Journal of Dermatology for Physician Assistants

The official journal of the Society of Dermatology Physician Assistants

Making Sense of the Expanding Class of Biologics: A Focus on Nail Psoriasis

By Pamela Korzeniowski, PA-C

Pamela Korzeniowski, PA-C, is a dermatology physician assistant with North Texas VA Dermatology and practices in Dallas and Fort Worth, Texas. She is a graduate of the University of Washington MEDEX Northwest PA program in Seattle, WA, and a current DMSc student at A. T. Still

ABSTRACT
This article reviews the different clinical presentations of nail psoriasis depending on which nail structure is involved, discusses which first-line treatments are most efficacious depending on the nail structure involved, and highlights the biologic therapies that stand out as superior in newer nail psoriasis studies. The expanding class of biologics and their associated nuances can be overwhelming when determining which is the best fit for a specific psoriasis patient; thus, this manuscript as well aims to reduce confusion related to biologics by presenting a brief history of biologics, providing a review of the current biologics approved for psoriasis and psoriatic arthritis in the United States, along with a concise set of tables to help simplify decision-making with biologics.

CME Credit Availble: This program has been reviewed and is approved for a maximum of 1 hours of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for 1 year from the issue date of March 1, 2021. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. SDPA members may access the post-test at https://www.dermpa.org/JDPA_Exams

Learning Objectives:

1. Identify clinical features that differentiate psoriasis affecting the nail matrix versus the nail bed.
2. Review which first-line treatment options are most efficacious depending on the nail structure involved.
3. Review of the biologics currently approved for psoriasis in the United States.
4. Review current research concerning efficacy of IL-inhibitors in the treatment of nail psoriasis.

KEYWORDS
psoriasis (PsO), nail psoriasis, biologic therapy, tumor necrosis factor (TNF) inhibitors, interleukin (IL) inhibitors, apremilast, adalimumab, brodalumab, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, risankizumab-rzaa, secukinumab, tildrakizumab-asmn, ustekinumab

INTRODUCTION
Brief history of biologics and understanding of psoriasis. Despite the ability to achieve complete or near-complete clearance of psoriasis in the majority of psoriatic patients with a biologic, one subtype of psoriasis, nail psoriasis, has remained challenging to treat in some patients.1 Nail psoriasis is easily visible and, especially when severe, has a devastating impact on the patient’s quality of life (QOL).1 Patients with moderate to severe nail psoriasis complain of pain, inability to grasp small items, fasten buttons or tie shoelaces, and have increased risk for secondary fungal and bacterial infections of the nails and fingers. Biologics have had some of the best results with nail psoriasis, but nail improvement tends to lag up to one year from initiation of a biologic and often does not completely clear the nail psoriasis.1,2 Prior to the 1990s, psoriasis was considered simply a disorder of keratinocytes.3 Advances in immunology and molecular biology revealed psoriasis to be a much more complex, T-cell mediated disease.3 Psoriasis is now known to be an inflammatory, immune-mediated, and chronic multisystem disorder that affects 1.5 to 3.6 percent of the North American population.4 The primary manifestation of psoriasis is psoriatic plaques on the skin that can be pruritic, painful, and cosmetically distressing. Psoriasis is associated with numerous comorbidities, including psoriatic arthritis, cardiovascular disease, cancer, obesity, and psychiatric disorders.4

