Response of palmoplantar pustulosis to upadacitinib: A case series of five patients

Dear Editors, Palmoplantar pustulosis (PPP) is a rare, chronic inflammatory skin disease with an estimated prevalence of 0.01 % to 0.05 %,1 characterized by sterile pustules, erythema, and hyperkeratosis on the palms and soles.2 Recently, the first case of a successful therapy with the Janus kinase inhibitor (JAKi) upadacitinib in PPP was published in your journal.3 Here, we report on five additional patients with PPP treated with upadacitinib (Tables 1, 2). Case 1 is a 73-year-old female ex-smoker (BMI 31.6) who developed PPP and mild plaque-type psoriasis 8 years ago. Previous systemic therapies of PPP had to be discontinued due to ineffectiveness. Then tofacitinib 5 mg twice daily combined with methotrexate 2.5 mg/week resulted in a significant improvement of the Palmoplantar Pustulosis Area and Severity Index (PPPASI) from 18.6 to 1.8 at week 12. After 12 months of therapy, methotrexate was discontinued and one month later, tofacitinib was switched to upadacitinib (in off-label use) because of a Direct Healthcare Professional Communication that was received at that time reporting an increased risk of serious adverse events with the use of tofacitinib compared with TNF-alpha inhibitors. Upadacitinib was chosen because it is a more selective JAKi and arguably has a better risk profile compared with tofacitinib.4 The PPPASI was 3.6 and the Psoriasis Area and Severity Index (PASI) was 0 (excluding hands and feet) at the time of switching from tofacitinib to upadacitinib, and the good therapeutic effect reached under tofacitinib remained stable under upadacitinib (Figure 1a, b). Case 2 is a 59-year-old female never-smoker (BMI 29.8) in whom PPP and nail psoriasis manifested five years earlier. Previous systemic therapies of PPP, most recently guselkumab, had to be discontinued due to insufficient therapeutic response. Under upadacitinib, PPPASI decreased from 19.2 to 1.8 within 6 weeks (Figure 1c, d). Concomitant psoriatic arthritis and nail psoriasis also improved under therapy. Case 3 is a 60-year-old female smoker (BMI 22.3) who was diagnosed with PPP 26 years ago. Apremilast, her systemic therapy for PPP, was switched to upadacitinib (in off-label use) due to side effects and an insufficient therapeutic response. Nine weeks later PPPASI had decreased from 10.5 to 4.0 (Figure 1e, f). In addition, her concomitant urticaria that had first manifested 10 years ago and had been treated with omalizumab for the previous 2.5 years improved under upadacitinib therapy, allowing omalizumab administration to be discontinued. As adverse events, a cystitis that was treated with antibiotics and a bronchitis occurred. Case 4 is a 56-year-old male smoker (BMI 34.3) who developed psoriatic arthritis and moderate PPP 1.5 years ago (Figure 1g). Previous systemic therapies included methotrexate, which improved PPP but was switched to guselkumab due to lack of efficacy on joint symptoms. Guselkumab also showed a good effect on PPP but also failed to control joint symptoms. Guselkumab therapy was switched to upadacitinib. The PPPASI was 4.8 when upadacitinib was initiated and dropped to 0.6 after 6 weeks of therapy (Figure 1h). Joint pain also decreased, while morning stiffness persisted. Case 5 is 59-year-old female never-smoker (BMI 24.1) in whom PPP had manifested 9 years earlier with a history of psoriatic arthritis. Previous systemic therapies were discontinued due to side effects or inefficacy. After a two-year interval without systemic therapy, therapy with upadacitinib was initiated. After three months of therapy, PPPASI decreased from 9.6 to 6.0. In this case series of five PPP patients, an average of 5.2 systemic therapies were used before upadacitinib therapy. In patient 1, good control by tofacitinib was maintained after switching to upadacitinib, in patient 2 and 3 there was a very good therapeutic response of PPP under upadacitinib, in patient 4, after a partial effect of guselkumab, PPP almost cleared after switching to upadacitinib, and in patient 5 there was only a moderate improvement of PPP. Thus, overall, this case series suggests a good effect of upadacitinib on PPP. JAKi are receptor-associated tyrosine kinases which transduce intracellular signals of type I and type II cytokine receptors.5-7 JAKi can be classified into different isotypes depending on their selectivity and thus contribute to a variety of effects.5-7 To date, there are only small case series and few case reports on the therapy of PPP with tofacitinib, a JAKi that primarily inhibits JAK1 and JAK3,8-12 and one case report on the successful therapy of PPP with upadacitinib.3 These, together with the cases reported here, suggest that upadacitinib may be a promising therapeutic option for PPP. Future studies are warranted to further investigate the role of JAKi in PPP. Open access funding enabled and organized by Projekt DEAL. R. Mössner has been an advisor and/or received speakers' honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbvie, Allmirall, Biogen IDEC GmbH, Böhringer-Ingelheim, Celgene, Janssen-Cilag GmbH, Leo Pharma GmbH, Lilly, MSD SHARP & DOHME GmbH, Novartis Pharma GmbH, Pfizer GmbH and UCB. J. Mohr has been an advisor and/or received grants and/or participated in clinical trials of the following companies: Abbvie, Allmirall, Biogen IDEC GmbH, Böhringer-Ingelheim, Celgene, Janssen-Cilag GmbH, Leo Pharma GmbH, Lilly, MSD SHARP & DOHME GmbH, Novartis Pharma GmbH, Pfizer GmbH and UCB. A. Tsianakas has been advisor and / or received speakers' honoraria or travel expense reimbursements and / or participated in clinical trials of the companies: AbbVie, Almirall, Amgen, Beiersdorf, Biogen, Boehringer Ingelheim Pharma, Celgene, Hoffmann-La Roche, Janssen-Cilag, Leo, Lilly, Novartis, Pfizer, Sanofi-Aventis, UCB Pharma. D. Wilsmann-Theis has been advisor and/ or received speakers' honoraria or travel expense reimbursements and/ or received grants and/ or participated in clinical trials of the companies: Abbvie, Almirall-Hermal, Amgen, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Forward Pharma, GlaxoSmithKline, Incyte, Janssen-Cilag, Klinge Pharma, Leo, Eli Lilly, Medac, Merck, Novartis, Pfizer and UCB. K. Kohl and N. Rahbar Kooybaran report no conflicts of interest.