Peficitinib

Advances in treating psoriasis in the elderly with small molecule inhibitors

Abigail Cline1; Leah A. Cardwell 2 and Steven R. Feldman2,3,4

Abstract

Introduction: Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems.
Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions.

Keywords: Psoriasis, Elderly, Small Molecule Inhibitors, Apremilast, Tofacitinib, Ruxolitinib

1. Introduction

Psoriasis is a common, chronic, multisystem, inflammatory disease that affects approximately 7.5 million Americans.1 The chronicity of psoriasis and the aging of the general population has led to the elderly comprising a large portion of the psoriasis patient population.2 The highest rate of psoriasis (113 per 100,000) occurs in the 60–69 years age group; psoriasis is the sixth most frequent skin disease in the geriatric population.3,4 Managing moderate-to-severe psoriasis in the geriatric population can be challenging due to the presence of comorbidities, polypharmacy, and age-related organ impairment.4 There is limited data pertaining to systemic treatment of psoriasis in the elderly population, as individuals older than 65 years are often excluded from participation in psoriasis clinical trials.5
Psoriasis is characterized by a pathogenic cycle in which inflammatory T-cells infiltrate within the skin and release cytokines, leading to keratinocyte activation and proliferation. Activated keratinocytes subsequently release chemokines, which recruit and activate myeloid dendritic cells, Th1, and Th17 cells to continue the pathogenic cycle. Within the upregulated Th1 and Th17 pathways, cytokines and growth factors such as interleukin(IL)-1, IL-6, IL-12, IL-17, IL-20, IL-23, interferon (IFN)-𝛾, and tumor necrosis factor (TNF)-𝛼 contribute to the immunopathogenesis of psoriasis.6-8
Biologic agents that target TNF-𝛼, IL-12/-23, and IL-17 inhibitors are highly efficacious in the treatment of psoriasis. However, biologic use may be challenging in elderly patients due to the risk of adverse events (AEs) and comorbidities. While ustekinumab demonstrates adequate efficacy and safety profiles in elderly patients, infliximab and adalimumab have increased risk of severe infections.9-12 Additionally, current guidelines advise to exercise caution in using biologics in patients with a history of cancer and to avoid the use of TNF-𝛼 inhibitors in patients with concomitant heart failure.13 Access to biologics remains a challenge for many elderly patients because of limited insurance coverage, prohibitive costs, and other factors.14 These hurdles and patients’ preferences create a need for other agents, such as small molecule inhibitors, in treating elderly psoriasis patients.
While biologic agents neutralize cytokines or cytokine receptors, small molecule inhibitors block intracellular targets such as transcriptional factors or enzymes. The small molecule inhibitors being studied in the treatment of psoriasis include the phosphodiesterase (PDE)-4 inhibitor apremilast and the Janus kinase (JAK) inhibitors tofacitinib, ruxolitinib, baricitinib, and peficitinib (Table 1).15 JAK is a family of tyrosine kinases that transduce cytokine-mediated signals. A number of psoriasis-related cytokines utilize the JAK-STAT pathway.16
In general, small molecule inhibitors are efficacious and have a favorable side effect profile; however, efficacy and safety data in elderly patients is scarce. Management of elderly psoriasis patients with systemic medications may be challenging because of comorbidities, immune system impairment, drug interactions, and dose adjustments.17 We aim to review the pharmacotherapy options for psoriasis in the elderly population, emphasizing small molecule medications.

2. Methods

Pubmed, Embase, and Google Scholar databases were used to search for literature published in English between 2000 to 2017 pertaining to elderly patients with psoriasis. Keywords included ‘psoriasis’, ‘elderly’, ‘geriatric population’, ‘small molecule inhibitors’, ‘apremilast’, ‘tofacitinib’, ‘ruxolitinib’, ‘baricitinib’, and ‘peficitinib’. The phase 2 and phase 3 clinical trials of treatment types were investigated. Treatment types were also combined with the keywords ‘geriatric’ and ‘elderly’. Article abstracts were reviewed for relevance to the subject matter. Articles included in the review discussed small molecule inhibitors as well as their use in the elderly, including safety profiles and/or adverse effects.

