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The Evidence for Biologics for Localized, Difficult-to-Treat Psoriasis
Multiple biologic therapies have been approved for the treatment of psoriatic arthritis and moderate to severe plaque psoriasis. These products fall into one of three general categories—tumor necrosis factor (TNF), interleukin (IL) 17, and IL-23 (including IL-12/23)—and have been found to be effective and safe in clinical trials for plaque psoriasis requiring phototherapy or a systemic therapy such as methotrexate, cyclosporine, and acitretin. These therapies have provided tremendous advances in the treatment of plaque psoriasis to date with a high level of safety for most patients.
There have been recent calls1 in the dermatology community for a wider “off-label” use of biologic medication to include mild to moderate disease, including treatment for limited localized areas of involvement. In this regard, some dermatologists may begin to question whether the admission criteria for these advanced therapeutics underestimated disease severity and impact on patient quality of life.2 Some specific localized areas that psoriasis affects can result in resistant disease, such as the nails, scalp, intertriginous areas (armpits, groin, under the breasts, other areas of skin folds), and palms and soles. The article herein discusses the evidence of biologic efficacy in difficult to treat areas and shares insight as to what dermatologists should consider when prescribing a biologic for localized disease.
Brief FDA History of Psoriasis Treatments
In the mid 1990s, the regulatory criteria for treatment success in plaque psoriasis clinical trials was related to a reduction in the Psoriasis Area and Severity Index (PASI) scores. Cyclosporine was approved as a therapy for severe widespread plaque psoriasis in 1997 by demonstrating statistically significant reductions in PASI scores as well as providing an acceptable safety profile for this drug.3 Patients enrolled in these studies were required to have widespread plaque psoriasis affecting greater than 5% body surface area (BSA).
The efficacy and safety of nonbiologic systemic therapies have been detailed in previous reports.4,5 These generally include methotrexate, cyclosporine, acitretin, and phototherapy. Mycophenolate mofetil and azathioprine are amongst additional treatment modalities for this degree of disease. Efficacy results are treatment-specific, but many times are not successful enough to satisfy the patient who requests additional therapeutic choices.
At the 1998 FDA Dermatology Advisory Committee6 on plaque psoriasis, additional treatment success parameters were introduced by the FDA to provide for even greater efficacy endpoints. As a result of that meeting, terms such as PASI 50, PASI 75, PASI 90, clear, and almost clear have become the hallmarks of treatment success in clinical trials for plaque psoriasis and in the marketing of individual biologic agents. While the language between individual biologics vary slightly, the FDA-approved indications generally state that the agent is for the treatment of moderate to severe plaque psoriasis in patients who are candidates for systemic therapy or phototherapy, indicating this therapeutic group is intended for widespread clinical disease. Attention to more treatment-resistant areas of psoriasis (eg, scalp, inverse, nails, palms and soles, localized pustular variants) went unanswered.
Because subgroup analyses of difficult to treat psoriasis subtypes were not a subject of attention at that time, there were probably too few patients with such presentations enrolled in the pivotal trials for the plaque psoriasis indication. However, following their plaque psoriasis approval, biologic agents have seen an increased focus on these subgroups in recent years.
Evidence of Biologics for Difficult to Treat Psoriasis
There is an overall paucity of data regarding difficult to treat areas of psoriasis. In short, the following paragraphs will highlight literature published to date on the three various classes of biologic agents for the treatment of psoriasis of the nails, scalp, and palmoplantar regions. However, it is important to note that post-hoc analyses are less persuasive to the FDA as evidence of efficacy and safety, and a priori study designs are required for meaningful analyses.
TNF. In 2017, adalimumab achieved treatment success with separate studies for fingernail psoriasis and gained FDA approval for this indication.7 Elewski et al8 reported the trial results that led to the fingernail psoriasis approval. This study was a 52-week, placebo-controlled trial in moderate to severe plaque psoriasis, in which participants had moderate to severe fingernail disease. Patients who were on placebo were switched to adalimumab at week 26 (or sooner starting at week 16 if their disease was worsening) in an open-label extension and continued for the remainder of the study. Treatment success required an improvement in the modified Nail Psoriasis Severity Index (mNAPSI) score as well as the Physician Global Assessment. For mNAPSI 75, 47% in the treatment group vs 3% in the placebo group achieved an improvement, and this was statistically significant.
In a study of plaque psoriasis of the palms, soles, and nails by Poulin et al,9 participants were treated with adalimumab for a 16-week period. NAPSI 50 was the primary endpoint for treatment success. Greater numbers of those treated with the biologic medication achieved NAPSI 50 at week 16 vs placebo (56.5% vs 12.5%, respectively). Additionally, scaling, fissuring, induration, scaling, and pain scores had greater improvement in the active treatment group vs the placebo. Leonardi et al10 reported on the long-term safety of adalimumab in clinical trials for 13 clinical trials on the treatment of moderate to severe plaque psoriasis. There were low numbers of serious adverse events and serious infectious adverse events. There was no evidence of cumulative toxicity with adalimumab.
