Chinese Experts Consensus on Biologic Therapy for Psoriasis#

Chinese Society of Dermatology, China Dermatologist Association, Dermatology and Venereology Specialized Committee of Chinese Association of Integrative Medicine, Ai-Jun Chen, Xing-Hua Gao,Heng Gu, Jun Gu, Fei Hao, Xian Jiang, Hong-Zhong Jin, Xiao-Jing Kang, Cheng-Xin Li,Yu-Zhen Li0, Xiao-Ming Liu, Yu-Ling Shi, Qing Sun, Gang Wang,*, Bin Yang,Jun-Ling Zhang, Xi-Bao Zhang, Xue-Jun Zhang,*, Yi Zhao, Min Zheng0

1Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;2Department of Dermatology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; 3Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China; 4Department of Dermatology, Changhai Hospital, The Second Military Medical University, Shanghai 200002, China; 5Department of Dermatology,The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China; 6Department of Dermatology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; 7Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; 8Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, China; 9Department of Dermatology, The First Medical Center, PLA General Hospital, Beijing 100853, China; 10Department of Dermatology, The Second Hospital of Harbin Medical University Harbin, Heilongjiang 150086, China; 11Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China; 12Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; 13Department of Dermatology, Qilu Hospital, Shandong University, Jinan,Shandong 250012, China; 14Department of Dermatology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China; 15Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong 510091, China; 16Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China; 17Institute of Dermatology, Guangzhou Medical University, Guangzhou, Guangdong 510095, China; 18Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China; 19Department of Dermatology and Venereology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; 20Department of Dermatology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, China.

Abstract Biologic drugs have been increasingly used in the treatment of psoriasis and are especially favorable for severe,recalcitrant, and special-type cases.Therefore, appropriate, effective, and safe use of biologic drugs has drawn attention from dermatologists.For this purpose, Chinese experts majoring in psoriasis analyzed domestic and international research data, summarized current clinical experiences, investigated features of Chinese patients with psoriasis,and finally formulated the present consensus,which provides detailed guidances to clinicians in terms of the principles and methods of the application of biologics,the efficacy and safety profile,patient screening and monitoring,main adverse events and corresponding solutions, and precautions for special patient populations.

Keywords: psoriasis, treatment, biologics, consensus

Introduction

Biologic therapy has become one of the main treatments for psoriasis and has played an active and effective role in treating severe,refractory,and special types of psoriasis.1-4 With the gradual increase in the number of biologic drugs approved for the treatment of psoriasis in China, and especially in light of the high prevalence of tuberculosis and hepatitis B (HBV) in the Chinese population,reasonable, safe, and effective use of biologic drugs has become a concern among clinicians.2Therefore, the Chinese Society of Dermatology,the China Dermatologist Association, and the Dermatology & Venereology Specialized Committee of the Chinese Association of Integrative Medicine have jointly organized experts in the field of psoriasis to formulate the Chinese experts' consensus on biologic therapy in psoriasis (hereinafter referred to as“this consensus”) on the basis of extensive discussion.The opinions in this consensus have been fully discussed by all experts involved.Agreement on the specific suggestions thereafter was reached by a vote among all experts, and all experts unanimously endorsed the voting results of this consensus.

This consensusis mainlybased on(1)data from registered clinical studies of various biologic drugs conducted in Chinese mainland, (2) data from registered international premarketing clinical studies of various biologic drugs,(3)guidelines or expert consensuses of biologic therapy published in recent years, (4) real-world research data of biologic therapy for psoriasis from China and other countries,and(5)the experts'personal clinical experience.

Biologic drugs included in this consensus

This consensus includes the following biologic drugs that have been approved for the treatment of psoriasis in China:(1)the tumor necrosis factorα(TNFα)inhibitors:etanercept, infliximab, and adalimumab; (2) the interleukin 12/23 inhibitor ustekinumab; and (3) the interleukin 17A inhibitor secukinumab.2This consensus does not include biologic drugs or biosimilars under development,biologic drugs that have been marketed in other countries but not in Chinese mainland or have not yet been approved for the treatment of psoriasis in Chinese mainland, and biologic drugs that lack research data and experience with their practical application in Chinese mainland.

This section briefly introduces the clinical application of various biologic preparations and the main issues to address.A detailed introduction is limited by the length of this consensus; therefore, product instructions and package inserts should be read carefully before using each biologic drug to fully understand its indications, usage,adverse reactions, and contraindications.