3. Phosphodiesterase-4 Inhibitor

3.1 Apremilast

Apremilast is an oral small molecule inhibitor that was approved by the US FDA in 2014 for the management of both psoriasis and psoriatic arthritis (PsA). Apremilast inhibits PDE-4, which consequently increases the intracellular levels of cAMP, thereby reducing secretion of inflammatory cytokines such as TNF-α, interferon-γ, IL-2, IL-12, and IL-23, and increasing production of anti- inflammatory cytokines, such as IL-6 and IL-10.18,19

3.1.1 Efficacy

Two multi-center, randomized, double-blind, placebo-controlled phase III trials investigated the efficacy and safety of apremilast in subjects with moderate-to-severe plaque psoriasis.20,21 The primary end point was the proportion of subjects who achieved a 75% reduction in Psoriasis Area and Severity Index score (PASI 75) at week 16. In both trials, significantly more subjects in the apremilast 30 mg twice daily (BID) group achieved PASI 75 compared to placebo at week 16 (33.1% versus 5.3%; p<0.0001, and 28.8% versus 5.8%; p <0.001). After 16 weeks, the mean change in PASI score from baseline was −52.1% versus −16.7% in apremilast and placebo groups, respectively (p <0.0001). The improvement in PASI was retained over 52 weeks in responders.20 In a phase III randomized controlled trial comparing apremilast 20 mg BID, apremilast 30 mg BID, and placebo in the management of PsA, 20% improvement in the modified American College of Rheumatology criteria (ACR20) at week 16 was achieved in 31% and 40% of subjects in the apremilast 20 mg BID and 30 mg BID groups respectively, compared to 19% of subjects in the placebo group (p<0.001).22 3.1.2 Safety Phase III clinical trials confirmed the safety and tolerability of apremilast. In these studies, adverse reactions were mostly mild-to-moderate in severity adverse reactions were mostly mild-to-moderate in severity, and the incidence of serious AEs was similar in placebo and treatment arms. The most frequent AEs were diarrhea (17.8%), nausea (16.6%), and upper respiratory tract infections (8.4%). Incidence of major adverse cardiac events, serious infections, opportunistic infections, and malignancies in the phase III clinical trials were comparable to placebo.23 No reactivations of tuberculosis were noted. There was no evidence to suggest that apremilast increases the risk of psychiatric events, including suicidality. There were no significant laboratory test abnormalities in apremilast and placebo groups.22,23 During weeks 0-16, 13.7% of subjects receiving apremilast experienced weight loss compared to 5.5% of subjects in the placebo group. Over 52 weeks of treatment, 19.2% of subjects receiving apremilast experienced weight loss, with a mean change from baseline weight of −1.99 kg. Weight loss was not associated with any medical issues, such as diarrhea, nausea, or vomiting.24 3.1.3 Tolerability Apremilast was generally well tolerated in subjects with psoriasis or active PsA. The incidence of diarrhea and nausea was higher during the first 2 weeks of treatment but typically resolved within 4 weeks. Discontinuations due to AEs, mainly due to diarrhea and nausea, occurred in 6.1% and 4.1% of patients receiving apremilast and placebo, respectively, during weeks 0–16 and did not increase with longer apremilast exposure. Long-term safety data up to 52 weeks of apremilast treatment did not show a higher incidence of AEs. Apremilast demonstrated an acceptable safety profile and was well tolerated for up to 104 weeks of treatment.23 3.1.4 Use in Elderly Populations In the phase III clinical trials evaluating the use of apremilast in psoriasis patients, 108 of the 1257 subjects enrolled were 65 years of age and older. No overall differences were observed in the efficacy and safety in elderly subjects ≥ 65 years of age and younger adult subjects in the clinical trials.20,21,25 Of the 1493 subjects enrolled in the clinical trials investigating apremilast in the management of PsA, a total of 146 psoriatic arthritis subjects were 65 years of age and older. No overall differences were observed in the safety profile of elderly subjects ≥65 years of age and younger adult subjects in the clinical studies.25-28 Given the favorable safety profile, apremilast is a generally safe drug for elderly patients. While apremilast has few drug interactions, CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin may decrease the serum concentration of apremilast.29 Apremilast is efficacious for both psoriasis and PsA, portends no increased risk of tuberculosis, requires no laboratory monitoring, is administered orally, and may lead to weight loss—a side effect which may be valuable to patients. The long-term safety and efficacy of apremilast must be further investigated. It remains to be seen whether there is reduced immunosuppression associated with apremilast compared with biologic agents. If there is reduced immunosuppression, apremilast may be an attractive option for elderly psoriasis patients given their increased risk of infection. 