NEW YORK CITY – Patients with long-standing sarcoidosis and skin involvement showed dramatic improvement after 6 months of treatment with Janus kinase inhibitor (JAK) tofacitinib (Xeljanz), a small open clinical series has shown.
Disease activity decreased by an average of 82.7% in 10 patients, six of whom had complete clinical resolution of the inflammation. Improvement was evident within 30 days and continued to increase with continued treatment.
Imaging and lab results showed improvement in internal organ damage and changes in molecular markers correlated with improvement in skin, reported William Damsky, MD, PhD, of the Yale School of Medicine at New Haven, Connecticut, at the Inflammatory Skin Disease Summit.
“Patients generally entered therapy with combined immunosuppressive regimens, although some did not follow therapy,” he said. “All 10 patients improved and were generally able to discontinue or significantly reduce their baseline immunosuppressive therapy. We found an average reduction in cutaneous sarcoidosis activity of about 80% and six patients were left with nothing left in their skin at the end of the study, a complete response. “
“All the patients completed the study, tofacitinib was well tolerated and there were no side effects,” added Damsky. “There is a great need for better treatments other than prednisone, and our trial and previous work has now shown that inhibiting JAK appears to be a very effective treatment. It really does appear that randomized controlled studies are not only warranted but need to further define its effectiveness. “
A systemic inflammatory disease involving the activation of T cells, sarcoidosis can affect almost any organ in the body, although the lungs and lymph nodes are the most common sites, Damsky pointed out. About a third of patients have skin manifestations, and occasionally the skin is the only site involved. The only therapy approved by the FDA is prednisone, which is limited to patients with lung involvement. Cutaneous sarcoidosis has no approved therapies.
The pathogenesis of sarcoidosis involves several cytokines regulated by JAK / STAT, suggesting that inhibition of JAK could be an effective treatment for the disease, he continued. Damsky said a colleague and mentor suggested tofacitinib for a 48-year-old patient, who had long-standing sarcoidosis with extensive skin involvement and a lack of response to several therapies including methotrexate and a factor inhibitor. tumor necrosis (TNF).
“The patient had a truly remarkable response [to tofacitinib treatment], so that all that was left after several months was post-inflammatory hyperpigmentation, ”said Damsky, who, along with several colleagues published a case report. “The biopsy under treatment showed that, while there were well-defined sarcoidosis granulomas at the start, they disappeared under treatment … We have treated other patients with off-label tofacitinib and have had full responses. so spectacular. “
Imaging of patients suggested that the treatment’s effect extended beyond skin manifestations of the disease to affected internal organs, he added.
A suite literature review revealed several case reports of the use of tofacitinib to treat sarcoidosis. The accumulation of evidence has led to a prospective evaluation of the JAK inhibitor in patients with cutaneous sarcoidosis.
The open-label study of 10 patients included nine patients with active disease of the internal organs. All patients received tofacitinib 5 mg twice daily for 6 months. The primary outcome measure was change in the instrument of cutaneous sarcoidosis activity and morphology (CSAMI). At the end of the study period, patients could continue, gradually decrease, or discontinue concomitant immunosuppressive therapy.
The patients ranged from 53 to 63 years and the disease duration ranged from 1 to 31 years. All patients were receiving methotrexate and prednisone at the time of enrollment, and some were also receiving infliximab (Remicade), hydroxychloroquine, or azathioprine.
Baseline CSAMI ranged from 20 to approximately 60. At 6 months, the reduction in CSAMI from baseline was on average 82.7% and six patients had complete resolution of skin disease.
Laboratory work has implicated several cytokines in the pathogenesis of sarcoidosis, Damsky said. The studies led to a working hypothesis that gamma interferon is the main driver of the disease process, which is consistent with the known effects of tofacitinib. TNF-alpha and interleukin-6 appear to be secondary signaling molecules.
In a post-presentation discussion, a participant asked Damsky to speculate on the relative importance of blocking different JAK tyrosine kinases (TKs). After briefly discussing the different cytokines affected by different TK, Damsky said that “the short answer is we don’t know”.
Last updated on November 07, 2021
Damsky disclosed relationships with Pfizer, Advanced Cell Diagnostics / Bio-Techne, AbbVie, Eli Lilly, Twi Biotechnology, Incyte, and EMD / Millipore / Sigma.