Etanercept Indications

A biosimilar of etanercept has been approved for the treatment of moderate and severe plaque psoriasis in adults in China.2Both the US Food and Drug Administration(FDA)and the European Medicines Agency(EMA)have approved the use of etanercept in the treatment of moderate and severe plaque psoriasis and arthropathic psoriasis.1,4Previously reported off-label indications include pustular psoriasis and erythrodermic psoriasis.5

Usage

Subcutaneous inje ction of 25mg twice a week or 50mg once a week is recommended.The dose for children(4-17 years old) is 0.8mg/kg per week.

Efficacy overview

Several randomized controlled trials in China have shown a 75% improvement in the Psoriasis Area and Severity Index(PASI 75)(i.e.,the percentage of patients who have achieved a ≥75% improvement in their PASI score from baseline) of 41%-76% after treating plaque psoriasis for 12 weeks using an etanercept biosimilar.2,6Studies in other countries have shown that 50mg of etanercept once a week and twice a week have similar effects in improving arthritis, but a higher dose is more effective in improving skin lesions.The efficacy of continuous use of etanercept is better than that of intermittent therapy.1,4

Adverse reactions

Reactions such as redness, swelling, and pruritus at the injection site are the most common adverse reactions of etanercept, most of which are mild to moderate and require no special treatment.Drug withdrawal and treatment for the symptoms may be needed in very rare cases.Uncommon adverse effects include headache,vertigo, rash, insomnia, and upper respiratory tract infection, most of which need no treatment.Compared with other TNFαinhibitors,etanercept has a lower risk of reactivating tuberculosis and HBV.

Infliximab Indications

The indications for infliximab approved in China include moderate and severe plaque and arthropathic psoriasis in adult patients who need systemic treatment and in whom cyclosporin A(CSA),methotrexate(MTX),or phototherapy and photochemotherapy (Psoralen Ultraviolet A,PUVA) are ineffective, contradicted, or unable to be tolerated.2The indications approved in the US and most European countries are also moderate and severe plaque and arthropathic psoriasis.Previously reported off-label indications include pustular psoriasis and erythrodermic psoriasis.1,4

Usage

The first dose is 5mg/kg;the same dose is given at 2 and 6 weeks after the first administration and every 8 weeks thereafter via intravenous infusion.The duration of each intravenous infusion should be longer than 2hours, and the patient should be observed for 1-2hours afterward.If no satisfactory effect is achieved after 14 weeks(after four administrations and before the fifth administration), the treatment should be discontinued.

Efficacy overview

A multicenter,double-blind,placebo-controlled phase III clinical study in China showed that 57.1% of patients with moderate and severe plaque psoriasis reached PASI 90 and 81.0% reached PASI 75 after 10 weeks of treatment.7The clinical efficacy of studies in the United States and Europe are basically consistent with the research data in China.8-9

Adverse reactions

An infusion reaction is one of the most common adverse reactions.Once an infusion reaction occurs, its severity should be determined in a timely fashion and measures should be taken,such as reducing the speed of infusion and administration of antihistamine drugs.In serious cases,the infusion of infliximab should be stopped immediately and countermeasures such as administration of glucocorticoids should be applied.In patients with a history of infusion reactions,intramuscular injection of 25mg of promethazine can be given before infliximab infusion.Upper respiratory tract infection is another common adverse reaction.Rare severe adverse reactions include HBV reactivation,congestive heart failure, severe infections (including septicemia,opportunistic infection, and tuberculosis),serum sicknesslike reactions, systemic lupus erythematosus/lupus-like syndrome,and demyelinating diseases.7-9

Adalimumab Indications

The indications for adalimumab approved in China are moderate and severe plaque psoriasis in adult patients who need systemic treatment, and the indications approved in other countries include arthropathic psoriasis.Previously reported off-label indications include pustular psoriasis and erythrodermic psoriasis.

Usage

A subcutaneous injection of 80mg is given at the first administration followed by 40mg in the second week and then 40mg every 2 weeks.Further administration should be carefully considered if no satisfactory effect is achieved after 16 weeks of treatment.Patients with an insufficient effect after 16 weeks may benefit from an increased frequency of 40mg every week.