4. JAK inhibitors 4.1 Tofacitinib Tofacitinib is an oral JAK inhibitor that preferentially inhibits JAK-1 and JAK-3, although it is active on all the JAK isoforms currently approved by the FDA for the treatment of RA. By inhibiting JAK signaling, tofacitinib prevents cytokine- or growth factor-mediated gene expression and intracellular activity of immune cells.30 Tofacitinib 5 and 10 mg BID was efficacious and safe in patients with moderate-to- severe rheumatoid arthritis (RA) in studies of up to 24 months’ duration.31 Currently, tofacitinib is undergoing Phase III trials for the treatment of plaque psoriasis. 4.1.1 Efficacy In a phase III randomized clinical trial, adults with moderate-to-severe psoriasis were assigned to treatment with tofacitinib 10 mg BID, tofacitinib 5 mg tofacitinib, etancerept 50 mg twice weekly, or placebo. At week 12, 63.6% of subjects in the tofacitinib 10 mg BID achieved PASI 75 compared to 39.5% in tofacitinib 5 mg BID, 58.8% in the etanercept group, and 5.6% in the placebo group. Tofacitinib 10 mg BID was superior to placebo and non-inferior to etanercept.32 Two additional phase III trials demonstrated efficacy of tofacitinib 10 mg BID compared to tofacitinib 5 mg BID and placebo in plaque psoriasis. In both clinical trials, subjects on tofacitinib achieved higher PASI 75 rates compared to those on placebo at week 16. In the first clinical trial, PASI 75 was achieved by 39.9%, 59.2%, and 6.2% of patients on tofacitinib 5 mg, tofacitinib 10 mg, and placebo, respectively. In the second clinical trial, PASI 75 was achieved by 46%, 59.6%, and 11.4% of patients on tofacitinib 5mg, tofacitinib 10 mg, and placebo, respectively.33 Efficacy was maintained in most patients through 24 months, with tofacitinib 10 mg providing greater efficacy than tofacitinib 5 mg.34 4.1.2 Safety In the clinical trials investigating tofacitinib treatment for plaque psoriasis, the rate of AEs and rates of discontinuation were similar across tofacitinib and placebo groups. Most AEs were mild-to-moderate, with the most common being nasopharyngitis and upper respiratory tract infection. However, in results from two phase III trials, 12 patients out of the 1486 patients treated with tofacitinib reported herpes zoster compared to none in the placebo groups.33 Although a dose-response was observed for serious infection, herpes zoster, and non-melanoma skin cancer, the 95% confidence intervals for each incidence rate overlapped and the incidence rate difference was small between dose groups.34 A recent analysis of phase, 2 phase 3, and long-term extension data demonstrated that tofacitinib is associated with a dose-dependent increased risk of herpes zoster relative to placebo in psoriasis patients. The incidence rate (IR) of herpes zoster was highest in elderly patients (IR 4.14, 95% confidence interval [CI] 2.14-7.23) compared to patients between 45-64 (IR 3.26, 95% CI 2.58-4.06) and those 18-44 (IR 1.64, 95% CI 1.16-2.24).35 Though no cases of tuberculosis were reported in psoriasis patients treated with tofacitinib, tuberculosis cases have been reported in the RA tofacitinib studies.36 Tofacitinib was associated with dose- dependent decreases in mean neutrophil counts and hemoglobin levels, but these changes did not require intervention as the blood counts normalized during the treatment period.37 Increases in mean low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and transaminase levels were also observed in some subjects treated with tofacitinib.38,39 4.1.3 Tolerability Tofacitinib appears to be well tolerated short-term and long-term in most patients.33,34 The rates of serious AEs and discontinuation because of AEs over 52 weeks of treatment with tofacitinib were similar to that of apremilast in psoriasis patients. In long-term exposure studies, 10.1% of patients on tofacitinib experienced serious AEs and 10.7% of patients discontinued because of AEs.34 In psoriasis patients taking tofacitinib, AEs leading to discontinuation include herpes zoster, worsening psoriasis, and liver function test abnormalities.33,40 With the exception of herpes zoster, Comparison of incidence rates between the first 52 weeks’ exposure and total exposure indicated no increased risk of safety events with increased tofacitinib duration.34 4.1.4 Use in Elderly Populations Of the 1859 patients treated with tofacitinib in two phase III trials, 117 were 65 years of age or older. In the tofacitinib 10 mg BID treatment group, an average of 73% of elderly patients achieved PASI 75, compared to 52% of elderly patients on tofacitinib 5 mg BID, and 5% of patients on placebo at week 16. In these studies, elderly patients on tofacitinib appeared to show greater efficacy of treatment compared to younger patients. 