Elevated IL-4 and IFN-γ Levels in Muscle Tissue of Patients with Dermatomyositis

Giriş, Murat; Durmuş, Hacer; Yetimler, Berrak; Tașlı, Hatice; Parman, Yeşim; Tüzün, Erdem

doi:10.21873/invivo.11108

Cited by 15 publications

(6 citation statements)

References 14 publications

(12 reference statements)

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“…The pathogenesis of DM is an interplay of environmental triggers and autoimmune reactions in individuals who are genetically susceptible . Studies from 2002 to 2020 revealed the role of cytokines and IFN in DM, including IFNγ and STAT pathways, TNF α, IL-4, IL-6, IL-17, IL-18, and IL-23. In addition, response to treatment and improvement in disease activity have been observed with downregulation of the aforementioned interferons and cytokines .…”

Section: Discussionmentioning

confidence: 99%

Apremilast in Recalcitrant Cutaneous Dermatomyositis

et al. 2022

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ImportanceCutaneous disease in dermatomyositis has no standardized treatment approach and so presents a challenging task for patients and clinicians.ObjectiveTo study the efficacy and safety of apremilast as an add-on therapy in patients with recalcitrant cutaneous dermatomyositis.Design, Setting, and ParticipantsThis phase 2a, open-label, single-arm nonrandomized controlled trial was conducted at a single center from June 2018 to June 2021. Participants were 8 patients with recalcitrant cutaneous dermatomyositis, defined by a cutaneous disease activity severity index (CDASI) score greater than 5 despite treatment with steroids, steroid-sparing agents, or both. Data were analyzed from June 2018 to June 2021.InterventionsApremilast 30 mg orally twice daily was added to ongoing treatment regimens.Main Outcomes and MeasuresThe primary outcome was the overall response rate (ORR) at 3 months. Key secondary outcomes were the safety and toxicity of apremilast and the durability of response at 6 months. The CDASI, muscle score, dermatology life quality index (DLQI), and depression assessments were performed at baseline and regularly until month 7. Skin biopsies were performed at baseline and 3 months after apremilast (defined as 3 months into active apremilast therapy) and tested for gene expression profiling and immunohistochemical stains. Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0.ResultsAmong 8 patients with recalcitrant cutaneous dermatomyositis (all women; mean [SD] age, 54 [15.9] years), a response was found at 3 months after apremilast among 7 patients (ORR, 87.5%). The mean (SD) decrease in CDASI was 12.9 (6.3) points at 3 months (P &lt; .001). Apremilast was well tolerated, with no grade 3 or higher adverse events. Sequencing of RNA was performed on skin biopsies taken from 7 patients at baseline and at 3 months after therapy. Appropriate negative (ie, no primary antibody) and positive (ie, tonsil and spleen) controls were stained in parallel with each set of slides studied. Of 39 076 expressed genes, there were 195 whose expression changed 2-fold or more at P &lt; .01 (123 downregulated and 72 upregulated genes). Gene set enrichment analysis identified 13 pathways in which apremilast was associated with downregulated expression, notably signal transducers and activators of transcription 1 (STAT1), STAT3, interleukin 4 (IL-4), IL-6, IL-12, IL-23, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) pathways. In immunohistochemical staining, there was a mean (SD) decrease in phosphorylation levels STAT1 (22.3% [28.3%] positive cells) and STAT3 (13.4% [11.6%] positive cells) at the protein level, a downstream signaling pathway for the downregulated cytokines.Conclusions and RelevanceThese findings suggest that apremilast was a safe and efficacious add-on treatment in recalcitrant dermatomyositis, with an overall response rate of 87.5% and associations with downregulation of multiple inflammatory pathways.Trial RegistrationClinicalTrials.gov Identifier: NCT03529955

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Section: Discussionmentioning

confidence: 99%

Apremilast in Recalcitrant Cutaneous Dermatomyositis

et al. 2022

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“…Additionally, we detected positive associations between Hsp90 levels and MCP-1 and IL-4. Interestingly, both MCP-1 and IL-4 have been implicated in the pathogenesis of IIM [ 21 , 22 , 33 , 34 , 35 , 66 , 67 , 68 ]. Nonetheless, in most cases, inflammatory cytokines/chemokines are not systemically upregulated in healthy volunteers following similar protocols [ 48 , 69 , 70 , 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Hsp90 as a Myokine: Its Association with Systemic Inflammation after Exercise Interventions in Patients with Myositis and Healthy Subjects

Švec

Štorkánová

Špiritović

et al. 2022

IJMS

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Compelling evidence supports the health benefits of physical exercise on the immune system, possibly through the molecules secreted by the skeletal muscles known as myokines. Herein, we assessed the impact of exercise interventions on plasma Heat shock protein 90 (Hsp90) levels in 27 patients with idiopathic inflammatory myopathies (IIM) compared with 23 IIM patients treated with standard-of-care immunosuppressive therapy only, and in 18 healthy subjects undergoing strenuous eccentric exercise, and their associations with the traditional serum markers of muscle damage and inflammation. In contrast to IIM patients treated with pharmacotherapy only, in whom we demonstrated a significant decrease in Hsp90 over 24 weeks, the 24-week exercise program resulted in a stabilization of Hsp90 levels. These changes in Hsp90 levels were associated with changes in several inflammatory cytokines/chemokines involved in the pathogenesis of IIM or muscle regeneration in general. Strenuous eccentric exercise in healthy volunteers induced a brief increase in Hsp90 levels with a subsequent return to baseline levels at 14 days after the exercise, with less pronounced correlations to systemic inflammation. In this study, we identified Hsp90 as a potential myokine and mediator for exercise-induced immune response and as a potential biomarker predicting improvement after physiotherapy in muscle endurance in IIM.

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“…The pathogenesis of dermatomyositis is multifactorial with environmental, genetic, and immune factor contribution 1 . T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental role in dermatomyositis 8 . There is an increase in proinflammatory cytokines including tumor necrosis factor α, interleukin (IL)-1, IL-6, and interferon-α and interferon-γ, all of which shift the immune balance to a Th1 response 1 .…”

Section: Discussionmentioning

confidence: 99%

“…There is an increase in proinflammatory cytokines including tumor necrosis factor α, interleukin (IL)-1, IL-6, and interferon-α and interferon-γ, all of which shift the immune balance to a Th1 response 1 . IL-4 released by lymphocytes infiltrating the skin and muscles in dermatomyositis patients contributes to increase in Th2 response in conjunction with Th1 response 8 …”

Section: Discussionmentioning

confidence: 99%