Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare

Abstract

Background: Sarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.

Objective: To evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.

Methods: A prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.

Results: Tofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA.

Limitations: The study is limited by the small number of participants.

Conclusions: Tofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.

Keywords: JAK inhibitor; JAK-STAT; granuloma annulare; sarcoidosis; tofacitinib.

Fig 1.

Clinical and histologic response to tofacitinib treatment in sarcoidosis and GA. A, Patient characteristics and change in CSAMI activity (sarcoidosis) or GASI (GA) clinical severity scores while receiving tofacitinib therapy. Square box shows that biopsy and/or blood was obtained. More detailed information can be found in Supplemental Table V. B, Clinical photographs. C, Hematoxylin-eosin staining of skin biopsy specimens and IHC in patient 2 with sarcoidosis. D, Quantification of IHC staining in patients with sarcoidosis (patients 1 and 2); bars represent mean and standard error of the mean. E, Hematoxylin-eosin staining of skin biopsy specimens and IHC in patient 4 with GA. F, Quantification of IHC staining in GA (patient 4); bars represent mean and standard error of the mean. cont, continued; CSAMI, Cutaneous Sarcoidosis Activity and Morphology Instrument; GA, granuloma annulare; GASI, Granuloma Annulare Scoring Index; H&E, hematoxylin-eosin; IHC, immunohistochemistry; On-Tx, levels after clinical response observed; pSTAT, phosphorylated signal transducer and activator of transcription; Pre-tx, baseline levels before tofacitinib; Pt, patient; SD, standard deviation.

Fig 2.

Molecular response in skin and blood to tofacitinib in sarcoidosis and GA. A, RNAseq gene expression data from skin biopsy specimens shown as heatmap of genes upregulated in response to IFN-γ (GSEA hallmark M5913). B, RNAseq gene expression data from PBMCs shown as heatmap of genes upregulated in response to IFN-γ (GSEA hallmark M5913). C, Plasma IFN-γ levels; bars represent mean and standard error of the mean. Normal (healthy volunteers), n = 4; GA pre-tx, n = 3; and Sarc pre-tx, n = 4; Pre-tx indicates baseline levels before tofacitinib or levels in patients not treated with tofacitinib; On-tx indicates levels after clinical response observed. On-tx GA indicates patient 4, On-tx Sarc indicates patient 2. The patients not treated with tofacitinib were included in this analysis. D, Plasma cytokine levels; shown are 2 replicate measurements from patient 2. GA, granuloma annulare; GSEA, Gene Set Enrichment Analysis; IFN, interferon; Norm, healthy control; NS, not significant; On Tx, levels after clinical response observed; PBMC, peripheral blood mononuclear cell; Pre, baseline levels before tofacitinib; RNAseq, RNA sequencing; S, sarcoidosis; Sarc, sarcoidosis; TNF, tumor necrosis factor; Tx, levels after clinical response observed.

Fig 3.

Patterns of JAK-STAT activation in sarcoidosis and GA biopsy specimens compared with normal skin. A, Representative pSTAT1 and pSTAT3 IHC staining patterns. B, Size quantification of clusters of pSTAT1- and pSTAT3-positive cells (bars represent mean and standard error of the mean). Quantification of IHC staining for (C) pSTAT1 and (D) pSTAT3 in cutaneous sarcoidosis (n = 22 cases), pulmonary sarcoidosis (n = 6 cases), GA (17 cases), and normal skin (7 cases). Three fields were scored per case. IHC score represents the percentage area of the field staining positively for the marker. GA, granuloma annulare; IHC, immunohistochemistry; JAK, Janus kinase; KEGG, Kyoto Encyclopedia of Genes and Genomes; p, phosphorylated; Pre Tx, baseline levels before tofacitinib; Pt, patient; SD, standard deviation; SIRP, signal regulatory protein; STAT, signal transducer and activator of transcription.

Fig 4.

Patterns of cytokine, chemokine, and receptor gene expressions are similar, but SIRPα staining differentiates sarcoidosis from GA. A, RNAseq gene expression data from skin biopsy specimens shown as a heatmap of genes for cytokines, chemokines, and their receptors. B, Representative SIRPα IHC. C, Quantification of IHC staining for SIRPa in cutaneous sarcoidosis (n = 7 cases), pulmonary sarcoidosis (6 cases), and GA (7 cases). Three fields were scored per case. IHC score represents the percent area of the field staining positively for the marker. GA, granuloma annulare; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; JAK, Janus kinase; RNAseq, RNA sequencing; SIRP, signal regulatory protein; STAT, signal transducer and activator of transcription.