Etanercept is the oldest TNF inhibitor on the market, and its efficacy in difficult to treat areas is well-documented, including as a comparator in newer clinical trials. Bagel et al11 looked at the efficacy and safety of etanercept for scalp psoriasis. Their randomized, placebo-controlled study examined the percentage change in Psoriasis Scalp Severity Index (PSSI) after 12 weeks of treatment with placebo or etanercept. At study completion, the mean PSSI improvement for patients treated with etanercept was 86.8% vs only 20.4% for those receiving placebo, and 86% of patients achieved PSSI 75.
It has also been established as an effective treatment for nail psoriasis. In 2013, Ortonne et al12 showed decreases in NAPSI of 4.3 and 4.4 for etanercept 50 mg twice weekly for 12 weeks followed by once weekly for 12 weeks and for 50 mg twice weekly for 24 weeks, respectively. The nail-specific results showed significant correlation with improvements in overall PASI. A 54-week study showed sustained NAPSI improvements as well.13
Golimumab, which is only indicated for PsA, is another TNF inhibitor that has several trials showing improvement in skin and nail psoriasis in patients with PsA.14,15 In addition, there is some evidence from 2014 that certolizumab pegol, another TNF inhibitor approved for PsA, can show rapid improvements in nail psoriasis in patients who have PsA.16 Given their wider use for treating PsA, to the best of the author’s knowledge, there is no specific analyses of the effectiveness of either golimumab or certolizumab pegol for scalp or palmoplantar psoriasis.
IL-17. An excellent review of fingernail psoriasis treatment with biologics was presented by Wind and Weinberg.17 They described a 60-week clinical trial in which the IL-17 antibody ixekizumab was superior for treatment of nail psoriasis over both the etanercept and placebo treatment arms and resulted in complete nail clearance in more than 50% of patients at study end. Langley et al18 reported on a clinical study involving scalp and nail psoriasis with ixekizumab at increasing doses vs placebo. At week 16, the placebo group was switched to ixekizumab, and all participants were treated with active drug to the 48-week evaluation. The PSSI and NAPSI were primary endpoints. Both scalp psoriasis and fingernail psoriasis had complete clearing in 78% and 51%, respectively.
Similarly, van de Kerkhof et al19 demonstrated significant improvements in fingernail psoriasis with ixekizumab. In a subgroup analysis of the UNCOVER-3 trial, they found that patients who received 80 mg of ixekizumab at 4-week maintenance dosing showed additional improvement through 60 weeks, with more than 50% of patients achieving complete resolution. Leonardi et al14 extended out the analysis through 3 years, finding sustained high responses of skin and nail clearance with ixekizumab. For scalp and palmoplantar psoriasis, the UNCOVER subgroup analysis through week 60 of treatment also revealed sustained clearance for these difficult to treat areas.21,22
As another IL-17 inhibitor approved for the treatment of psoriasis, brodalumab was studied as monotherapy for scalp and nail psoriasis in the phase 3 AMAGINE studies. At week 12, more patients receiving brodalumab had lower mean PSSI scores vs placebo; after 52 weeks of treatment, the brodalumab arm had a lower mean NAPSI vs ustekinumab.23
In a phase 2 regiment-finding study, secukinumab was evaluated for the treatment of psoriasis of the hands, feet, and/or nails.24 Patients received either secukinumab 150 mg in a single dose (week 0), a monthly dose (weeks 0, 4, 8), an early dose (weeks 0, 1, 2, 4), or placebo. At week 12 of treatment, more patients with hand and/or foot psoriasis achieved an Investigator Global Assessment (IGA) response with the early doses of secukinumab vs placebo, and the composite fingernail score was improved with the early and monthly regiments. In 2017, Bagel et al25 found secukinumab was efficacious and well-tolerated for the treatment of scalp psoriasis in a phase 3b study. A more recent study published in British Journal of Dermatology found that secukinumab demonstrated significant and clinically meaningful improvements for patients with nail psoriasis up to 32 weeks.26
IL-23. Foley et al27 reported on a post-hoc data analysis of clinical trials for guselkumab in the treatment of moderate to severe plaque psoriasis vs a placebo group and an active treatment arm (adalimumab) for a 24-week study. At week 16, the placebo group was switched to guselkumab while adalimumab subjects continued therapy. The scalp, palms, and soles were graded for clear or near clear in the IGA and nails were graded by NAPSI. At week 24, guselkumab was superior to placebo for treatment success in all areas studied and had improved results against adalimumab for scalp, palm, and sole psoriasis. There was no difference in the success rates between the two biologic medications for fingernail disease. A Japanese phase 3 trial has found that guselkumab demonstrated a significant decrease in mNAPSI score in a subgroup analysis among patients with nail psoriasis.28
The only anti-IL-12/IL-23 biologic, ustekinumab has conflicting evidence for certain difficult to treat areas. In the PHOENIX 1 trial, Rich et al29 assessed the improvement in fingernail psoriasis by comparing the efficacy of 45 mg vs 90 mg dose of ustekinumab vs placebo over a 52-week study. After week 24, there was no statically significant difference between the percentage improvement in NAPSI for the ustekinumab doses (46.5% for 45mg vs 48.7% for 90mg). Maintenance treatment showed improvements until up to 1 year of treatment with ustekinumab. However, another phase 2/3 study out of Japan reported no significant NAPSI improvement with ustekinumab vs placebo after week 12.30 Ustekinumab has also been frequently used as a comparator product for newer biologics, showing various degrees of efficacy.