Efficacy overview

A randomized,double-blind,placebo-controlled phase III clinical study of moderate and severe plaque psoriasis in China showed that 77.8%of patients achieved efficacy of PASI 75 after 12 weeks.10A 52-week phase III clinical study in another country showed that 71% of patients reached PASI 75 after 16 weeks of treatment.Subsequent open studies have shown that in patients who initially reached PASI 75, the treatment efficacy was stable for 3 years.The effect of adalimumab in the treatment of arthropathic psoriasis is remarkable.A randomized double-blind phase III clinical study of moderate and severe plaque psoriasis in children (≥4 to ＜18 years old)conducted outside of China showed that more than 75%of children achieved PASI 75 after 16 weeks of treatment.Another clinical trial showed that 58%of children reached PASI 75 after 16 weeks of treatment.11

Adverse reactions

The most commonly reported adverse reactions are infection (e.g., nasopharyngitis, upper respiratory tract infection,and sinusitis),injection site reactions(erythema,pruritus, bleeding, pain, or swelling), headache, and musculoskeletal pain.Other adverse reactions include systemic infection, skin tumors, allergic reactions, blood cell abnormalities, hypertension, and metabolic abnormalities.Rare serious adverse reactions include fatal infection, heart failure, malignant tumors, and HBV recurrence.10-14

Ustekinumab Indications

The indications for ustekinumab approved in China are moderate and severe plaque psoriasis in adult patients who cannot tolerate, are unresponsive to, or have contraindications for other systemic treatments such as CSA,MTX, or PUVA.2Indications approved in European countries and the United States include moderate and severe plaque psoriasis and arthropathic psoriasis.1,4,15

Usage

The first administration is 45mg given by subcutaneous injection followed by the same dose 4 weeks later and then every 12 weeks.For patients who weigh more than 100kg,90mg is recommended for each administration.If the patient shows no improvement by week 28(after the third administration and before the fourth administration),drug withdrawal should be considered.

Efficacy overview

A multicenter, double-blind, placebo-controlled phase III clinical study of moderate and severe plaque psoriasis in China showed that 82.5% of participants achieved PASI 75 and 66.9% reached PASI 90 by the 12th week of treatment.16By the 28th week of treatment, 91.5% of participants had achieved PASI 75.17Clinical studies in the United States and Europe showed that 67.1% of participants reached PASI 75 and 41.6% reached PASI 90 by 12 weeks of treatment;15,17-1971.2% of the participants reached PASI 75 and 49.2%reached PASI 90 by 28 weeks of treatment; and 63.4% and 57.6% of participants maintained PASI 75 and PASI 90,respectively, after 5 years of treatment.A clinical study of patients with moderate and severe plaque psoriasis aged 12-17 years showed that 80.6%of participants reached PASI 75 and 61.1% reached PASI 90 by the 12th week of treatment.16

Adverse reactions

Common adverse reactions include upper respiratory tract infection,nasopharyngitis,dizziness,headache,oropharyngeal pain, diarrhea, nausea, vomiting, skin pruritus, back pain, myalgia, joint pain, fatigue, and injection site erythema.Uncommon adverse reactions include cellulitis,herpes zoster,and allergic reactions,and rare severe adverse reactions include severe hypersensitivity,eosinophilic pneumonia,exfoliative dermatitis,and erythrodermic psoriasis.

Secukinumab Indications

In China, secukinumab is approved for the treatment of adult patients with moderate and severe plaque psoriasis who meet the indications for systemic treatment or phototherapy.2Indications approved in the US and European countries also include arthropathic psoriasis.Application of secukinumab for treatment of pustular psoriasis has been reported in the literature;however,it should be used with caution and should be considered only when other drugs are ineffective or unable to be tolerated.1,20-22

Usage

Treatment is begun with a subcutaneous injection of 300 mg at weeks 0,1,2,3,and 4;the same dose is then given every 4 weeks.Published reports and clinical observations show that some patients can achieve satisfactory results with administration of 150mg per injection;thus,150mg can also be tried in patients weighing less than 50kg.

