Session Information
Date: Monday, November 13, 2023
Title: (1155–1182) Muscle Biology, Myositis & Myopathies – Basic & Clinical Science Poster II
Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: MDA5-DM is characterized by high mortality due to rapid progressive ILD. We reported that in MDA-5DM, (1) RIG-1-like receptor signaling is enhanced, (2) antiviral responses are also enhanced, and (3) the key for survival is suppression of RIG-I-like and IFN signaling (ACR2022, Oral 0508).Our experience with an autopsy case suggests that uncontrolled activation of macrophages may play a role in the etiology of ILD. Recently, it has been reported that tacrolimus (TAC) and cyclophosphamide (CY) combination therapy (TC-Tx) administered early in the course of the disease improved the prognosis, however, some cases could not be saved.
Therefore, we devised BRT therapy (BRT-Tx).The regimen of the treatment combines baricitinib (BAR), which inhibits GM-CSF and IFN signaling and effectively suppresses uncontrolled macrophages, with rituximab (RTX) and TAC, which rapidly inhibits B cell-T cell interaction and ultimately prevents anti-MDA5 antibody production. In this report, we determine the differences in gene expression between BRT- and TC-Tx for MDA5-DM patients in peripheral blood.
Methods: Transcriptome of peripheral blood from 6 MDA5-DM (TC: 3, BRT: 3) patients with multiple poor prognostic factors were analyzed. Differentially expressed genes (DEGs) were identified between pre- and 2-3 months after treatment. Geneontology (GO), clustering, and gene set variation analysis(GSVA) were performed for the DEGs. As one BRT case was added since our last year’s presentation, we reanalyzed the difference between surviving and fatal cases. The IFN signature was scored separately for Types 1, 2, and 3, and the changes between pre- and post-treatment were investigated.
Results: Two of three cases with TC died during treatment, while all three cases on BRT recovered. Cluster analysis of DEGs separated fatal cases from survivors, not by the type of treatment. Comparing surviving and fatal cases, GO analysis revealed that the immune system via immunoglobulins and B cells was significantly suppressed in surviving cases. GO analysis of DEGs in each therapeutic group showed that expression of B cell-related genes were significantly suppressed after BRT-Tx. Meanwhile, TC-Tx significantly suppressed such pathways as cell proliferation, and was less specific for the target cells than BRT-Tx. The changes in IFN signature score after treatment showed an increase in type 2 and 3 IFN scores in all fatal cases and an increase in type 1 IFN score in one fatal case.
Conclusion: BRT-Tx significantly suppressed gene expression associated with B cells, while TC-Tx was characterized by low specificity of therapeutic targets. Comparison of surviving and fatal cases revealed that the combination of RTX was a key to success, as suppression of the immune system via immunoglobulins and B cells is the critical for survival. Analysis of the IFN signature revealed an increase in the IFN score after treatment in fatal cases, indicating that the combination of BAR is beneficial. The superiority of BRT-Tx seems clear from the fact that all patients survived while only one/three patients survived with TC therapy. This regimen is also superior to the existing TC regimen in terms of cytotoxicity and can become the standard of care in the future.
To cite this abstract in AMA style:
Koyama Y, Sato Y, Nakai Y, Tokunaga(Sakamoto) M. Transcriptome Analysis of Peripheral Blood Reveals Superiority of the Triple Combination of Baricitinib, Rituximab, and Tacrolimus Therapy (BRT-Tx.) for anti-MDA5 Antibody-positive Dermatomyositis (MDA5-DM) [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/transcriptome-analysis-of-peripheral-blood-reveals-superiority-of-the-triple-combination-of-baricitinib-rituximab-and-tacrolimus-therapy-brt-tx-for-anti-mda5-antibody-positive-dermatomyositis-md/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptome-analysis-of-peripheral-blood-reveals-superiority-of-the-triple-combination-of-baricitinib-rituximab-and-tacrolimus-therapy-brt-tx-for-anti-mda5-antibody-positive-dermatomyositis-md/