Biosimilars for psoriasis: worldwide overview of regulatory guidelines,uptake and implications for dermatology clinical practice

The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of ‘big data’ should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies.     

Pyoderma gangrenosum: a review with special emphasis on Latin America literature

Pyoderma gangrenosum is a neutrophilic dermatosis characterized by chronic ulcers due to an abnormal immune response. Despite the existence of diagnostic criteria, there is no gold standard for diagnosis or treatment. In Latin America, recognizing and treating pyoderma gangrenosum is even more challenging since skin and soft tissue bacterial and non-bacterial infections are common mimickers. Therefore, this review aims to characterize reported cases of pyoderma gangrenosum in this region in order to assist in the assessment and management of this condition. Brazil, Mexico, Argentina, and Chile are the countries in Latin America that have reported the largest cohort of patients with this disease. The most frequent clinical presentation is the ulcerative form and the most frequently associated conditions are inflammatory bowel diseases, inflammatory arthropaties, and hematologic malignancies. The most common treatment modalities include systemic corticosteroids and cyclosporine. Other reported treatments are methotrexate, dapsone, and cyclophosphamide. Finally, the use of biological therapy is still limited in this region.     

Biosimilars: a systematic review of published and ongoing clinical trials of antipsoriatics in chronic inflammatory diseases

Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In‐Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab – all in rheumatoid arthritis patients – were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial.     

Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know

The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide.     

Safety profiles and efficacy of infliximab therapy in Japanese patients with plaque psoriasis with or without psoriatic arthritis,pustular psoriasis or psoriatic erythroderma: Results from the prospective post‐marketing surveillance

A large‐scale prospective post‐marketing surveillance was conducted to evaluate the safety and efficacy of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. This study was conducted in all psoriasis patients treated with infliximab after its Japanese regulatory approval. Infliximab was administrated at 5 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter. Patients were serially enrolled and observed for 6 months to evaluate the safety and efficacy. The safety and efficacy were evaluated in 764 and 746 patients, respectively. Incidences of any and serious adverse drug reactions were 22.51% and 6.94%, respectively, and those of any and serious infusion reactions were 6.15% and 1.31%, respectively, which were comparable with the results in the post‐marketing surveillance with 5000 rheumatoid arthritis patients in Japan. Major adverse drug reactions during the follow‐up period were infections (5.10%) including pneumonia, cellulitis and herpes zoster, however, no tuberculosis was observed. The safety profiles were equivalent, regardless of the psoriasis types. No new safety problems were identified. The response rates on global improvement and median improvement rate of Psoriasis Area and Severity Index in all patients were 88.0% and 85.0%, respectively. Of note, the efficacy was equivalent for each psoriasis type as well as for each body region. Infliximab was also effective in pustular psoriasis symptoms, joint symptoms and nail psoriasis, as well as improvement of quality of life. Infliximab was confirmed to be highly effective and well tolerated in treating refractory psoriasis, including pustular psoriasis and psoriatic erythroderma.     

Biosimilars bei Psoriasis: Was können wir erwarten?

Biosimilars are biotechnologically processed drugs whose amino acid sequence is identical to the original biopharmaceutical. They are of considerable clinical, economical, and health care interest. As patents for biologicals used to treat psoriasis expire, biosimilars will become more and more important within the field of dermatology. The patents for the two top‐selling drugs (adalimumab and etanercept) will terminate in the next few years. Applications for biosimilars will presumably be submitted to the EMA and the FDA for all patent‐free biologicals. Both regulatory bodies have issued guidelines on the assessment of bioequivalence, as well as the benefits and risks of biosimilars. While the preclinical requirements of the FDA and EMA are largely comparable, the formal requirements for clinical bioequivalence, including clinical efficacy and safety, differ markedly. Therefore, from a medical and health care perspective before biosimilars enter the market, specific evidence‐based regulatory conditions need to be created and fulfilled. Only then biosimilars can be a less expensive option for a large number of patients, providing them with substances of the same value. Adequate, unequivocal proof of their bioequivalence, quality, and related patient safety should have priority over any ostensible economic benefits.     