Efficacy overview

In total, 543 patients wit h moderate or severe plaque psoriasis were enrolled in a 52-week phase III clinical trial including mostly Chinese patients.The results showed PASI 75 and PASI 90 of 97.7%and 80.9%,respectively,at 12 weeks of treatment; the PASI 90 was 87.0% at 16 weeks.Several randomized, double-blind, controlled phase III clinical trials have been carried out in other countries.One study showed that after 16 weeks of treatment, PASI 75 was achieved in 93.1% of patients,PASI 90 was achieved in 79.1%, and 82.9% of patients achieved an Investigator's Global Assessment score of clearance or near clearance.20-22

Adverse reactions

Common adverse reactions include upper respiratory tract infection, nasopharyngitis, oral herpes, headache, diarrhea, and urticaria.Uncommon adverse reactions include Candida infections of the skin or oral mucosa,tinea pedis,neutropenia, and conjunctivitis.In clinical studies, aggravation of Crohn disease has been observed in both the secukinumab and placebo groups.20-22

Application principles of biologic therapies

Biologic drugs are mainly used in patients with severe,refractory, and special types of psoriasis.Specific treat-

ment suggestions are as follows: (1) For moderate and severe plaque psoriasis,biologic therapy can be considered when traditional treatment is ineffective,fails,or is unable to be tolerated or when the disease has a substantial impact on the patient's quality of life or causes substantial health risks.(2) For arthropathic psoriasis with definite joint symptoms, biologic therapy can be considered when the symptoms cannot be effectively alleviated using diseasemodifying antirheumatic drugs or when the spinal or sacroiliac joints are involved.(3)Biologic therapy has not yet been approved for the treatment of generalized pustular psoriasis and erythrodermic psoriasis, but its clinical application has been reported in China as well as in other countries.23-27If biologic drugs are needed, a comprehensive evaluation should be carried out according to the personal situation.

Before beginning treatment, the clinician should carefully weigh the advantages and disadvantages of treatment, strictly identify the treatment indications, and fully consider the possible adverse reactions and patient's economic factors.Clinicians should communicate clearly with patients and obtain their informed consent.For patients with off-label indications, possible benefits and risks should also be specified.Doctors and patients should agree on the approaches to drug administration,monitoring, and follow-up.

Treatment selection process

When select biologic drugs,clinicians should consider the disease severity and joint involvement; the treatment objectives; the influence of the disease on the patient;and the patient's age,weight,complications,fertility plans,and preference for and compliance with drug administration and frequency.Secukinumab, ustekinumab, or TNFαinhibitors can be considered for plaque psoriasis.23-27TNFαinhibitors are preferred for arthropathic psoriasis;however, ustekinumab or secukinumab can also be considered.1,2,25-26Among TNFαinhibitors, infliximab and adalimumab have the advantages of more rapid onset and greater efficacy.

With respect to safety, secukinumab and ustekinumab may be safer than TNFαinhibitors in patients with high risk or a history of tuberculosis, HBV, or heart failure.6-7,10,17For patients prone to allergies and patients at high risk of connective tissue disease, fully humanderived preparations are preferred, including human monoclonal antibodies such as ustekinumab, secukinumab, and adalimumab as well as non-monoclonal antibody preparations such as etanercept or its biosimilars.Secukinumab should be avoided in patients with a history or family history of systemic fungal infections and inflammatory bowel disease.21-22

Efficacy evaluation

Efficacy and safety should be continuously evaluated during biologic therapy.When evaluating the treatment efficacy, doctors should consider the degree of disease improvement, treatment objectives, physiological and psychological effects and patients' social functioning,benefits and risks of continuing treatment, and patients'wishes and compliance.Because the effect of biologics is better than that of traditional treatments, a satisfactory effect is considered to have been achieved when skin lesions completely disappear or PASI 90 and Investigator's Global Assessment score of 0/1 are achieved;the minimum effective standard should be PASI 50 or improvement in quality of life(e.g.,a ≥4-point improvement in the Dermatology Life Quality Index or relief of depression).22,26

Maintenance treatment and withdrawal time

Psoriasis is a recurrent disease.Most treatment plans involving biologic drugs have two stages (i.e., induction therapy and maintenance treatment),and long-term maintenance is considered superior to intermittent treatment in improving patients'quality of life.1,13,15,17According to the conditions in China and considering the demand, safety,and affordability of treatment, the following is suggested:(1)When a treatment effect is achieved and maintained for more than 6 months, the drug can be withdrawn or the treatment can be maintained at a lower dosage by either reducing the single dose by 20%-50% or increasing the interval between administrations.(2)For severe,refractory,and recurrent cases,especially those involving joint damage and serious impairment of the patient's quality of life,longterm treatment should be maintained.2,28