In the late 1990s, developments in the capacity for labs to identify and produce protein antibodies directed at specific cytokines and an improved understanding of the cellular and molecular pathogenesis of autoimmune inflammatory diseases converged into a brave new world of biologic therapies for autoimmune disorders such as rheumatoid arthritis (RA), Crohn’s disease, psoriatic arthritis (PsA), ankylosing spondylitis (AS), and multiple sclerosis (MS).3 Many of these autoimmune inflammatory conditions have overlapping molecular mechanisms, and so the development arcs for treatments have sometimes overlapped.3 Tumor necrosis factor (TNF) inhibitors were the first widely successful biologics on the market, initially approved in 1998 for Crohn’s disease (infliximab) and RA (etanercept).3,5,6 These same drugs were approved within several years for PsA and psoriasis. More TNF inhibitors for psoriasis and PsA followed, up until the most recently approved TNF inhibitor, golimumab, released in 2009.9 Interleukin (IL) inhibitors were first introduced in 2009 with ustekinumab, an IL-12/23 inhibitor.10 The next group of IL inhibitors, the IL-17s, first appeared in 2015 with secukinumab.11 The introduction of the first IL-23 inhibitor (guselkumab) came in 2017.14 While there is 20-plus years of data on the TNF inhibitors, the IL inhibitor drugs are relatively new, and thus less data are available for these. However, the newer biologics have fewer expected side effects due to their more downstream-specified cytokine target.17 Biologics, which receive this title because they are created from living cells in a lab or via a biological process, are not the only immune-targeting drugs now available to treat psoriasis and related autoimmune conditions.17 mall molecule immune-targeted drugs such as apremilast, a phosphodiesterase-4 inhibitor (PDE4) and tofacitinib, a janus kinase (JAK) inhibitor, have also been developed, targeting other immune cells that in turn inhibit various inflammatory responses in the immune system.1 With the multitude of immune-targeted therapies on the market or soon to be on the market, considering which treatment option is best for a patient can become overwhelming. This article focuses on the nuances of the biologics alone, particularly in the treatment of nail psoriasis.

SAFETY CONCERNS OF BIOLOGICS
Biologics share the following safety concerns: serious infections (mainly with infliximab, the oldest of the TNF inhibitors), hepatitis B and C virus (HBV/HCV) reactivation, interstitial pneumonia, immunogenicity (failure to respond, loss of response and/or anti-drug antibodies), and increased risk of some malignancies (primarily skin and lymphoma).18 Biologics should be avoided during pregnancy and should not be used if the patient has active infection. Live vaccines need to be updated prior to initiation of a biologic.5-16

Specific TNF inhibitor concerns. While TNF inhibitors have demonstrated a good safety profile over more than 20 years, they do carry some safety concerns that should be considered when selecting a treatment plan for a particular patient. First, TNF-alpha plays an important role in immune control of mycobacterium (particularly Mycobacterium tuberculosis [TB]), and so it is critical to screen patients for TB prior to initiation of a TNF inhibitor.18 A patient found to have latent TB infection (LTBI) needs to be treated before initiating a TNF inhibitor.18 Also, more common with TNF inhibitors are paradoxical reactions, Lupus-like reaction, and infusion-reaction with infliximab.18 TNF inhibitors are contraindicated for class III or IV heart failure patients.18

Specific IL-12/23 inhibitor concerns. The first IL inhibitor approved for use in the United States in 2009 was the IL-12/23p40 antibody, ustekinumab, which was then approved for psoriasis and PsA in 2013.8 Some concern for serious salmonella infections and cases of posterior leukoencephalopathy syndrome have been reported with ustekinumab.18 Possibly associated with increased risk for major adverse cardiovascular events (MACE) in early studies; however, further research has not reinforced this finding.18

Specific IL-17 inhibitor concerns. Interleukin-17 has a significant role against infections, particularly those due to Candida species.18 Almost all Candida infections associated with IL-17 inhibitor treatment have been mucocutaneous, mild to moderate in severity, and did not require the patient to stop treatment.18 IL-17s should be avoided in patients who have known inflammatory bowel disease (IBD) or a strong family history of IBD and patients should be monitored for IBD-like symptoms after initiating treatment with an IL-17.18 Neutropenia can occur but is rare and usually mild if it occurs; periodic monitoring for neutropenia is recommended.18 Brodalumab was associated with three suicide attempts, and one completion, during its Phase 3 studies; however, no other IL-17 inhibitors have been associated with depression or suicide attempts.18

See Tables 1 and 2 for a complete listing and special considerations for usage of approved TNF-inhibitor and IL-inhibitor biologics for psoriasis and/or psoriatic arthritis.

