Honorary) in Medicine,
The Chinese University of Hong Kong,
Hong Kong SAR

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Dr. Leong, Nga-Cheng

Physician, Department of Dermatology,
Kiang Wu Hospital,
Macau SAR

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Prof. Zeng, Fan-Qin

Department of Dermatology,
Sun Yat-Sen Memorial Hospital,
Sun Yat-Sen University,

China

Experts of dermatology and related specialties from the Greater Bay Area gathered for the IL-17 summit. With the honor to have Professor Huang Zheng-Ming to give the opening speech, experts shared their insight and latest scientific findings on psoriasis – a complex disease of the skin. The two-day event created an excellent platform for knowledge exchange, raising the quality of healthcare for autoimmune skin disorders and ultimately benefit the patients.

An overview of psoriasis in the mainland China

Psoriasis is a chronic disease with high recurrence rate and difficult management that does not only affect the patient’s appearance and joints, but also correlates to other systemic diseases such as cardiovascular disease or metabolic syndromes.1 Even though ethnic Chinese is not the most susceptible ethnic group in acquiring psoriasis, a multi-city study found a prevalence of 0.47% in China, which indicated that the disease is causing a burden on the healthcare system that cannot be ignored.2

With evidence suggesting that the length of psoriasis is positively correlated with the disease severity and incidence of comorbidities,3,4 Prof. Zeng Fan-Qin urged that the disease should be treated promptly to control the symptoms and reduce complications. In China, there are multiple treatment strategies for psoriasis, but the principle follows the Chinese dermatology experts’ consensus written in 2014, suggesting that a standardized, safe, and personalized treatment should be selected for the patient’s benefit.5

Given serious adverse events do exist in standard systemic treatment, with an inadequate response failing to meet the patients’ expectations, the development of a novel therapy to meet the unmet medical needs became the top priority when treating psoriasis patients.6-8 The advent of biologics offered a potential solution for these issues. With studies discovering the importance of inflammatory pathways in causing psoriasis related comorbidities,9,10 biologics designed to target these pathways may bring great benefit to psoriasis patients.11 With evidence showing patients on biologics have better tolerance for non-life threatening adverse effects than patients on systemic drugs,12 biologics showed a promising potential to become the long-term treatment option for patients with moderate-to-severe psoriasis.

New progress on IL-17 inhibitors for treating psoriasis

Dr. Huang Yu-Huei presented the clinical data of secukinumab, an interleukin (IL)-17A inhibitor.13 Secukinumab has been tested in various phase 3, randomized controlled, clinical trials (ERASURE, FIXTURE, CLEAR, and SCULPTURE).14-16 ERASURE and FIXTURE are the two earliest trials that tested the efficacy and safety of secukinumab as induction (12 weeks) and maintenance (52 weeks) therapy for moderate-to-severe psoriasis.14 Both trials involved treatment arms with secukinumab 150mg, secukinumab 300mg, or placebo, with an addition of etanercept 50mg in the FIXTURE trial, all administered subcutaneously.14

In the CLEAR study, secukinumab was compared with ustekinumab.15 Patients in this study were randomly assigned to receive secukinumab 300mg or ustekinumab (dosage per label).15 The results at week 52 showed secukinumab as the superior treatment with significantly more patients responded with PASI 100, 90 and 75 (Figure 1).15

 

 

The research team of the SCULPTURE study followed an extended 5 years on patients who received secukinumab from their main trial.17 When compared to baseline, the PASI 75, 90, and 100 response rates were sustained throughout year 1 to year 5.17 More importantly, patient-reported outcomes measured with dermatology life quality index (DLQI) and Health Assessment Questionnaire Disability Index (HAQ-DI) were also improved with sustainability for 5 years in secukinumab-treated patients.17

The benefit of secukinumab is not only limited to the suppression of psoriasis, but also in cardiovascular disease risk reduction by improving the endothelial function, a marker of early atherosclerosis.18 Patients who completed a 52-week treatment course with secukinumab reported significant improvement from the baseline on flow-mediated dilation, a measurement of endothelial function, thereby reducing cardiovascular disease progression in psoriatic subjects.18

Guidance on the management of tuberculosis complicating the use of immunomodulators

Biologics have gradually became a common choice for treating psoriasis. However, the use of biologics is not entirely risk-free, with a systematic review suggesting that patients who received biologics had a 2.7-12.5 fold increased risk of tuberculosis (TB), as compared to those who received conventional disease-modifying antirheumatic drug.19

Most people with latent TB infection (LTBI) will remain asymptomatic for their entire life, but in the cases where the immune system is compromised, the bacteria could be reactivated, which forms the logic behind the higher risk of TB in those patients receiving biologics.20 Considering this, the screening and prevention of LTBI represent a current worldwide challenge for the use of biologics.