Biosimilars for psoriasis: preclinical analytical assessment to determine similarity

Biosimilars, sometimes called ‘generic biologics’, are no longer a vision for the future but a present‐day reality. Drug manufacturers and regulatory authorities are charged with ensuring that these products are safe and effective. Because biologically produced medications are large, complex proteins, many factors affect the quality of the end product, including glycosylation and presence of impurities, and thus many factors need to be compared between an emerging biosimilar and its originator biologic. Indeed, preclinical analytical assessments to determine similarity to an originator biologic are critical and are considered to be the foundation for regulatory approval of biosimilars. Here, the science behind the preclinical development of biosimilars is discussed by members of the International Psoriasis Council, and suggestions are put forth to try to ensure that future biosimilars are produced in a high quality and standardized manner.     

Biosimilars in Dermatology – theory becomes reality

Biosimilars are biological medicines that are analogues of a specific reference product. Biosimilars of the tumor necrosis factor alpha inhibitors infliximab and etanercept are already approved and available for dermatological indications. Regulatory agencies require in‐depth analysis of physicochemical and functional properties of these highly complex molecules as well as clinical data on their similarity regarding efficacy and safety in at least one clinical trial in a sensitive and homogeneous population. Thus, it must be shown that biosimilars are essentially the same as the originator product if they are to be licensed in regulated drug markets. As a consequence, these data are extrapolated from one molecule (the originator) to another (biosimilar) resulting in an approval that includes the same indications as the originator product. While extrapolation is well accepted and regulated, clear recommendations regarding the interchangeability of originators and biosimilars as well as data on multiple consecutive switching are missing. Current scientific knowledge does not argue against the use of biosimilars for dermatological indications, but sequential switching of biosimilars should be considered carefully. To increase confidence and enhance evidence for biosimilars, accurate documentation of the specific products given to each patient is essential and should preferably be included in patient registries.     

Pathophysiological basis of systemic treatments in psoriasis

Over the past 15 years, the spectrum of systemic antipsoriatic treatments has dramatically expanded. Until the end of the last millennium, systemic therapy had been restricted to four oral agents: methotrexate, cyclosporine, acitretin, and fumaric acid esters. Today, there are additionally seven biologics and one new oral antipsoriatic drug, as well as the first available biosimilars. Six more biologics with novel target structures and at least four biosimilars are currently being developed (phase III). This progress has been based on new insights into the pathogenesis of psoriasis, in which tumor necrosis factor and especially Th17 immune responses with their associated cytokines interleukin 23 and 17 play a key role. The development of new‐generation biologics as well as immunomodulatory small molecules can be attributed to these pathophysiological findings. Phosphodiesterase 4 inhibitors, dimethyl fumarate, and Janus kinase inhibitors all interact with Th17 immune responses. Some of these drugs are in advanced clinical development and are also beneficial in psoriatic arthritis. Today, psoriasis and psoriatic arthritis therefore rank among the most readily treatable inflammatory autoimmune disorders. Dermatology is increasingly becoming a specialty of modern targeted immunotherapies.     

Epidemiology and quality of life of patients with psoriasis in Chile

BackgroundClinical characteristics of psoriasis vary between different races and climates. There are few data on Latin American and even fewer on Chilean patients with psoriasis.ObjectivesTo assess that clinical characteristics and quality of life (QoL) of a group of Chilean patients with psoriasis.MethodsA cross-sectional, observational and analytic study was conducted at the Dermatology Department of the Clinical Hospital of the University of Chile between July 2006 and December 2008 applying an epidemiological and QoL-related survey to psoriatic patients.ResultsOne hundred fifty-three patients with psoriasis were included in the study. The mean (SD) age was 42.7 (14.9) years and 60.1% of the patients were male. The most frequent disease subtype was plaque psoriasis (71.9%), followed by “guttatiform” (guttate morphology without confirmed streptococcal infection) psoriasis (17.7%). In 38.6% of patients, less than 10% of body surface area (BSA) was affected. Joint involvement was reported in 28.8% of patients. Those with early onset of disease (before 30 years of age) were more likely to have a positive family history of psoriasis. Hypertension and diabetes were present in 20.3% and 11.1% of patients, respectively. The mean Dermatology Life Quality Index was 14. Greater impact of the disease on QoL was associated with male sex, young age of onset, newly diagnosed disease, facial involvement, and widespread disease.ConclusionChilean patients with psoriasis have clinical characteristics and QoL comparable to patients in other countries. A notable difference, however, was the greater impact of psoriasis on the QoL of Chilean men compared to women.     