After the withdrawal of biologic drugs,attention should be paid to changes in the disease condition.When the disease recurs, topical drugs, ultraviolet phototherapy, or traditional systemic drugs can be given as appropriate,and treatment with biologic preparations can be restarted if required.Restarting biologic therapy can refer to the following:(1)For patients with severe disease conditions,induction treatment with the same loading dose as the previous treatment is usually required (except for etanercept).(2) Reinduction of infliximab may lead to a higher incidence of allergies; therefore, reinduction treatment is not recommended.Infliximab can be given again according to the maintenance treatment plan.(3)Patients with mild recurrence may also receive maintenance treatment if they wish to continue using biologics.When serious drug-related adverse reactions occur,such as serious infections (e.g., active tuberculosis), heart failure, tumor, demyelinating diseases, and lupus-like syndrome, the drug should be stopped immediately and the patient should be treated accordingly.29

Screening before biologic therapy and monitoring during the course of treatment

The patient's health status must be fully evaluated before biologic treatment, focusing on the presence of systemic diseases such as infections,malignancies,and autoimmune diseases.It is also important to ask about existing cardiac dysfunction when planning to use TNFαinhibitors and any history of inflammatory bowel disease when planning to use interleukin 17A inhibitors.Dynamic follow-up observations are required during treatment to ensure patient safety.2,23-27,29In the case of abnormal examination results,comprehensive analysis should be performed and, if necessary, specialists from the relevant disciplines should be consulted for an overall assessment to determine the use(or continued use)of biologic drugs or which measures need to be taken.The auxiliary examination items that need to be performed before and during treatment with different biologics are shown in Table 1.

Combination of biologic drugs and other treatments

Biologics have obvious effects for most patients with psoriasis, but a few patients cannot obtain satisfactorytherapeutic effects with a single biologic preparation or at a certain disease stage; these patients need to undergo a combination of other treatment methods: (1) Topical drugs:A combination of topical drugs at the beginning of treatment can improve the disease more rapidly; topical drugs can be combined for refractory or recurrent skin lesions during the course of treatment.Several clinical studies have shown that biologic preparations combined with topical glucocorticoids or vitamin D3 derivatives can improve efficacy.(2) Ultraviolet phototherapy: The combined application of etanercept, adalimumab, infliximab, and ustekinumab together with narrowband ultraviolet B can further improve the curative effect.However, because this combination is not necessary for most patients and may increase the risk of malignant skin tumors,it is not recommended as a routine treatment.(3)

Table 1 Recommended examinations before and during biologic treatment2,23-27,29

Traditional systemic drugs: Combinations that include MTX can improve the effects of biologics such as etanercept and reduce the production of antidrug antibodies(ADA)to biologic preparations such as infliximab.For patients with unsatisfactory effects using biologic preparations alone or with unstable long-term effects,acitretin can be used in combination.The combination of biologics and other immunosuppressive agents such as CSA is not recommended.(4) Combined application of different biologic drugs: Although some case reports and case series analyses have involved combinations of different biologic drugs to treat refractory psoriasis, the safety and effectiveness of these combinations remain unknown.In theory,a combination of different biologics is more likely to lead to a risk of serious infection or a malignant tumor; therefore, such combinations are not recommended as a routine choice.2,26,30-32

Attenuation of the effect of biologic therapy and its countermeasures

The essence of effect attenuation during the course of biologic treatment (or biologics fatigue) is secondary treatment failure.31Treatment failure of biologic preparations can be divided into primary treatment failure and secondary treatment failure.In primary treatment failure,the course of treatment does not meet the clinical response standard after the initial application of a biologic preparation according to the recommended dose.In secondary treatment failure, the biologic preparation shows a good effect in the early stage of treatment, but the effect declines with the course of treatment.

There are different degrees of effect attenuation in clinical treatment with biologic drugs.The related causes and mechanisms include the production of ADA,administration of an insufficient drug dose, and reduced sensitivity of the patient's condition to the biologics.31-33In dealing with effect attenuation of biologic drugs, the following countermeasures can be taken: (1) Combining the treatment with immunosuppressants to reduce the production of ADA, and MTX is the first-choice for this purpose; (2) Increasing the dose of biologic drugs or

shortening the administration interval; (3) Switching to other biologic preparations, including those targeting the same or different molecules; and (4) Switching to traditional treatment methods.6,26,30,32

Effect attenuation of one biologic preparation does not rule out a satisfactory effect using other inhibitors targeting the same molecule.For primary treatment failure, however, biologic drugs that target different molecules should be applied instead.