73% of patients 65 years or older on tofacitinib 10 mg achieved PASI 75 compared to 60% of patients aged 45-62 years and 57% of patients less than 45 years of age on the same dose. Statistical analysis was not completed to determine whether these differences were significant.33 The use of tofacitinib is elderly psoriasis patients may be complicated by significant drug interactions. Tofacitnib should not be used with TNF-α agents or other disease modifying antirheumatic drugs (DMARDS), which may enhance the adverse or toxic effects of tofacitinib.41 Additionally, tofacitinib may cause hematologic, lipid, and liver function laboratory abnormalities effects. There is increased risk of herpes zoster with tofacitinib treatment in patients older than 65 years old.35,42 The tofacitinib drug insert warns that the frequency of serious infection among patients 65 years of age and older treated with tofacitinib was higher than patients under the age of 65. This has been shown both from clinical trials evaluating tofacitinib in RA patients and in analysis of phase 2, phase 3, and long- term extension data in psoriasis patients.35,43 As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly with tofacitinib.41 Taking these potential AEs into account, use of tofacitinib in elderly psoriasis patients warrants further investigation. 4.2 Ruxolitinib Approved by the FDA for the treatment of myeloproliferative disorders, ruxolitinib has primarily been studied as a topical ointment for the treatment of mild-to-moderate psoriasis. Ruxolitinib inhibits JAK1 and JAK2 pathways by blocking STAT3 phosphorylation, which results in the suppression of pathogenic Th17 cells differentiation.44,45 This leads to decreased production of IL-17, IL-20, and IL-22. Additionally, the suppression of STAT3 phosphorylation reduces IFN-𝛾 expression, which is a potent activator of keratinocyte proinflammatory function.45 4.2.1 Efficacy A phase II study assessed the efficacy of ruxolitinib 0.5%, 1.0%, and 1.5% cream compared to calcipotriene 0.005% cream, betamethasone dipropionate 0.05% cream, and vehicle over a 28-day course.46 The lesions were evaluated by the total lesion score, which was a composite of the target lesion scores for erythema, scaling, and thickness. On day 28, ruxolitinib 1.0% cream once daily and ruxolitinib 1.5% cream BID decreased subject lesion scores by 53% and 54% respectively; this was in comparison to 32% and 32% in the respective vehicle cohorts (p = 0.033; p=0.056). The onset and efficacy of ruxolitinib 1.5% cream BID was comparable to topical calcipotriene and betamethasone dipropionate. In a study assessing the efficacy of ruxolitinib phosphate cream 1.0% daily or 1.5% BID in treatment of psoriasis, both regimens resulted in improvement of lesion scores. Ruxolitinib phosphate 1.5% cream BID decreased the mean baseline scores by 60% after 28 days of treatment.47 In a phase II clinical trial assessing the efficacy of ruxolitinib cream, the 1% cream cohort achieved a mean PASI improvement of 40% compared to 1% in the placebo group over the 3-month study period.48 4.2.2 Safety Serious AEs were rare, but 20% patients treated with ruxolitinib experienced localized irritation. The most common AEs were mild and included stinging, itching, irritation, pain, dryness, exfoliation, and/or redness at the application site. Subjects treated with ruxolitinib ointment had fewer adverse effects than those who received vehicle, calcipotriene, or betamethasone topically.46 Mean plasma concentrations of ruxolitinib, with use of all topical ruxolitinib concentrations, were well below the plasma level determined to be pharmacologically active. This suggests that the topical preparations are unlikely to cause systemic adverse effects.47 4.2.3 Tolerability In clinical trials, application of ruxolitinib was safe and well tolerated, with all patients completing the treatment course.46,47 Although the safety and tolerability profile of ruxolitinib appears promising, these findings cannot confirm ruxolitinib safety with long-term use. Therefore, further studies are needed to determine their long-term safety profile. 