Current Severity Definitions vs Difficult to Treat Areas
Psoriasis is a complex skin disease, and severity cannot be judged by involved surface area only. Great examples of the limitations of the current definition of severity based on BSA or PASI are the difficult to treat areas of the groin, buttocks, axillae, scalp, palms, soles, and nails. While psoriatic involvement may be entirely limited to these anatomical locations (thus considered mild severity by BSA alone), they still may be considered by providers as moderate to severe disease.
Over the past 15 years since the very first FDA approval, biologic agents for plaque psoriasis in less difficult to treat areas (eg, trunk, extremities) have converted many doubtful physicians into believers for the treatment of widespread plaque disease based on BSA. The addition of biologics to our armamentarium has resulted in higher treatment success rates. While adalimumab was successful for clinical trials to show safety and efficacy for fingernail psoriatic disease, few other biologics have received additional clinical indications in difficult to treat disease. We need further evidence from clinical trials that study these difficult to treat localized areas of psoriasis. The literature is just beginning to demonstrate biologic safety and efficacy in these localized areas of psoriasis.
Individual holders of each FDA biologic medication (ie, sponsors) would need to make such requests to the FDA to claim additional clinical indications for psoriasis and will hopefully obtain approved label changes and advertising rights in the future. As always, the risk-benefit ratio will determine its use for any patient by the medical provider based on disease severity, morbidity, quality of life factors, and any disability from psoriasis. Sometimes the cost of biologics is prohibitive for individual patients and biosimilars may be helpful for the future to allow wider use.
Biologic Safety Information
As with most medications, there are adverse events that are well tolerated and occur in small numbers that led to approval of these medications. On occasion, there are serious adverse events as well as death.
Dermatologists should always keep in mind that these biologics are not appropriate for all patients with psoriasis, including those with psoriasis in difficult to treat areas previously discussed. Patients who may not be candidates for biologic therapies include those who have reduced immunity to infections, those with a current or history of malignancies, and other specific concurrent or past conditions. The FDA-approved product label for these biologics frequently has warnings/precautions about infections, tuberculosis, hypersensitivity, and inflammatory bowel disease. Adverse events include injection site reactions, headache, anaphylaxis, diarrhea, flu-like illness, rash, nasopharyngitis, and upper respiratory tract infections, and mucocutaneous Candida. Extra consideration should be given to the elderly population because mature patients are usually more susceptible to demonstrating adverse events. The medical provider must assess the risk-benefit ratio and judge whether a biologic is safe to use for a particular
patient. Further study of long-term safety would be helpful for each biologic medication approved for psoriasis.
Conclusion
Biologics for psoriasis offer a compelling treatment consideration for both plaque and difficult to treat psoriasis in limited areas because they directly target the inflammatory markers for this disease. They result in reduced inflammation and greater numbers of patients having a clear and almost clear treatment status. This heightened efficacy over traditional systemic agents must be weighed against the unknown long-term side effects of biologics as well as their tendency to result sometimes in infections and possible malignancy in the elderly population.
Biologic agents for psoriasis are becoming a first-line therapy to treat this disease for both plaque and resistant types of disease. The FDA may wish to expand the indications for biologics to the treatment of psoriasis and localized psoriasis than moderate to severe disease.
Acknowledgements
Dr Rand is formerly a clinical associate professor of medicine at Georgetown University Medical School in Washington, DC. Dr Rand also served as an acting supervisory medical officer in the Dermatology Group at FDA’s Center for Drug Evaluation and Research. He currently resides in Hummelstown, PA.
Disclosures: The authors report no relevant financial relationships.
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