Pilot, open-label, single-arm clinical trial evaluating the efficacy of topical crisaborole for steroid refractory morphea

Morphea, or localized scleroderma, is characterized by skin and soft tissue inflammation and sclerosis. Systemic phosphodiesterase-4 inhibitors demonstrated antifibrotic effects in mouse models.1Maier C. Ramming A. Bergmann C. et al.Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages.Ann Rheum Dis. 2017; 76: 1133-1141https://doi.org/10.1136/annrheumdis-2016-210189Crossref PubMed Scopus (55) Google Scholar Crisaborole, which is a topical phosphodiesterase-4 inhibitor, is Food and Drug Administration–approved for mild-to-moderate atopic dermatitis in patients aged ≥2 years.2Paller A.S. Tom W.L. Lebwohl M.G. et al.Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.J Am Acad Dermatol. 2016; 75: 494-503.e6https://doi.org/10.1016/j.jaad.2016.05.046Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar We aimed to study the efficacy of topical crisaborole 2% ointment for morphea. We conducted a single-arm, open-label, pilot study and treated 7 adult patients with active morphea involving <20% total body surface area between September 2018 and March 2020. The study was approved by the Duke University Institutional Review Board, and all patients gave written informed consent. All patients received crisaborole 2% ointment and applied twice daily for 12 weeks on all active plaques. A 4-mm punch biopsy analysis was performed at baseline and at 12 weeks on a sentinel plaque (a site with most severe disease) (Supplementary Methods, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1). Blinded histologic assessment was performed by an experienced dermatopathologist. The sentinel plaque was evaluated using the Dyspigmentation, Induration, Erythema, and Telangiectasias score.3Dytoc M. Wat H. Cheung-Lee M. Sawyer D. Ackerman T. Fiorillo L. Evaluation of the efficacy and safety of topical imiquimod 5% for plaque-type morphea: a multicenter, prospective, vehicle-controlled trial.J Cutan Med Surg. 2015; 19: 132-139https://doi.org/10.2310/7750.2014.14072Crossref Scopus (20) Google Scholar Disease severity was evaluated using the Localized Scleroderma Cutaneous Assessment Tool.4Condie D. Grabell D. Jacobe H. Comparison of outcomes in adults with pediatric-onset morphea and those with adult-onset morphea: a cross-sectional study from the morphea in adults and children cohort.Arthritis Rheumatol. 2014; 66: 3496-3504https://doi.org/10.1002/art.38853Crossref PubMed Scopus (52) Google Scholar Health-related quality of life was measured using Skindex-29.5Chren M.M. Lasek R.J. Flocke S.A. Zyzanski S.J. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases.Arch Dermatol. 1997; 133: 1433-1440Crossref PubMed Google Scholar Changes in dermal thickness and clinical feature scores at 12 weeks compared with baseline were assessed using paired t tests, and differences were considered statistically significant if the P value was <.05. Statistical analysis was performed using JMP (SAS Institute Inc). Additional methodology is available (Supplementary Methods, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1). The study was designed to detect a 30% reduction in dermal thickness with at least 11 patients but was concluded prior to achieving our target sample size due to COVID-19–related restrictions. Eight patients were enrolled in the study. One was lost to follow up due to scheduling conflicts. Seven female patients with median age of 51 (IQR, 33, 66) years and median disease duration of 46 (IQR, 15, 92) months completed the study (Table I). All patients had failed topical steroid therapy, and 4 of 7 were still on long-term stable doses of systemic medications (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1).Table IPatient characteristicsBaseline characteristicsMean n, (SD)Median n, (Q1, Q3)RangeAge (y)53.3 (17.4)51 (33, 66)31-78Body surface area (m2)11.1 (3.7)12 (8, 15)5-15Dermal thickness (mm)2.8 (1.4)2.7 (1.7, 4.3)1-5DIET5.9 (1.3)6 (5, 7)4-8mLoSSI19.0 (12.4)24 (6, 32)5-34LoSDI23.0 (12.9)18 (13, 29)12-48Skindex 29 symptoms17.0 (6.5)17 (12, 21)7-27Skindex 29 functions25.6 (12.9)26 (14, 35)12-47Skindex 29 emotions29.1 (12.0)27 (19, 38)13-47Duration of disease (mo)51.7 (37.3)46 (15, 92)12-93Subtypes of morphea, n (%)Plaque morphea4 (57.1)Linear morphea1 (14.3)Generalized morphea2 (28.6)Treatments failed or with incomplete response, other than topical therapy∗Of the 7 patients, 3 patients were not on any systemic medications and 4 patients were on stable doses of systemic medication for at least 5 months with no improvement in symptoms before crisaborole was started (Supplementary Table I and Supplementary Methods, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1). All topical therapy was discontinued at least 2 weeks prior to starting treatment., n (%)Prednisone1 (14.2)Methotrexate2 (28.6)Hydroxychloroquine4 (57.1)NBUVB2 (28.6)DIET, Dyspigmentation, Induration, Erythema, and Telangiectasias; mLoSSI, modified Localized Scleroderma Skin Severity Index.∗ Of the 7 patients, 3 patients were not on any systemic medications and 4 patients were on stable doses of systemic medication for at least 5 months with no improvement in symptoms before crisaborole was started (Supplementary Table I and Supplementary Methods, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1). All topical therapy was discontinued at least 2 weeks prior to starting treatment. Open table in a new tab DIET, Dyspigmentation, Induration, Erythema, and Telangiectasias; mLoSSI, modified Localized Scleroderma Skin Severity Index. Although no statistical significance was observed in the 35% reduction in average histologic dermal thickness (P = .175), reduction in histologic dermal fibrosis was seen in 5 of 7 patients as a spontaneous observation by a dermatopathologist (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/p7t4d94zzh/1). Six of 7 patients had a clinical reduction in the size and induration of the sentinel plaque. We observed improvements in both physician- and patient-reported outcome measures, including reductions in the following: (1) Dyspigmentation, Induration, Erythema, and Telangiectasias score by an average of 32.8% (P = .015); (2) modified Localized Scleroderma Skin Severity Index component of Localized Scleroderma Cutaneous Assessment Tool by an average of 63.2% (P = .014); and (3) Skindex-29 emotion score by an average of 29.2% (P = .008). No statistically significant difference was observed in the Skindex-29 symptoms or function scores (Fig 1). In summary, we found that crisaborole 2% ointment showed promising trends in improvement for morphea, even among patients who had long-standing disease and failed other therapies. This study is limited by the small sample size, lack of a placebo arm, and short evaluation time. Larger, prospective, placebo-controlled studies are needed before the results can be applied widely. Dr Cardones was the recipient of the study grant from Pfizer, which was used to fund this study. Authors Petty, Emge, Blanchard, Selim, Scoggins, Liu, and Green have no conflicts of interest to declare.