4.2.4 Use in Elderly Populations Current studies suggest ruxolitinib is an effective topical therapy with limited systemic absorption. No significant AEs, laboratory, or EKG abnormalities were noted during ruxolitinib clinical trials.46,47 Given its topical administration and limited systemic absorption, it is unlikely that ruxolitinib would have any negative interactions with concomitant medications. 4.3 Baricitinib Baricitinib is not yet FDA approved but is in clinical trials for RA, psoriasis, and atopic dermatitis. Baricitinib is an oral reversible inhibitor of JAK1 and JAK2.15 4.3.1 Efficacy In a phase II, dose ranging, randomized trial assessing the efficacy of baricitinib in the treatment of psoriasis, subjects were treated with daily doses of baricitinib 2, 4, 8, or 10 mg, or placebo over a 12- week study period. At 12 weeks, more patients in the baricitinib 8 and 10 mg groups than those in the placebo group achieved PASI 75 (42.9%, 54.1%, and 16.7%, respectively).49 4.3.2 Safety Serious AEs were uncommon. The percentages of patients who experienced at least one treatment- emergent AE were higher for the 8 mg and 10 mg dose groups compared to placebo (57.8% and 63.8% vs 44.1%, respectively). The most common AE in all groups was nasopharyngitis. No opportunistic infections were reported. Blood and lymphatic system AEs occurred in 6.3% and 8.7% of patients in the 8 mg and 10 mg groups, respectively. Baricitinib treatment was associated with small dose-related decreases in neutrophil count and hemoglobin levels. The combined baricitinib group had a 9.3% incidence of abnormal laboratory results, the most common being an elevation in blood creatine phosphokinase. Small increases in creatinine and high- and low-density lipoprotein were observed with baricitinib treatment.49 4.3.3 Tolerability Overall, 87.8% of patients in the phase II clinical trial completed the first 12 weeks of the study. The highest rate of discontinuation due to lack of efficacy was in the placebo group (8.8%), and the highest rates of discontinuation due to AEs were in the 8 mg and 10 mg groups (6.3% and 5.8%, respectively). The 8 mg group had the most study drug interruptions due to AEs (9.4%).49 4.3.4 Use in the Elderly The treatment associated changes in hematologic parameters and laboratory results suggests that baricitinib may not be tolerated in certain populations. Larger subject size and a longer treatment period are required to better determine the efficacy, safety, and tolerability of baricitinib in elderly psoriasis patients. 4.4 Peficitinib Peficitinib (ASP015K) is an oral JAK inhibitor with moderate selectivity for JAK3 over JAK1. The drug is efficacious in patients with RA. Since peficitinib is a more selective JAK3 inhibitor, it is hypothesized that the drug may have a more favorable efficacy and AE profile than other JAK inhibitors.15 4.4.1 Efficacy In a phase II randomized clinical trial assessing the efficacy of peficitinib 10, 25, 60, and 100 mg versus placebo in the treatment of psoriasis, the mean change in PASI score was higher in the treatment arms than in the placebo arm (-4.2) at week 6. There was a dose-dependent relationship, peficitinib 60 mg BID (-8.3, p<0.001) and 100 mg BID groups (-11.9, p<0.001) had the highest mean changes in PASI score. PASI 75 was achieved at week 6 in 31.6% of subjects in the peficitinib 10 mg BID group (p<0.05), 26.3% of subjects in the peficitinib 60 mg BID group (p<0.05), and 58.8% of subjects in the peficitinib 100 mg BID group (p<0.001), compared with 3.4% of subjects in the placebo group.50 4.4.2 Safety Overall, 46.3% of subjects who received peficitinib experienced a mild or moderate AE compared with 37.9% of subjects on placebo. There were no serious AEs. The most common AEs were nasopharyngitis and diarrhea, occurring in 5.2% and 3.1% of subjects who received peficitinib versus 10.3% and 6.9% of patients on placebo.50 4.4.3 Tolerability Seven subjects discontinued the study, three subjects experiencing drug-related AEs including neutropenia, stomach discomfort, and vomiting. The discontinuation rate was higher in the peficitinib 60 mg BID (10.5%) and 100 mg BID groups (17.6%) than in the placebo group (3.4%).50 4.4.4 Use in the Elderly Peficitinib is a promising treatment for elderly psoriasis patients because it is generally well tolerated with no serious AEs. In data pooled from other peficitinib studies pertaining to psoriasis and rheumatoid arthritis treatment 443 subjects received peficitinib and 77 received placebo. No deaths or serious AEs were reported during treatment with either peficitinib or placebo. The most common AEs were mild and consisted of nasopharyngitis, diarrhea, and acne. Though decreased neutrophil count was reported in some patients, the rate was low.51 Larger prospective trials are required with an extended treatment period before clinically useful conclusions can be drawn. 