Apremilast in Combination With an Interleukin 17A Inhibitor in the Treatment of Recalcitrant Palmoplantar Psoriasis

Introduction

Palmoplantar psoriasis (PPP) is a chronic, immune-mediated, inflammatory disorder affecting the palms and soles. As PPP is disproportionately associated with higher functional impairment and pain, ¹ the National Psoriasis Foundation classifies it as severe despite the smaller body surface area (BSA) it covers in comparison to psoriasis vulgaris. ²

Marked improvement in patient outcomes is seen with the use of systemic biologic therapy for plaque psoriasis, such as with the anti-interleukin 17A (IL-17A) antibodies secukinumab ³ and ixekizumab. ³ In ESTEEM 1 and 2, the phosphodiesterase-4 (PDE-4) inhibitor apremilast was shown to demonstrate efficacy in plaque psoriasis. ⁴ Despite the power of these treatments to improve patients with plaque psoriasis, the same effectiveness does not necessarily carry over to patients with PPP.

In a prospective trial evaluating secukinumab for PPP, 33.2% of patients achieved a Palmoplantar Investigator Global Assessment (ppIGA) of 0 or 1 corresponding to clear or almost clear compared to 1.5% of patients on placebo. ⁵ In a prospective trial evaluating apremilast for PPP, 14% of patients achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 compared to 4% of patients on placebo and failed to meet the trial’s primary end point. ⁶

The disabling nature of PPP and the difficulty to treat this condition warrant further search for alternative therapeutic options. In this retrospective case series, we present patients diagnosed with PPP at Tufts Medical Center who were recalcitrant to treatment and then underwent anti-IL-17A and apremilast combination therapy.

Methods

The study was approved by institutional review board of Tufts Medical Center on August 22, 2017. We performed a retrospective review of patients seen in Tufts Medical Center’s dermatology outpatient clinic who met the criteria of being diagnosed with PPP without pustules and received an anti-IL-17A concurrently with apremilast for a period of no less than 12 weeks. Data collected included patients’ age, gender, diagnosis, current and previous treatments, BSA, and PPPGA. Four patients who met the criteria were included in the study, and descriptive analysis was performed due to the small sample size.

Palmoplantar psoriasis was measured using a 5-point PPPGA scale. It is based on the ppIGA scale used in GESTURE, a prospective trial evaluating secukinumab for PPP. Applied only to the palms and soles, the scale is as follows: 0 = clear: no signs of psoriasis, postinflammatory hyperpigmentation may be present; 1 = almost clear: no thickening, normal to pink coloration, no to minimal focal scaling; 2 = mild: just detectable to mild thickening, pink to light red coloration, predominantly fine scaling; 3 = moderate: clearly distinguishable to moderate thickening, dull to bright red, clearly distinguishable to moderate thickening, moderate scaling; 4 = severe: severe thickening with hard edges, bright to deep dark red coloration, severe/coarse scaling covering almost or all lesions. ^5,7

Results

Of the 4 patients, 2 were females and 2 were males. Their ages ranged from 32 to 60 with a mean age of 43. All 4 patients had failed ixekizumab or secukinumab prior to initiating combination therapy with apremilast except one, who was still significantly impacted by his disease despite having a PPPGA of 1 and being on adalimumab, methotrexate, and acitretin. He was switched directly to methotrexate, ixekizumab, and apremilast. All 4 patients had plantar involvement, with 2 patients having additional palmar involvement.

Patients 1, 2, and 3 had PPPGAs of 2, 4, and 2 at baseline, respectively. All 3 patients had a PPPGA of 3 while on an anti-IL-17A prior to initiating combination apremilast and anti-IL-17A therapy. Their PPPGAs were 1, 1, and 0 after combination therapy, respectively. Patient 4 had a PPPGA of 1 while on adalimumab 40 mg weekly, methotrexate 37.5 mg weekly, and acitretin 35 mg daily and a PPPGA of 0 after switching treatment to methotrexate 25 mg weekly, ixekizumab, and apremilast. The combination of apremilast and anti-IL17A biologics was well tolerated by the 4 patients. All 4 patients achieved a PPPGA of 0/1 (Table 1 and Figure 1).

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Table 1.

Patient Demographics, Course of Treatment, Side Effects, and Previous Systemic Medications.