Dr. Lai Sik-To demonstrated the current practice for TB in Hong Kong, which stated LTBI screening procedure is mandatory prior to receiving biologics.21 Screening tests may include chest X-ray, tuberculin skin test (TST), or interferon gamma release array (IGRA).22 Of note, IGRA is not affected by Bacillus Calmette–Guérin (BCG) vaccination, making it the preferred screening test for BCG-vaccinated patients.22 Also, those with a higher chance of TB exposure should be screened annually even in cases where the initial TB test results were negative.21

If the screening test result is positive, chest X-ray will be carried out to determine the TB disease status.21 If the infection remained in its dormant form, prophylaxis with anti-TB medications (isoniazid for 9 months, isoniazid plus rifampicin for 3 months, or rifampicin for 4 months) would be given 1 month prior to receiving biologics.21 However, if the TB is active at any time before or during the therapy, the infection has to be managed with appropriate anti-TB treatment, and biologics should only be restarted after 6 months, which usually corresponds to anti-TB treatment completion.21 However, in cases of severe flare with high disease activity, low-risk biologics can be used 2 months after the initiation of TB treatment.21

The choice of biologics can be determined by calculating the estimated relative risk of developing active TB based on existing risk factors, with a relative risk above 10 arbitrarily categorized as high risk.23 The choices of biologics corresponding to the different risk groups are shown in Table 1.21

 

 

Practical guidelines for the treatment of patients with chronic hepatitis B on immunosuppression

There were reports of patients with occult hepatitis B (OHB) experiencing HBV reactivation after treatment with potent immunosuppressants such as rituximab.24 Secukinumab in 10 phase 2 and phase 3 trials has not been found to cause hepatitis B (HBV) reactivation, but patients with HBV were excluded from the trials, meaning the results should be interpreted with caution.25

Prof. Lai Ching-Lung shared a case of a 72 year old female patient diagnosed with large B-cell lymphoma stage 4. The patient had normal liver function test results, hepatitis B antigen (HBsAg) negative, hepatitis B antibody (anti-HBs) less than 10mIU/mL, and anti-hepatitis C virus antibody negative. The patient received chemotherapy R-CEOP with rituximab for 6 cycles and the lymphoma disappeared entirely. However, 11 months after the treatment, she was admitted to hospital with hepatitis symptoms and eventually died after 16 days, due to rituximab-induced fulminant reactivation of OHB. The mechanism of reactivation appeared to be the profound depletion of B cells, followed by its slow rise, which primes the hepatitis B core antigen (HBcAg)-specific cytotoxic T cells.26,27

Prof. Lai then shared a prospective study, which followed 63 OHB patients receiving rituximab-containing chemotherapy for the presence of HBV reactivation during September 2011 and September 2013.28 The cumulative rate of reactivation at 2 years is 41.5%, with an undetectable anti-HBs level at rituximab treatment initiation being a significant risk factor for HBV reactivation, although reactivation in patients with anti-HBs positive was still possible.28 Most importantly, the deployment of antivirals as soon as HBV DNA became detectable was able to control the reactivation effectively, avoiding HBV-related liver complications and mortality.28

Prof. Lai suggested that patients receiving anti-CD20 or anti-CD52 should be checked for HBsAg, anti-HBs, and hepatitis B core antibody (anti-HBc). HBV DNA and liver function tests should be conducted if any of the HBV markers were positive. Prophylactic antivirals should be given to all HBsAg-positive patients regardless of their HBV DNA levels, as recommended in the major guidelines.29 Regarding treatment, entecavir, tenofovir (both alafenamide [TAF] and tenofovir disoproxil fumarate [TDF]), and lamivudine are the recommended options, but drug resistance to lamivudine will increase longitudinally over time, making it the less preferred choice.29

IL-17A inhibitors for treating moderate-to-severe psoriasis, a case series study

Dr. Leong Nga-Cheng shared a case series study of 11 patients. These patients had a PASI score ranging from 17.7 to 40.8. Mean age was 38.72 ± 10.95-year-old, ranging from 19-year-old to 55-year-old. The duration of psoriasis ranged from 4 to 40 years (mean: 12.27 ± 10.32 years). Among the 11 cases, two were psoriatic arthritis cases.

Nine patients received treatment for psoriasis before receiving secukinumab (acitretin: 4 patients; methotrexate: 3 patients; adalimumab: 1 patient; narrowband ultraviolet B: 1 patient). All patients were tested for biochemical, urinalysis, liver function, kidney function, electrolytes, and anti-nuclear antibody. Patients were screened for HBV, HIV, and TB. Finally, a thorough medical history was also taken.