5. Conclusion The management of psoriasis in the elderly is complicated by comorbidities, polypharmacy, and potential drug interactions. The first-line therapy for the elderly patients with mild-to-moderate psoriasis is topical agents. Although these agents have minimal systemic effects, elderly patients may be at higher risk of steroid-induced AEs, such as atrophy, purpura, and telangiectasias.52 For moderate-to- severe psoriasis, the choice between systemic and biologic treatments can be difficult. Physicians hesitate to use traditional systemic agents such as cyclosporine, acitretin, or methotrexate due to complications including hypertension, increased lipid levels, or reduced renal and hepatic function.2-4,53 While biologics show clear efficacy in elderly patients, safety and tolerability profiles remain controversial. While some studies show comparable rates of AEs between elderly and non-elderly patients using biologics, others have shown increased rates of AEs between elderly and non-elderly patients, specifically with regard to infection risk.9,10,54,55 Elderly patients should be treated with biologics when required, however the potential for increased AEs calls for periodic patient monitoring.56 Small molecule inhibitors such as apremilast, ruxolitinib, and peficitinib are effective agents with favorable side effect profiles. However, physicians should exercise caution in using tofacitinib or baricitinib in elderly populations due to AEs such as increased risk of infection, herpes zoster, neutropenia, and abnormal laboratory results. Elderly patients receiving these agents should be monitored closely. Small molecules represent a promising treatment option for elderly patients that are preferable to traditional systemic drugs such as methotrexate, cyclosporine, and acitretin due to more favorable safety profiles. Biologics appear to demonstrate better efficacy than small molecule inhibitors, although more head-to-head trials are necessary. The ease of administration and lower cost compared to biologics may make small molecule inhibitors attractive to elderly patients. Further investigations are required to compare safety and tolerability profiles between biologics and small molecule inhibitors. Limited data was available pertaining to small molecule inhibitor use in the elderly psoriasis population. Subjects aged 65 years and older were typically reported in the context of the whole study population. Too few studies provided results stratified in such a way as to permit making therapeutic conclusions for this specific age group. Therefore, it should be emphasized that the results presented are limited to short term studies and warrant reexamination once clinical trials have been completed. While the use of small molecule inhibitors in elderly patients with psoriasis remains to be comprehensively investigated, it is likely that these agents will become an important part of psoriasis treatment for this patient population. 6. Expert Opinion Although the psoriasis armamentarium continues to expand, a substantial proportion of psoriasis patients do not receive treatment or are undertreated. Reasons for this include poor tolerability, failure to achieve or maintain treatment goals, patient tolerability of administration route, long-term safety concerns, access, medication cost, and reimbursement.58,59 The elderly comprise a substantial portion of these undertreated patients. Physicians may avoid using traditional systemic therapies in older psoriasis patients out of concern for systemic toxicities. Biologic therapies may be used less often in the elderly due to the absence of safety studies in this population.60 Prescription of topical therapies alone may be inadequate and insufficient.53 The advantages of newer small molecule medications over older systemic therapies and biologics include absence of clinically significant organ toxicity, no requirement for nutrient supplementation, and ease of administration. Small molecule agents have become a practical and popular treatment option for elderly patients. Currently, apremilast is the only small molecule medication which is