High impact of a national psoriasis telementoring clinic on medical practices for patients in underserved areas

Argentina is a large country in which important asymmetries exist in the knowledge and management of psoriasis. For this reason, in 2015 we launched Project ECHO Psoriasis, a telementoring strategy for dermatologists aimed at providing best medical practices in this population. The main objective of this study was to explore the reasons why the physicians participating in Project ECHO Psoriasis Argentina sought remote assistance. Cross‐sectional study of the consultations made by dermatologists to the panel of experts. 213 consultations, which involved 158 patients in 60 teleclinics, were analyzed. The most frequent reasons for consultation were to implement changes in ongoing treatment, to support the treating physician approach to the patient, and to choose a de novo treatment, which were observed in 63 (39.9%), 47 (29.7%) and 46 (29.1%) consultations, respectively. The experts suggested modifying the approach to the patients in two thirds of the consultations (69.6%; 95% CI 61.8‐76.7). Complete and partial compliance with the suggestions were observed in 66.4% (95% CI 56.7‐75.1) and in 4.5% (95% CI 1.5‐10.3), respectively. The main barriers identified were adherence by the patients and health services access issues. Telementoring for psoriasis is useful in reducing asymmetries in knowledge between dermatologists and ensuring access to the best clinical practices.     

Reconsideration of 2008 decision: Food and Drug Administration approval of etanercept for systemic treatment of moderate to severe pediatric psoriasis

Although systemic etanercept was approved in 2004 for adults, the Food and Drug Administration (FDA) denied approval for use in children with psoriasis in 2008. Revision of the FDA's risk‐benefit assessment in response to understanding of disease burden, unmet medical need, and the effect of off‐label use in children with psoriasis led to the 2016 approval as the first systemic biologic product for the treatment of children aged 4‐17 with moderate to severe psoriasis. This article delineates the thinking that led to this reconsideration. The underlying thinking paved the way to inform current pediatric drug development as the FDA continues to bring needed medical products to children.     

Combining systemic retinoids with biologic agents for moderate to severe psoriasis

Background Moderate to severe psoriasis, which is defined as psoriasis affecting more than 20% of the body surface area, often requires a combination of therapies to achieve remission. Although numerous data exist regarding the use of acitretin and biologic agent therapy alone for psoriasis, little is known about the efficacy, safety, and tolerability of acitretin combined with biologic agents. Methods Fifteen patients with psoriasis treated with concomitant acitretin and a biologic agent were identified, and their charts were reviewed for response to therapy, additional therapy necessary for disease management, side‐effects, and laboratory abnormalities whilst on combination therapy. The Institutional Review Board did not require approval for this chart review. Results Twenty‐nine per cent of patients showed clearance of psoriasis, 43% of patients showed an improvement of 90%, 14% showed an improvement of 75%, and 7.1% showed no change. During treatment with acitretin and biologic agent, five patients required no adjunctive treatment. Three patients were able to stop narrow‐band ultraviolet‐B (UV‐B) therapy after an average of 2.33 months of combination therapy. Only one patient continued to require phototherapy (UV‐B) in addition to the biologic agent. Three patients developed squamous cell carcinoma (SCC) whilst on combination therapy, but all patients had a previous history of SCC. One patient developed non‐Hodgkin's lymphoma after 3 years of etanercept and acitretin, and the etanercept was discontinued. Conclusions Acitretin combined with biologic agents offers a promising method of managing refractory psoriasis. More research is needed to determine the long‐term safety and efficacy of this combination.     

