Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

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Purpose: In this work, we proposed a triple-factor non-negative matrix factorization (TNMF) method to semiautomatically segment the regions of interest (ROIs) of the left ventricular (LV) cavity and myocardium to improve the reproducibility of myocardial blood flow (MBF) quantification from dynamic 82 Rb positron emission tomography (PET). Methods: The proposed TNMF method was evaluated using NCAT phantom simulation with three noise levels. The segmented ROIs, time-activity curves (TACs), and K 1 derived from the TNMF method were compared with the ground truth simulated. The TNMF method was further evaluated in two patients each undergone both rest and stress 82 Rb PET studies. The TNMF and manual segmentations were implemented by two different observers, and the interoperator variations of MBF and myocardial flow reserve (MFR) were compared between the two methods. Results: Our simulation results showed that the TNMF method for dynamic PET image segmentation was robust as evidenced by the high Dice similarity coefficient, regardless of high or low count level. The relative bias in K 1 estimation was less than 1%. Our patient results also showed that reasonable ROIs for the LV cavity and myocardium could be obtained precisely for patients with and without myocardial perfusion defects. The TACs derived from the TNMF method were highly correlated with those obtained with the manual method (R 2 ≥ 0.964). The interoperator variations of MBF and MFR were markedly reduced using the TNMF method. Conclusions: In conclusion, the TNMF method is highly feasible for semiautomatic segmentation of the LV cavity and myocardium, with the potential to improve the precision of MBF quantification by improving segmentation.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of ≥50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-gamma as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-gamma, larger, controlled studies are warranted.

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