No consensus has yet been reached regarding the interval between the termination of one biologic preparation and the application of another biologic preparation(washout period).This should be assessed on a case-bycase basis depending on the severity of disease,the type and therapeutic response to the previous preparation, and any complications.Theplannedtimeforthenextadministration of the original biologic preparation is generally taken as the time to start a new one.It is preferable to use a new biologic drug after three to four half-lives of the original preparation,if possible.When a biologic preparation is stopped and changed to traditional treatment, a washout period is not required.The half-lives of commonly used biologic drugs are 3.5 days for etanercept,10 days for infliximab,14 days for adalimumab,21 days for ustekinumab,and 27 days for secukinumab.

Application of biologic drugs in special populations

Pregnancy and lactation

Biologic drugs can be considered as third-line treatment of plaque psoriasis during pregnancy.Obtaining fully informed consent from the patient is very important to maintain maternal health in serious or unstable cases.The US FDA currently lists biologic preparations as pregnancy category B.Few reports to date have described reproductive toxicity or teratogenicity in the offspring of experimental animals and human patients who have received biologic treatments.

The use of TNFαinhibitors during pregnancy and in those who are planning to conceive is generally considered safe.34Few studies have been performed to assess the application of ustekinumab during pregnancy, and its safety is thus uncertain;no increase in the rate of abortion or congenital malformation was noted in a small case series.Insufficient data are available regarding the use of secukinumab during pregnancy.Animal studies have shown no direct or indirect harmful effects of secukinumab on pregnancy, embryonic or fetal development, delivery,or postpartum development.1,2,4,26For women who plan to conceive,the recommended withdrawal time of biologic drugs before pregnancy is 3 weeks for etanercept,20 weeks for adalimumab, 24 weeks for infliximab, 20 weeks for secukinumab, and 15 weeks for ustekinumab.

For generalized pustular psoriasis during pregnancy,TNFαinhibitors can be considered when CSA, systemic glucocorticoid therapy, or a combination of these is ineffective or contraindicated or when the life of the patient or fetus is at risk.5

Infliximab and ustekinumab have been shown to be secreted in animal milk, and the safety of these drugs in human fetuses and infants is unclear;therefore,breastfeeding should be avoided during treatment.26,29Whether secukinumab is secreted in milk is unknown.Thus, given the unclear risk of potential adverse reactions in breastfeeding infants, doctors should weigh the pros and cons of treatment with secukinumab and decide whether to stop breastfeeding or stop treatment during and within 20 weeks of treatment.

Children

Because of the short period of use of biologic drugs in China,little clinical data are available on the application of these agents for psoriasis in children.At present, the use of biologic drugs in children with psoriasis in China is mainly based on the recommendations of the US FDA or EMA.1,26-27,35-37(1) Etanercept: In 2009, the EMA approved etanercept for the treatment of severe plaque psoriasis in children aged＞6 years who had unsatisfactory effects with a traditional treatment system.In 2016,the US FDA approved etanercept for the treatment of moderate and severe psoriasis in children aged 4-17 years.The minimum age of patients with psoriasis treated with etanercept is reportedly 22 months.(2) Infliximab:The application of infliximab for the treatment of psoriasis in children has not been approved in China or in other countries.Case studies of 8- and 9-year-old children with generalized pustular psoriasis have been reported.(3) Adalimumab: The EMA approved adalimumab as a first-line treatment in children aged＞4 years with severe plaque psoriasis; the indications for children with psoriasis in China have not yet been determined.(4)Ustekinumab:In 2015,the EMA approved the application of ustekinumab for the treatment of severe plaque psoriasis in adolescents aged＞12 years with a poor response to other systemic therapies or phototherapy;the use of ustekinumab for psoriasis in children aged＜18 years has not been approved in China.(5) Secukinumab: The application of secukinumab for the treatment of psoriasis in children aged＜18 years has not been approved in China or in other countries.There are few reports on the use of secukinumab in children with psoriasis.