The decentralization of the health system in Colombia and Brazil and its impact on leprosy control

Decentralization policies are an integrated component of health sector reform in an increasing number of countries. The ability of such policies to improve the health system's quality and efficiency is backed up by limited scientific evidence. This study intends to evaluate the impact of decentralization on a specialized field of disease control (leprosy control) in Colombia and Brazil. It analyses the respective juridical base, epidemiological indicators and local publications. Furthermore, 39 semi-structured interviews with key informants were conducted. In both countries, the devolution of technical responsibility and financial resources to the municipalities was the implemented form of decentralization. Access to preventive and curative health care and the community participation in decision-making improved clearly only in Brazil. The decentralization to private providers in Colombia had dubious effects on service quality in general and still more on public health. The flow of finances (including finance collection through state-owned taxes instead of insurance companies) seemed to be better controlled in Brazil. Leprosy control in Brazil took advantage of the decentralization process; in Colombia, it came close to a collapse.     

白细胞介素17A及其受体拮抗剂治疗银屑病的不良反应

【摘要】 白细胞介素17A在银屑病的发生发展中具有关键作用。目前,有多种白细胞介素17A及其受体拮抗剂在多个国家上市并应用于银屑病的治疗,取得了明确疗效。然而,该类生物制剂在临床试验阶段及上市后,仍然有多项不良反应报道,包括上呼吸道感染、念珠菌感染、中性粒细胞减少和炎症性肠病等,严重者甚至可危及生命。本文综述3种白细胞介素17A及其受体拮抗剂司库奇尤单抗、ixekizumab和brodalumab的临床安全性。     

Psoriasis in Latin America and the Caribbean: a systematic review

Psoriasis is a chronic inflammatory disease that generally affects the skin, nails and joints. The burden of psoriatic disease in Latin America and the Caribbean (LAC) remains largely unknown. To estimate the burden of psoriasis in LAC. We conducted a systematic review following the MOOSE and PRISMA statements. We searched published studies in MEDLINE, EMBASE, LILACS and CENTRAL from 1st January 2000 to 5th August 2015. We included studies that reported incidence, prevalence, health resource use and health expenditures, treatment patterns, comparative effectiveness of different drugs, patients reported outcomes, adherence to treatment and patient preferences in LAC. Risk of bias was assessed evaluating selection of participants, control of cofounders, measurement of exposure and outcome and conflict of interest. Pairs of reviewers independently selected, extracted and assessed the bias risk of the studies. The systematic review was registered at PROSPERO (CRD42016038325). A total of 18 studies from 12 LAC countries were included. Most were observational studies, between which there was a large heterogeneity of outcomes. Population‐based studies were not found and most data came from hospital registries. One study reported an incidence of psoriatic arthritis in 6.26 cases per 100 000 person‐years. Another study found an incidence of psoriasis 1020 per 100 000 patient‐year attending at a dermatology clinic. The prevalence reported in the Argentinean health service was 74 cases per 100 000. Further, psoriasis has been shown to have a substantial negative impact on quality of life. A number of studies also indicated that non‐communicable disease burden increases with the presence and severity of psoriasis. With regard to treatment pattern, methotrexate was the dominant systemic therapy. In conclusion, there is an important lack of information from LAC concerning the burden of psoriasis. Further studies investigating the burden of psoriasis in representative LAC populations are needed.     

Understanding patient and physician perceptions of male androgenetic alopecia treatments in Asia–Pacific and Latin America