FDA approved for the treatment of psoriasis. Although apremilast is less efficacious than many of the newer biologic agents, it is safe and well tolerated by patients. Due to the wide array of downstream targets which JAK inhibition affects, there was some concern that JAK inhibitors may impair the immune system and hematopoiesis.61,62 Although the safety profiles of tofacitinib and ruxolitinib were acceptable in early phase trials, long-term safety has not been extensively studied.63 It is important to follow the safety profile of medications in clinical trials and in post-marketing registries to ensure long-term medication safety. Safety studies through post-marketing registries are vital tools to evaluate long-term safety and tolerability in specific populations, such as the elderly. Understanding age-associated outcome differences across medication types may aid in the treatment decision-making process. Small molecule medications may become the intermediate step on the psoriasis treatment ladder between traditional oral systemic therapies and biologic medications. They also present an alternative option for patients who have developed anti-drug antibodies or failed treatment on biologics. Apremilast is especially useful in patients with concomitant PsA, nail psoriasis, or psoriatic scalp disease. Another possible role for small molecules may be as concomitant treatments alongside biological agents. Future clinical trials would be needed to determine the efficacy, safety, and tolerability of concomitant usage of small molecule medications and biologics. Although small molecule inhibitors are a promising new addition to psoriasis management strategies, concerns about their high cost may limit their use.64 Small molecule inhibitors may be more affordable than biologics, but they are still more expensive than traditional systemic agents. A recent study compared the efficacy and cost effectiveness of apremilast versus methotrexate.65 In terms of clinical improvement, there was no statistically significant difference between apremilast and methotrexate. However, the annual cost of apremilast was $26,501 compared to $1,920 for methotrexate treatment. Biologics tend to be even more expensive, the cost of ustekinumab 90 mg is estimated to be between $150,060 and $171,072 annually.66 Over 90% of the elderly population in the United States receives medical coverage through the Medicare system.67 Medicare beneficiaries without a low-income subsidy (LIS) under Medicare Part D were 70% less likely to receive biologics than those with LIS that allowed for minimal out-of-pocket drug costs. Patients without LIS faced substantially greater costs for several of the Part D covered biologics.68 Whether similar barriers will exist for small molecule inhibitors remains to be seen. Despite promising clinical trials, the high cost of these drugs in the United States may limit their prescription by cost-conscious dermatologists. As more small molecule medication become available to psoriasis patients, they will require larger head-to-head studies to determine efficacy, safety, and position amongst the range of systemic psoriasis drugs that are currently available. Article Highlights Box • Elderly patients with psoriasis can be difficult to treat due to the presence of comorbidities, polypharmacy, age-related organ impairment, and the limited data available pertaining to systemic treatments. • The use of traditional systemic medications is restricted by renal and hepatic toxicities, while biologics may be limited by the patient comorbidities, increased risk of infections, cost, and method of administration. • While small molecule inhibitors are promising new treatment options that offer few side effects, affordable cost, and easy administration, only apremilast is currently FDA approved for use in psoriasis patients. • Apremilast, ruxolitinib, and peficitinib may have favorable side effect profiles in elderly patients, but the use of tofacitinib or baricitinib in elderly populations should be monitored due to adverse events such as increased risk of herpes zoster, abnormal lab values, and infections.
• Small molecule inhibitors may demonstrate efficacy in elderly patients with psoriasis, but larger head-to-head studies and post-marketing registries are required to evaluate long-term efficacy, safety, and tolerability in specific patient populations.

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Papers of special note have been highlighted as:
* of interest
** of considerable interest

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