Patients with tuberculosis

China currently has the second highest burden of tuberculosis worldwide.Pulmonary tuberculosis, extrapulmonary tuberculosis, and blood-disseminated tuberculosis have been reported in many patients who use TNFαinhibitors.Although the risk of tuberculosis reactivation with non-TNFαinhibitors is low or nonexistent, all patients with psoriasis in whom use of biologic drugs is planned should be carefully screened and evaluated for tuberculosis.The two main items in screening are(1) the detailed tuberculosis-related history of the patient,including assessment of risk factors, contact history,tuberculosis history, treatment history, and previous bacillus Calmette-Guérin vaccination, and (2) necessary auxiliary examinations to exclude active tuberculosis,including chest radiographs, purified protein derivative,chest computed tomography, and T-SPOT.TB, if necessary (Table 1).29,38-39

Biologic drugs are prohibited in patients with active tuberculosis.For patients with latent tuberculosis and inactive tuberculosis, biologic drugs should be used with caution and, if necessary, prophylactic antituberculosis treatment should be given first.The prophylactic antituberculosis treatment plans developed in different countries are inconsistent.The following schemes are proposed in the latest World Health Organization tuberculosis treatment guidelines: (1) Isoniazid combined with rifampicin:Isoniazid at 5mg/(kg·d) in adults and 10mg/(kg·d) in children, with a maximum dose of ≤300mg/day;rifampicin at 10mg/(kg·d) in adults and 15mg/(kg·d) in children, with a maximum dose of ≤600mg/day;continuous treatment for 3-4 months.(2) Isoniazid treatment alone: Same dose as already described, with continuous treatment for 6-9 months.(3) Rifampicin treatment alone: Same dose as already described, with continuous treatment for 3-4 months.Because of the large number of patients with tuberculosis in China and the high proportion of drug-resistant tuberculosis, combined treatment is strongly recommended.Treatment with biologic drugs can be given after at least 4 weeks of prophylactic antituberculosis treatment.38-39

Because antituberculosis drugs have a certain incidence of adverse reactions (including nausea, vomiting, druginduced liver damage,and drug allergy),some of which are serious, patients should be examined for hematuria and liver and kidney function before the use of antituberculosis drugs.They should then be reexamined at weeks 2 and 4 after administration as well as every 4 weeks thereafter to ensure the safety of antituberculosis drugs.

Although preadministration screening and preventive antituberculosis treatment can reduce the risk of activation of latent tuberculosis, the possibility of tuberculosis still exists during treatment with biologic drugs.Therefore,patients must undergo close monitoring of the symptoms and signs of active tuberculosis infection as well as related auxiliary examination indicators.For patients with latent tuberculosis and inactive tuberculosis in whom biologic therapy is planned after preventive antituberculosis treatment, chest radiograph/computed tomography findings and purified protein derivative/T-SPOT.TB results should be reviewed at 3 and 6 months and every 6 months thereafter,up to 3 months after withdrawal.For patients in whom the use of TNFαinhibitors is planned and for patients with high risk,the frequency of follow-up should be increased and the patients should be encouraged to seek medical guidance if tuberculosis symptoms(e.g.,persistent cough, weight loss, and low-grade fever) occur during or after treatment with biologic drugs.

Figure 1.Tuberculosis screening procedure.CT, computed tomography; PPD, purified protein derivative.

The tuberculosis screening procedure when biologic drugs are being considered is shown in Figure 1.

Patients with HBV infection

The prevalence of HBV infection in China is high.Therefore, attention should be paid to the risk of latent HBV reactivation caused by treatment with biologic preparations as well as the risk of death caused by the resulting liver damage and even liver failure.No matter which biologic drug is used,serum HBV antigen/antibody should be routinely screened.If necessary, HBVDNA should also be detected to distinguish between noninfection, immunization after vaccination, immunization after infection, chronic inactive infection, and chronic active infection.The following situations are commonly encountered in HBV screening1,26,29,40: (1) All HBV antigens/antibodies are negative,generally suggesting that no infection is present and that biologic treatment can be used.(2) Only hepatitis B surface antibody (HBsAb) is positive, indicating that mostly protective immunity is present after vaccination and that biologic treatment can be used.(3) Only hepatitis B core antibody (HBcAb) is positive or both HBcAb and HBsAb are positive, usually indicating that immunity is present after infection and sometimes that low-level latent HBV infection is present;further tests should be conducted to detect HBVDNA.If tests are negative for HBVDNA,biologic treatment can be used.Positive results for HBVDNA indicate latent HBV infection, which should be treated according to chronic HBV infection; biologic treatment should be used with caution.Regardless of whether tests for HBVDNA are positive or negative, HBV antigen/antibody and HBVDNA should be reexamined every 3-6 months once biologic therapy is given to detect HBV reactivation in a timely manner.A change from HBsAb-positive results to hepatitis B surface antigen (HBsAg)-positive results after treatment suggests that latent HBV has been reactivated and that the patient should be treated for chronic HBV infection.(4) HBsAg positivity suggests the existence of chronic HBV infection, regardless of the results of other indexes.The analysis should combine the results of testing for HBeAg or HBeAb and HBVDNA.Simultaneous HBeAg positivity and/or HBVDNA of＞105copies/mL suggests chronic active HBV infection, while HBeAb positivity and/or HBVDNA of＜104copies/mL suggests chronic inactive infection.In such cases,the use of biologic drugs is not recommended for patients with abnormal liver function.Specialists in liver disease should be consulted regarding the use of biologic drugs in patients with normal liver function; this should be considered comprehensively based on the virus replication level, risks, and benefits.A combination of anti-HBV treatment should be considered,if necessary.Liver function,serum HBV antigen/antibody levels,and HBVDNA levels should be monitored every 1-3 months during the course of treatment to track the changes in HBV infection and liver function,thus allowing effective and timely treatment.