This survey aimed to explore patient and physician attitudes towards male androgenetic alopecia (AGA), satisfaction with currently available male AGA treatments and investigate the factors affecting treatment choice. The survey was carried out in five countries (Japan, South Korea, Taiwan, Mexico and Brazil) between November and December 2015 using a standard market research methodology. Questionnaires were completed by patients with male AGA or hair loss/thinning and practicing physicians who were responsible for prescribing AGA treatment. In total, 835 patients and 338 physicians completed the questionnaire. Overall, 37.6% of patients reported satisfaction with the treatments they had used. The highest patient satisfaction was reported for 5‐alpha‐reductase inhibitors (53.9% of patients satisfied). In all countries, physicians were more likely than patients to think that male AGA has a major impact on patient confidence (89.3% vs 70.4%, respectively). There was agreement by physicians and patients that male AGA patients who are involved in their treatment decisions have better outcomes. Patients who were satisfied with AGA treatments were more likely to have the level of involvement they desired in treatment decisions (69.1% of satisfied patients) than dissatisfied patients (56.4% of dissatisfied patients). This survey provides valuable insights into the attitudes of patients and physicians in Asia and Latin America about male AGA and its treatments. The survey identified areas of disconnect between physicians and patients regarding the impact of male AGA, treatment consultations and the importance of treatment attributes. It also highlights the need for physicians to spend sufficient time with patients discussing AGA treatment approaches.     

Stellenwert von Biologics in der Psoriasis‐Therapie: Ein Konsensus‐Papier der Arbeitsgruppe Psoriasis,Arbeitsgemeinschaft dermatologische Forschung

About 20 % of all psoriasis patients require photo‐ and/or systemic therapy because of the severity of their disease. Side effects, contraindications, insufficient clinical responses, and lack of long‐term efficacy underline the need for novel and improved anti‐psoriatic therapies. In recent years, the technology has been established to generate therapeutic molecules from living cells capable of inhibiting disease‐relevant mediators or cell‐cell interactions. Several of these so‐called biologics interfering with key steps in the immunopathogenesis of psoriasis have the potential to meet this need with regard to treating moderate to severe psoriasis. Here, the Psoriasis Study Group of the Arbeitsgemeinschaft Dermatologische Forschung (ADF) analyses the established anti‐psoriatic treatment modalities. With the shortcomings of these options in mind, biologics with an immediate relevance for clinical application in the treatment of psoriasis are discussed. The focus is on their potential medical advantages along with safety aspects. Moreover, legal and economical aspects with an impact on the use of biologics are addressed.     

A multidimensional assessment of the burden of psoriasis: results from a multinational dermatologist and patient survey

Psoriasis is a common, chronic, inflammatory skin disease which affects between 0.09% and 11.4% of the population worldwide. It causes symptoms such as itch and skin pain, but its effects can actually extend beyond the skin. It is often associated with additional co‐occurring diseases (comorbidities) such as cardiovascular disease, psoriatic arthritis (PsA), obesity, diabetes and anxiety or depression. Altogether psoriasis can cause significant negative impact on the quality of life (QoL) as well as work productivity of psoriasis patients. Additionally, the presence of common and bothersome symptoms such as itch and psoriasis lesions on different body areas can further increase the burden of disease on patients. In this large and multinational survey of dermatologists and their psoriasis patients, we estimated the incremental burden of comorbidities, itch, and affected body areas among patients with moderate to severe psoriasis. Anonymised responses were collected from 524 dermatologists and 3,821 psoriasis patients across 9 countries (UK, France, Germany, Spain, Italy, Russia, South Korea, Mexico and Brazil) using questionnaires and analysed to assess the impact of psoriasis on patients. Questionnaires collected data regarding psoriasis symptoms (presence/extent of itch, sleep disturbance due to itch, presence of skin pain), QoL and medical resource utilisation in the past 12 months (e.g. number of consultations that patients had with their dermatologist and number of hospitalisations). Overall, the results indicate that the presence of physical and psychological comorbidities, symptoms such as itch, presence of psoriasis lesions especially on visible (e.g. scalp, face, hands) and sensitive areas (e.g. genitals, scalp, face) significantly affect psoriasis patients’ QoL and cause significant financial burden due to work productivity impairment and increased usage of medical resources.     

Pharmacodynamic analysis of apremilast in Japanese patients with moderate to severe psoriasis: Results from a phase 2b randomized trial

We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long‐term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman’s rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)‐17A, IL‐17F and IL‐22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor‐α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL‐17A, IL‐17F and IL‐22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis.