Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis

Abstract

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).

Figures

Figure 1.. Clinical Remission of Sarcoidosis with Tofacitinib Therapy.

Panel A shows photographs of skin disease before treatment and during treatment. The before-treatment sample was obtained from the circled area. Skin-lesion samples that were obtained during treatment were obtained after 10 months of therapy. Panel B shows the time course of tofacitinib therapy. The clinical response with therapy and the clinical worsening when the patient was not receiving therapy are indicated by the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) score for disease activity. The CSAMI was used to gauge the severity of cutaneous sarcoidosis; scores range from 0 to 165 for disease activity, with higher scores indicating greater disease activity. Although the disease activity score extends to 165, the patient’s maximum disease activity score never exceeded 85; hence the y axis for this graph extends only to 100.

Figure 2.. Histologic Remission of Sarcoidosis with Tofacitinib Therapy.

Shown are the results of immunohistochemical testing of skin-lesion samples obtained before and during treatment. Hematoxylin and eosin staining on the sample obtained before treatment showed well-organized, noncaseating granulomas and mild patchy lymphocytic inflammation in the dermis — findings that are typical of sarcoidosis. Staining was also performed with CD68, phosphorylated signal transducer and activator of transcription (STAT) 1 (pSTAT1), and phosphorylated STAT3 (pSTAT3).

Figure 3.. Levels of pSTAT1 and pSTAT3 in Skin-Lesion Samples from Patients with Cutaneous Sarcoidosis, Xanthelasma, or Normal Skin.

The immunohistochemical test score represents the percentage of the tissue area that was stained positively for the marker (pSTAT1 in Panel A and pSTAT3 in Panel B). Each black dot represents the score for one 100× microscopic field from each skin-lesion sample (three fields quantified per sample). The bar graph shows the mean score, and I bars the standard deviation.