The patients received secukinumab 300mg per injection, given at week 0, 1, 2, 3, 4, and every month after, as per indication.13 Injection sites that were tender, bruised, erythematous, indurated, or affected by psoriasis were avoided.13

PASI response was examined at week 4 and week 12 after the first injection. At week 4, only 18.2% of the patients responded with a 75% reduction in their PASI score. However, at week 12, almost all patients (90.9%) had a PASI 75 response. Of the 11 patients, 63.7% even reached PASI 90 response after treated for 12 weeks, showing noticeable improvement after the therapy.

The patients were monitored for any adverse events due to the therapy. During the study period, only 1 case of abdominal pain and diarrhea, and 1 case of sore throat were observed, with no serious adverse events reported.

The case series study showed that secukinumab has high efficacy for moderate-to-severe psoriasis with mild adverse effect. However, due to the small number of cases and short follow-up time, an extended observation period is needed before making a solid conclusion.

Treatment for severe psoriasis

Treatment failure can be classified into primary and secondary, where the former means failing to achieve an initial response, and the latter meaning a lost in efficacy during therapy.30 From there, Dr. Ho Ka-Keung shared a case in the Hong Kong private sector which demonstrated the strategy to hurdle treatment failure in patients with severe psoriasis.

The case was a 40-year-old male patient weighing 60kg, with no drinking and smoking habit. He was diagnosed with plaque psoriasis for 15 years. At 2012, the psoriasis affected more than 80% of his body surface area (BSA), including the scalp, back, legs, and nails, but with no sign of arthritis. The PASI score was 42 at the time.

Prior treatment with methotrexate and narrowband ultraviolet B were given, but the effect was less than ideal, causing the need for therapy switching. Tests were performed before putting him on a new therapy, including biochemical test, liver function, HBV, hepatitis C, HIV, and TB – the results were all normal.

The patient was then given infliximab at a dosage of 5mg/kg every 2-3 months and was effective at first. However, the effect began to fade off after 3 years with infliximab, even with increased dosage and frequency. So, the patient was switched to adalimumab, but the response was only PASI 50 even with the addition of methotrexate.

Treatment failure due to immunogenicity is frequent in the use of anti-tumor necrosis factor (TNF)-alpha, notably with infliximab and adalimumab.31 Studies have shown both drugs can be cleared from the body with the formation of antibodies to the drug, which is associated with inadequate treatment response.32,33

In 2016, the patient was switched to secukinumab 300mg. The PASI score was 48 at baseline and quickly improved to 13 with only 4 weeks of treatment. The rapid and efficacious effect was also demonstrated in a clinical trial when secukinumab showed superiority over ustekinumab.15

The case demonstrated the problem of treatment failure in treating patients with severe psoriasis, and how secukinumab was able to solve this issue. Dr. Ho added at the end, saying secukinumab was able to maintain an improvement after discontinuation of the treatment, with some patients still relapse-free.34 There also appeared to be a positive correlation with the probability of relapse and disease duration, suggesting the importance of early treatment.34

Precautions with the use of biologics for treating psoriasis

Prof. Guo Qian shared the World Congress of Gastroenterology’s recommendation (in 2009) for managing treatment failure to anti-tumor necrosis factor (TNF).35 Strategies include shortening the dosing interval, and increasing the dosage to 10mg/kg (i.e. the measurement for diminished or suboptimal response to infliximab).35 Switching to a different anti-TNF agent can be considered if diminished or loss of response continues after dosage and frequency were increased.35 However, the statement also pointed out that patients losing response to the first anti-TNF agent will also have less probability of responding to a second anti-TNF agent.35

With regards to the use of anti-TNF such as infliximab during pregnancy, reports have shown that the use of infliximab until gestational week 30 leads to fetal intra-uterine exposure to infliximab at levels that exceed those in the mother’s peripheral blood. There was a case where the infant of a mother who was taking infliximab for Crohn’s disease died at an age of 4.5 months.36 The infant received BCG vaccine at 3 months old and developed an unusual complication known as disseminated BCG.36 The case demonstrated a significant risk of having an infection from live vaccine, due to the immune system being suppressed by the anti-TNF passing from the mother. Therefore, infliximab should be stopped at 16 weeks after pregnancy, as per guidelines released by the British Society for Rheumatology and British Health Professionals in Rheumatology in 2016.37

A study on 500 patients with Crohn’s disease who were followed for a median of 17 months demonstrated the safety profile of infliximab.38 However, infliximab is associated with adverse events including serious infections, infusion reaction, serum sickness-like disease, drug-induced lupus, cancer, non-Hodgkin’s lymphoma, demyelination, and worsening of heart failure.38 Even though the drug is generally well tolerated, clinicians must remain vigilant for the occurrence of infrequent but severe adverse events.38

Conclusion

In the IL-17 summit, experts have shared their insights on the management of psoriasis. Together with the latest clinical data on secukinumab available, active exchange of expert knowledge as well as consensus guideline recommendation have raised the standard of care for treating patients with psoriasis.

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