NAIL PSORIASIS
Special challenges. While biologics have made safe and complete clearance of psoriasis an achievable goal of treatment, nail psoriasis has continued to be more challenging.19 Part of the challenge is that patients who have severe nail disease more often have PsA, and patients who have PsA often have more severe psoriasis.3, 19 While the most common form of psoriasis is plaque psoriasis, the prevalence of nail psoriasis in patients with plaque psoriasis is well over 50 percent, with estimated lifetime incidence of 80 to 90 percent.19 In patients with PsA, the incidence of nail psoriasis may be more than 80 percent.19 Nail psoriasis is considered an indicator for future development of PsA.19 Studies have indicated that up to 42 percent of psoriasis patients will develop psoriatic arthritis (PsA) over the course of their disease.20,21 Because psoriasis and PsA share common pathophysiologic mechanisms, the majority of patients with PsA also have psoriasis.20 PsA presents with pain, stiffness, and swelling in and around the joints, similar to other rheumatologic diseases.

Distinguishing features of PsA include seronegativity for rheumatoid factor, enthesitis (heel pain at the insertion of the Achilles tendon is a classic finding), dactylitis, spondylitis, and dystrophic nail changes.20 Nail psoriasis poses a particular challenge due to the small surface area of the nails, the anatomy of the nail, and frequent injury or irritation to fingertips from regular use of the hands.1,19 Nail psoriasis can be especially devastating to patients as it is readily visible to others, leading to emotional distress, loss of job opportunities, social ostracization, and impairment of a person’s ability to pick up small items or do fine work with the hands.1,19 Even when a patient with plaque psoriasis is successfully treated with a biologic drug, his or her nail psoriasis takes much longer to improve.18

Different presentations of nail psoriasis. Psoriatic nail disease will have different presentations depending on the structure involved within the nail.19 When present in the nail matrix, it can cause pitting, leukonychia, red spots of the lunula, Beau’s lines, and crumbling of the nail plate.19 Psoriasis affecting the nail bed will present as oil-drop discoloration (also known as oil spots), splinter emorrhages involving the distal third of the nail, subungal thickening, and onycholysis to loss of the nail.18 Psoriasis can also cause chronic psoriatic paronychia, via involvement of the periungal region of the nail.19 Signs of nail psoriasis are not exclusive to psoriasis and may be seen in other nail conditions, however, in most cases, the diagnosis of nail psoriasis can be made clinically.18

Nail psoriasis treatments. Conventional systemic treatments, including methotrexate, cyclosporin, acitretin, and apremilast as well as intralesional steroids, calcipotriol, tacrolimus and tazarotene, have been shown to have some efficacy for treatment of nail psoriasis, mainly in mild cases.1,19 Topical and intralesional steroids seem to work better on nail matrix involvement whereas calcipotriol has better effect on nailbed psoriasis.19 In 2019, the Journal of the American Academy of Dermatology published a dermatologist and nail expert group consensus by Rigopoulos et al.22 This group consensus concluded that with nail psoriasis affecting three or more nails, systematic treatment should be considered including acitretin, methotrexate, cyclosporin, small molecules and biologics; whereas if three or fewer are affected, topicals could be offered first.22 While most biologic studies have only included nail psoriasis as a secondary focus, all biologics from TNF inhibitors to IL-22/23 inhibitors have shown a slow but good effect for nail psoriasis.19, 22 Non-pharmacologic treatments including phototherapy, photodynamic therapy, laser therapy, and radiotherapeutic options are sometimes used but not considered first-line treatments.19