Patients with malignant tumors

There is no clear evidence that the use of biologic drugs alone can increase the risk of malignant tumors in patients with psoriasis.However, considering that biologic drugs have the potential to lead to tumor progression, they should be used carefully after weighing the risks and benefits.For patients with malignant tumors who have undergone radical surgery more than 5 years ago without recurrence or metastasis, biologic drugs can be used cautiously after a comprehensive assessment of the patient's condition.In patients who have been treated with biologic drugs together with long-term phototherapy or who have been treated with ultraviolet A or PUVA more than 200 times, the occurrence of skin cancer must be closely monitored.When biologic drugs are combined with other immunosuppressive agents,the occurrence and recurrence of tumors should be closely monitored and evaluated.Biologic drugs are not recommended in patients with lymphoid malignancies.29-30

Patients receiving vaccination

During the course of treatment with biologic preparations in patients with psoriasis, vaccination with inactivated or recombinant vaccines does not decrease safety but may affect immunity.Live virus vaccines theoretically have a risk of viral spread,which should be dealt with cautiously.The duration of withdrawal required before and after receiving live vaccines remains controversial.Some experts suggest that the use of biologic drugs should be stopped for at least two to three half-lives before and after receiving live vaccines; other experts suggest that biologic preparations should be stopped for ≥4 weeks before vaccination, depending on the half-life of the biologic preparation.Live virus vaccines can be received 2-3 weeks after the last administration of etanercept, 6 months after the last infliximab infusion, and 15 weeks after withdrawal of ustekinumab.Drugs should be withdrawn for 12 months before receiving live herpes zoster vaccine.1,24,26

Because biologic drugs may be transmitted to the fetus via the placenta,infants born to women who used biologic drugs after 16 weeks of pregnancy should be considered immunosuppressed for 6 months after birth, and live vaccines should be avoided.34

Patients with surgery

No large-scale and conclusive studies on the effects of biologic drugs during the perioperative period have been performed to date.Although studies have shown that the withdrawal or continued use of TNFαinhibitors before surgery has no effect on the occurrence of surgical complications, including infection, biologic drugs may theoretically affect wound healing and increase the risk of infection.Therefore,moderate-risk surgeries(e.g.,urinary,chest, abdomen, and head and neck surgeries) and highrisk surgeries (e.g., complex thorac operitoneal and genitourinary surgery and infection site surgery) should usually be considered after biologic drugs have been withdrawn for three to five half-lives.Some experts also suggest that these surgeries should be considered 2,4,and 8 weeks after the last administration of adalimumab,infliximab,and ustekinumab,respectively.Biologic therapy can be restarted if no signs of infection are observed and wound healing is good after the operation.However, the use of biologic drugs is not affected by low-risk surgeries(e.g., endoscopic surgery of the digestive, urinary, or respiratory tract; dental treatment; skin surgery; breast biopsy or excision; eye surgery; plastic surgery; or joint replacement).1,24,26-27

Limitations of this consensus

The content of this consensus represents the guiding opinions of the involved experts on biologic therapy for psoriasis and can be used as a reference for clinicians.Although extensive consultations and discussions among experts have been conducted,limitations may remain.The recommendations,opinions,and methods provided in this consensus are not mandatory, and measures that are inconsistent with this consensus may not be incorrect or inappropriate.The development of biologic therapy for psoriasis is progressing very rapidly.With the accumulation of clinical experience and the emergence of new biologic drugs,this consensus must be revised and updated regularly in future.