	Patient 1	Patient 2	Patient 3	Patient 4
Gender	Female	Female	Male	Male
Age	60	48	33	32
Smoking status	Nonsmoker	Smoker	Nonsmoker	Nonsmoker
Psoriatic arthritis	Yes	No	No	Yes
PPPGA (baseline)	2	4	2	1a
IL-17A inhibitor	Secukinumab	Ixekizumab	Secukinumabb	NA
PPPGA	3	3	3	NA
Discontinuation reason	Primary failure	Primary failure	Secondary failure	NA
Combination	Ixekizumab and apremilast	Ixekizumab and apremilast	Ixekizumab and apremilast	Ixekizumab and apremilast and methotrexate
PPPGA	1	1	0	0
Duration	4 months	7 months	4 months	8 months
Side effects	Folliculitis, Transient nausea and diarrhea	None	None	None
Prior systemic medications	Infliximab, etanercept, adalimumab, acitretin, PUVA, methotrexate, ustekinumab, certolizumab	Ustekinumab, PUVA, cyclosporine, adalimumab, acitretin	Acitretin, cyclosporine	Adalimumab, acitretin

Abbreviations: PUVA, psoralen and ultraviolet A; IL-17A, interleukin 17A; NA, not applicable; PPPGA, Palmoplantar Physician Global Assessment.

^aPatient 4 was on adalimumab 40 mg subcutaneously (SC) and methotrexate 37.5 mg weekly and acitretin 35 mg daily prior to initiation of ixekizumab, apremilast, and methotrexate therapy.

^bPatient 3 was on acitretin throughout data capture.

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Figure 1.

Palmoplantar Physician Global Assessment (PPPGA) improvement.

Discussion

Although IL-17A has been identified as a main perpetrator in psoriasis pathogenesis, ⁸ a subset of patients fail to achieve satisfactory results despite highly targeted antagonism of IL-17A. In a propsective double-blind, randomized controlled trial, 33.2% of participants on secukinumab 300 mg achieved ppIGA of 0 or 1 compared to 1.5% on placebo. ⁵ A prospective double-blind, placebo-controlled, randomized study of apremilast in PPP failed to show a difference in achieving a PPPGA score of 0 or 1 compared to placebo. ⁶ In comparison, there tends to be greater responses in plaque psoriasis than in PPP with anti-IL17As and the PDE-4 inhibitor apremilast. ^{2 -4}

In our retrospective review, all 4 patients who were treated with combination apremilast and anti-IL17A therapy achieved a PPPGA of 0 or 1. The medicine was well tolerated, and no serious adverse events were noted. Two of the 4 patients were also switched from secukinumab to ixekizumab at the time of starting apremilast. It is a possibility that switching the class of anti-IL17A also had an impact on improving their recalcitrant disease. Although it is a relative contraindication to combine biologics, there are other studies that evaluated combining apremilast and methotrexate with other systemic treatments. A chart review of 81 patients with chronic plaque psoriasis who were treated with apremilast in combination with at least 1 systemic or biologic agent demonstrated an efficacy of 81% PASI-75 and a favorable safety profile (25% transient nausea/diarrhea, 15% weight loss). ⁹

Bissonnette et al biopsied lesions from patients with palmoplantar pustular psoriasis, nonpustular palmoplantar psoriasis (NPPPP), and plaque psoriasis. Interestingly, patients with NPPPP had significantly lower IL-17 messenger RNA (mRNA) levels than its counterparts, while IL-23 subunits’ mRNA levels were similar across lesions. ¹⁰ As increasing the dose of anti-IL17 biologics will not always lead to complete clearance of psoriasis lesions, we hypothesize that there is involvement of multiple pathways in the subset of patients with PPP who are resistant to treatment with a single agent. The higher incidence of PPP in anti-TNF-induced psoriasis also provides evidence that additional pathways besides TH17 may be involved, particularly with PPP. ¹¹

The failure of current psoriasis therapies to always achieve satisfactory results in patients with PPP ^5,6 prompts investigation for further treatment options. The enhanced efficacy that may be observed when concurrently adding apremilast to IL-17A inhibitors may provide an additional way for the dermatologist to help patients who suffer with PPP. Further research is needed to better understand how PPP differs from plaque psoriasis and how to best treat these patients.

Limitations

Limitations include small sample size, retrospective nature of the study, and high cost of treatment.