REVIEW OF THE LITERATURE
Most significant studies on biologic treatment for nail psoriasis. One of the limiting factors in many nail psoriasis studies is that nail involvement was often considered as a secondary endpoint.19 Another problem is that the severity of the nail psoriasis was not measured using a universal measurement. For example, the most commonly used scoring system, The Nail Psoriasis Severity Index (NAPSI), can be measured differently depending on how the study was set up. Usually, each fingernail is assigned a total possible score of 8: up to 4 points for the nail plate if all four quadrants are affected, and up to 4 points for the nail matrix if all quadrants are affected, making a maximum score of 80 for all 10 fingernails.19 Some studies included the toenails as well (with total score of 160).19 Other studies used a “target NAPSI,” where only the most severe nail is treated.19 Alternatively, some researchers opted to use target NAPSI scores (NAPSI-50, NAPSI-75, and NAPSI-90) to represent the percentage of patients that achieved NAPSI of 50, 75 or 90, respectively.19 Although the original NAPSI score does not always correspond well between studies, the NAPSI and the modified NAPSI (mNAPSI) have been adopted more often over time.19 Rigopoulos et al22 compared a number of nail psoriasis studies that used NAPSI and mNAPSI to measure nail psoriasis improvement with various biologics including infliximab, adalimumab, ustekinumab, secukinumab, and ixekizumab.1 As a whole, each biologic reviewed showed good to excellent improvement in nail psoriasis despite lack of direct comparability using various NAPSI scoring systems.1

In 2020, Wasel et al reported results of their IXORA-S trial, a study comparing ixekizumab and ustekinumab, to examine efficacy in nail psoriasis. IXORA-S was a 52-week, phase 3b, multicenter, double-blinded, head-to-head, randomized trial with 302 patients.2 For both the ixekizumab and ustekinumab arms, over 60 percent of the patients had significant fingernail psoriasis at baseline (defined in the study as NAPSI > 16 with > 4 fingernails involved).2 Significantly more patients had nail psoriasis clearance (NAPSI = 0) by Weeks 16 to 20 in the ixekizumab group.2 While the patients in the ixekizumab group had faster results, both the ixekizumab and ustekinumab groups nail and skin psoriasis continued to improve over the 52 weeks.2

Based on the IXORA-S study, ixekizumab stands out as one of the most efficacious biologics for nail psoriasis. It is important to note, however, that both ustekinumab and ixekizumab performed well, while ixekizumab showed clearance of nail psoriasis several weeks faster than ustekinumab.2 At the end of the 52 weeks, only 21.5 percent of the patients from the ustekinumab arm and 7.8 percent of patients from the ixekizumab arm continued to present with significant nail psoriasis.2 The older studies on biologics and nail psoriasis have also showed good efficacy1 though less impressive than results from the more recent IXORA-S study.2 One limitation in comparing prior studies on the usage and efficacy of biologics for the treatment of nail psoriasis is that scoring systems and study design varies widely.

Table 3 summarizes the major studies evaluating biologics in the treatment of nail psoriasis and lists NAPSI improvement results.

DISCUSSION
The best biologic for nail psoriasis depends on the patient’s particular health history, comorbidities, physical exam, past treatments, and patient preferences. Whichever biologic fits your patient’s needs the best is likely the best for that patient. According to the available literature, all biologics, including TNF inhibitors, IL-17 inhibitors, and the IL-12/23 inhibitor, have shown to be effective in treating nail psoriasis. Given the connection between nail psoriasis and psoriasis, clinicians can conclude that most systemic treatments, which have proven effective for PsA or psoriasis, will also treat nail psoriasis. At the time this manuscript was written, the most recent IXORA-S study showed that the IL-17 inhibitor ixekizumab worked faster in clearing nail psoriasis for the majority of participants.

CONCLUSION
Biologic therapies have been shown to be safe and effective in the treatment of psoriasis and related inflammatory autoimmune conditions. When determining whether a patient with severe nail psoriasis would benefit from a biologic, the clinician should consider the patient’s health history, family history, and personal preferences to treatment to the individual. Nail psoriasis often presents with other related conditions, such as psoriasis and PsA, so the clinician might also recommend a biologic with secondary benefits for the patient. For instance, the clinician might recommend a biologic therapy that also treats PsA if the patient displays symptoms suggestive of early PsA, then carefully re-review the patient’s history to reasonably ensure against conflicts between the biologic in question and the patient’s other health conditions. With biologics currently at the forefront of treatment and on the horizon, it is critical for dermatology clinicians to stay up to date on these and other immune-modulating drugs as they emerge.

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Disclosures: The author has disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.

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