How can we manage the safety concerns associated with the increase in biologics for psoriasis?

KEYWORDS:

• Adverse events
• biologics
• concerns
• IL-17
• IL-23
• psoriasis
• safety
• tumor necrosis factor alpha inhibitors

1. Introduction

Psoriasis is a chronic, systemic, inflammatory disease affecting 2–3% of the worldwide population. It is associated with multiple comorbidities including cardiovascular disease, metabolic syndrome, diabetes, obesity, arthritis, and negative psychosocial issues [1,2]. Often, the choice of appropriate biologic therapy is driven by an individual’s comorbidities and conditions [3]. The spectrum of biologic therapies for the treatment of moderate-to-severe plaque psoriasis (MTSPP) has expanded significantly over the past decade, exhibiting increasing efficacy and safety. Currently, eleven biologics are available for the treatment of MTSPP. These include 4 tumor necrosis factor-alpha (TNF-α) inhibitors, a single molecule targeting IL-12/IL-23 combination, 3 IL-17 agents, and 3 IL-23 agents. Each novel therapy exhibits its own benefit/risk profile and generally, less adverse effects than those of the older systemic non-biologic agents [4]. Data suggest that most patients are likely to maintain effective and safe long-term treatment on these medications. Despite this, both patients and providers have important safety concerns [4–6].

2. Body

To this day, patients who are candidates for systemic therapy tend to remain untreated or are undertreated with only topical medications [7]. Psoriasis is a life-long disease, therefore it is important that both providers and patients fully understand and weigh up the safety risks involved in treatment with biologic medications. Below, we summarize the most common adverse events and concerns associated with the available biologic agents to provide clinicians with a concise reference for managing all safety concerns associated with the increase of biologic agents used in moderate-to-severe psoriasis.

2.1. Tnf-alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol)

TNF-alpha inhibitors have been available for psoriasis therapy for over 10 years. These agents do have a relatively small increased number of safety risks compared to more recent biologic agents. These safety issues include injection site reactions (ISRs), nasopharyngitis, and upper respiratory infections (URIs). Other reported AEs of TNF-α inhibitors include: infusion reactions (infliximab; occurs more frequently with intermittent therapy), hepatotoxicity (especially with infliximab), drug-induced reversible lupus erythematosus, new or worsening congestive heart failure, cytopenia, and multiple sclerosis (rarely). Hepatitis B reactivation and invasive fungal infections are also a concern [8]. In some cases, TNF-α inhibitors can have a paradoxical effect, causing worsening or new onset of the pustular form of psoriasis [9,10]. In general, infliximab carries a greater risk of AEs compared to adalimumab, etanercept, and certolizumab pegol. However, infliximab tends to be superior in efficacy ab initio but not long-term. Treatment with TNF-α agents appears to exhibit a small increased risk of non-melanoma skin cancer [11]. All TNF-α inhibitors carry FDA boxed warnings for serious infection and malignancy. However, when used as monotherapy for MTSPP, TNF-α inhibitors are not associated with an increased risk of solid tumor or lymphoreticular malignancy. The safety profile of TNF agents in regard to malignancy are altered with the addition of oral immunosuppressant therapies [12].

TNF-α is critical to the maintenance of granuloma formation, and thus, TNF-α inhibitors can cause an increased risk of reactivation of TB. As such, it is important that TB screening occur prior to the initiation of treatment and annually with any TNF-α inhibitor in order to prevent development of active TB and reactivation of latent TB [9]. There have been reports of several cases of interstitial pneumonia in patients receiving TNF-α inhibitors, however this association is controversial and has not been determined to be an absolute risk of these agents [13].

Certolizumab pegol may be used safely in pregnancy and during breastfeeding due to its pegylated molecular structure which lacks an Fc region and limits transfer across the placenta and from plasma to breast milk [9].

2.2. IL-17 agents (secukinumab, ixekizumab, brodalumab)

The most common AEs reported in clinical trials for the IL-17 inhibitors include: nasopharyngitis, diarrhea, URIs, headache, arthralgias, mild transient neutropenia, and ISRs [9]. Infrequent cases of hepatotoxicity with these agents have also been observed [9,14,15].

A unique safety concern for the IL-17 inhibitors is the small (2-3%) risk of mild-to-moderate mucocutaneous candidal infection. Since IL-17 plays a key role against candidal infection, a dose-dependent risk in patients on IL-17 inhibitors has been seen at a higher rate with IL-17 agents compared to placebo. Most patients showed complete resolution after anti-fungal treatment. Rates of serious infections for all IL-17 agents are comparable to placebo [13,14].

Another concern with IL-17 inhibitors, specifically in patients with a personal or family history of inflammatory bowel disease (IBD), is the 0.1–0.2% potential for activation or exacerbation of IBD [8,14]. Both psoriasis and IBD exhibit shared immunological pathways and overlapping genetic profiles, with studies showing an increased prevalence of IBD in patients with psoriasis [2]. There have been potential risks of occurrence or exacerbation of Crohn’s and ulcerative colitis in clinical trials of secukinumab and ixekizumab [16]. Brodalumab is contraindicated in patients with Crohn’s disease because one subject undergoing maintenance treatment with brodalumab had an occurrence of Crohn’s disease. Although a direct causal relationship has not been established between IL-17 agents and IBD, appropriate screening and caution is recommended when considering IL-17 agents in patients with a history of IBD. Alternative treatment options should be considered in patients with a definitive IBD diagnosis [13,14].

A concern of brodalumab use is suicidal ideation (SI) and behavior [8]. In the brodalumab AMAGINE trials, four suicides were reported all of which were found in patients with major pre-trial psychological issues. These trials did not exclude patients with previous or current psychological disorders. Psoriasis itself can create a significant psychological burden for patients, with a higher incidence of both SI and completed suicide in this population. Although no causal relationship was found, the Federal Drug Administration (FDA) has nonetheless assigned a boxed warning to brodalumab. No other IL-17 inhibitors have been associated with depression or suicide. It is important to note that depression and anxiety symptoms improve significantly with all forms of biologic psoriasis therapies.

2.3. IL-23 agents - IL-23p19 inhibitors (guselkumab, tildrakizumab, risankizumab), IL-12/23p40 inhibitor (ustekinumab)

The most common AEs seen with treatment of MTSPP with IL-23 inhibitors include: non-serious infections (nasopharyngitis and upper respiratory tract infection most prevalent), ISRs, fatigue, and headache [1,8,12]. In clinical trials with risankizumab, rare cases of back pain, diarrhea, and tinea infections were reported [17]. Rarely, increased liver transaminase levels have occurred with IL-23 inhibitor use. There is no evidence to suggest that the IL-23 inhibitors induce or worsen IBD in patients with psoriasis. Treatment with IL-23 agents avoids the risk of tuberculosis reactivation seen with TNF-α inhibitors and of fungal infection with IL-17 agents. Although this class of biologics has impressive clinical efficacy and favorable safety data in the treatment of MTSPP, the long-term safety of the newer IL-23 agents is yet to be determined. Open-label extension studies and long-term registries are thus important to determine long-term safety data of this newer class of biologics.

In a meta-analysis of AEs occurring in treatment with brodalumab, guselkumab, ixekizumab, risankizumab, secukinumab, and tildrakizumab, the most prevalent AEs were infections, nasopharyngitis, and headache across all 6 therapies. A very small proportion of patients reported serious AEs. The proportion of patients with any AEs was slightly lower in treatment with IL-23 inhibitors compared to treatment with IL-17 inhibitors [15]. In general, malignancy rates are slightly higher in psoriatic patients than the common adult population [13]. Limited data exist regarding any carcinogenic potential of the IL-17 and IL-23 agents, but to date, these treatments do not appear to increase malignancy risk. Future long-term studies are necessary.

3. Expert opinion

Before initiating therapy with a biologic agent, due diligence by healthcare providers to establish a patient’s baseline health is essential (Table 1). Basic vitals should be recorded including: height, weight, pulse, and blood pressure. A thorough medical history should be taken, paying special attention to any history of serious infections, immunocompromised status, malignancies, cardiovascular illness, hepatic or renal illnesses, psoriatic arthritis, IBD, tobacco and alcohol use, and immunizations. Pregnancy status and future plans for pregnancy should be discussed in women of child-bearing potential. It is generally recommended to obtain the following labs prior to beginning biologic therapy: complete blood count, comprehensive metabolic panel including lipid testing and fasting blood glucose, hepatitis B and C screening, TB testing (interferon‐γ‐release assay or T-spot test preferred over the less sensitive and specific TB skin test), chest x-ray, plus pregnancy testing (if indicated). After initiation of therapy, follow-up evaluation is recommended every 3–6 months to assess tolerability and clinical response.

Table 1. Recommended screening prior to starting biologic therapies in psoriasis patients.

History (Personal or Family) Chronic or active infections Immunocompromised status Immunization status Psoriatic arthritis Inflammatory bowel disease Demyelinating diseases, including multiple sclerosis Cardiovascular illnesses Hepatic or renal illnesses Hematologic conditions Malignancies Lymphoproliferative disease, including lymphoma

Social history including: tobacco and alcohol use, pregnancy status and future plans for pregnancy

Basic vitals including: height, weight, pulse, and blood pressure

Baseline Labs Complete blood count Comprehensive metabolic panel including: lipid panel and fasting blood glucose Hepatitis B screening Hepatitis C screening HIV testing TB testing Chest x-ray Pregnancy test (for women of child-bearing potential)

Safety concerns regarding biologic therapy are frequently an issue for patients with psoriasis. With appropriate explanation (‘We are not suppressing, but modulating your immune system.’) and monitoring, biologics are considered relatively safe. Overall, TNF-α inhibitors exhibit a higher incidence of AEs (although still low) compared to that of newer biologic agents (IL-12, 23 or 17 inhibitors). Serious AEs with these biologics are relatively uncommon with benefits certainly outweighing the minimal risk. Biologics have greatly shifted treatment and efficacy expectations for patients and providers treating MTSPP. It is no longer a rare feat to achieve complete or near-complete clearance of psoriasis in a patient on biologic monotherapy. Short-term data are encouraging, but long-term safety data are important and lacking with our newer biologic medications (IL-17 and IL-23). Long-term clinical tolerance needs to be further observed. Pharmacovigilance registries are key contributors to gathering relevant information on biologic long-term efficacy and safety. Head-to-head trials, both short-term and long-term, are warranted to establish efficacy and safety of these interventional agents.

Novel biologic therapies are safer and more manageable than our conventional oral systemic therapies. As a result, dermatologists and other providers treating psoriasis are increasingly expected to be knowledgeable about, and comfortable prescribing, these medications for patients whose psoriasis and quality of life would significantly benefit. Clinicians should ensure that patients are fully educated regarding the potential adverse events prior to initiation of treatment with a biologic for their psoriasis.

4. Conclusion

The field of biologic therapy continues to expand as our understanding of psoriasis and its immunopathogenesis increases. We fully expect therapies to continue becoming increasingly effective and specific. As the specificity of biologic therapies develops, biologic medications will become increasingly safe with less potential for adverse effect. Novel biologic therapies already show considerable promise in the treatment of psoriasis with clearance in up to 90% of patients. With more long-term data and newer agents, we can potentially effect improvement on the multiple systemic co-morbidities associated with psoriasis as well. Biomarker research could help clinicians individualize their approach to treating psoriasis in the future, allowing for even more optimization of treatment, safety, and efficacy in each individual patient. As the biologic armamentarium expands, the expectation is rising for clinicians to better understand the safety and efficacy of these medications. The future of biologics for psoriasis continues to be extremely bright.

Declaration of interest

A Menter is on the advisory board for Abbott Labs, Amgen, Boehringer Ingelheim, Janssen Biotech, Inc., LEO Pharma, and Sienna Pharmaceuticals; is a consultant for Abbott Labs, Amgen, Eli-Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Sienna Pharmaceuticals, and UCB; is an investigator for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli-Lilly, Dermira, Incyte, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Sienna Pharmaceuticals, Sun Pharmaceuticals, and UCB; is a speaker for Abbott Labs, AbbVie, Amgen, Janssen Biotech, Inc., LEO Pharma, Sienna Pharmaceuticals, and UCB; and has received compensation from Abbott Labs, AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli-Lilly, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Sienna Pharmaceuticals, and UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Alvotech, Leo Pharma, BMS, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Ortho Dermatology, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. They also consult for others through Guidepoint Global, Gerson Lehrman and other consulting organizations. They are a founder and majority owner of www.DrScore.com and a founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. A reviewer on this manuscript has disclosed that they are an employee of Mount Sinai and received research funds from Abbvie, Boehringer Ingelheim, Celgene, Eli Lilly, Incyte, Janssen/Johnson & Johnson, Leo Pharmaceuticals, Medimmune/Astra Zeneca, Novartis, Pfizer, Sciderm, Valeant, and ViDac. They are also a consultant for Allergan, Aqua, Boehringer-Ingelheim, LEO Pharma, Menlo, Mitsubishi, Promius and Theravance. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.