Treating Skin Manifestations of Connective Tissue Diseases

Skin conditions are traditionally perceived as surface-level issues, but they are often an outward display of a variety of internal and systemic diseases. Patients with connective tissue diseases experience systemic inflammation that often manifests through the skin. For example:

• Lupus involves an overactive immune system resulting in healthy cells and tissues being attacked, which affects the joints, skin, kidneys, heart, lungs, and brain. Skin manifestations appear as rashes, discoid lesions, and photosensitivity.
• Dermatomyositis, a chronic inflammatory myopathy, presents with rashes, papules, and photosensitivity and affects the muscles and blood vessels.
• Scleroderma is characterized by excessive collagen production, leading to skin thickening and damage to internal organs.

Despite advances in understanding these autoimmune diseases, there is currently no cure. However, they share a common driver: inflammation. As a result, treatment and disease management are centered around suppressing inflammation through different courses of action, including corticosteroids, NSAIDs, and other immunosuppressants. Though these provide some relief, they often yield suboptimal results and carry toxicity risks with long-term use.

Research efforts are constantly underway to find innovative and targeted therapies that treat the disease-specific inflammation pathologies, particularly as second-line treatments. Notably, type I interferon (T1 IFN), an inflammatory cytokine mediated by the Janus kinase (JAK) pathway, is upregulated and activated in lupus, dermatomyositis, and scleroderma. For this reason, T1 IFN suppressing therapies, including JAK inhibitors and T1 IFN monoclonal antibodies (mAb), have gained increasing attention.

Off-Label Use of JAK Inhibitors

JAK inhibitors are recognized for their ability to block a broad spectrum of inflammatory pathways while maintaining selectivity to one target. Known for their fast action, high efficacy, and topical application, JAK inhibitors are an appealing option for long-term treatment, offering a safer alternative to the risks of prolonged glucocorticoid therapy.

While no JAK inhibitors are currently FDA-approved for lupus, dermatomyositis, or scleroderma, studies have shown their potential in managing these diseases. Off-label use of tofacitinib has been shown to improve skin stiffness and healing in dermatomyositis, and baricitinib has demonstrated promise in reducing skin fibrosis in scleroderma. Topical direct JAK inhibitors, such as ruxolitinib, and JAK pathway inhibitors, such as deucravacitinib, have been shown to control skin lesions in cutaneous lupus erythematosus (CLE).

Exploring the Use of TI IFN mAb

T1 IFN targeting monoclonal antibodies (mAb) have also gained attention for their highly targeted and selective anti-inflammatory mechanism. Alirocumab, a T1 IFN mAb, was FDA approved to treat systemic lupus erythematosus (SLE) in 2021. Although it’s not approved to treat CLE, reports show significant improvement in these patients.

Dazukibart is another T1 IFN mAb that is currently in a phase III clinical trial to treat dermatomyositis and under investigation to treat CLE. The phase II clinical trial showed dazukibart significantly reduced dermatomyositis activity. Similarly, previous studies have shown reduced inflammation and collagen accumulation in scleroderma patients after being treated with the T1 IFN mAb, anifrolumab; however, no T1 IFN therapies have been approved.

As our understanding of inflammatory pathways evolves, so too does the potential to more safe and effective treatment options for patients with connective tissue diseases. At this week’s Maui Derm conference, Dr. Ruth Ann Vluegels, a renowned expert in connective tissue disorders, will expand on this topic. Don’t miss her insights into the evolving landscape of targeted therapies for connective tissue diseases.

References:

A Study to Understand How the Study Medicine Dazukibart Works in People With Idiopathic Inflammatory Myopathies. Retrieved January 16 from https://clinicaltrials.gov/study/NCT06698796?intr=Dazukibart&rank=1

Ceobanu, G., & Edwards, C. J. (2024). JAK inhibitors in systemic lupus erythematosus: Translating pathogenesis into therapy. Lupus, 33(13), 1403-1415. https://doi.org/10.1177/09612033241287594

Ezeh, N., Vleugels, R. A., & Shahriari, N. (2024). Discoid lupus erythematosus successfully treated with deucravacitinib. JAAD Case Rep, 49, 59-61. https://doi.org/10.1016/j.jdcr.2024.04.032

Fiorentino, D., Mangold, A. R., Werth, V. P., Christopher-Stine, L., Femia, A., Chu, M.,…Vleugels, R. A. (2025). Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet, 405(10473), 137-146. https://doi.org/10.1016/S0140-6736(24)02071-3

Guo, X., Higgs, B. W., Bay-Jensen, A. C., Karsdal, M. A., Yao, Y., Roskos, L. K., & White, W. I. (2015). Suppression of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, Anifrolumab, in Adult Patients with Systemic Sclerosis. J Invest Dermatol, 135(10), 2402-2409. https://doi.org/10.1038/jid.2015.188

Kakkar, V., Assassi, S., Allanore, Y., Kuwana, M., Denton, C. P., Khanna, D., & Del Galdo, F. (2022). Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit. Curr Opin Rheumatol, 34(6), 357-364. https://doi.org/10.1097/BOR.0000000000000907

Khan, M. A., Khan, F. H., Khan, H. B., Saadeh, C., & Davey, N. (2023). Role of Anifrolumab in Refractory Cutaneous Manifestations of Lupus Erythematosus: A Case Series and Literature Review. Cureus, 15(5), e39553. https://doi.org/10.7759/cureus.39553

Park, J. J., Little, A. J., & Vesely, M. D. (2022). Treatment of cutaneous lupus with topical ruxolitinib cream. JAAD Case Rep, 28, 133-135. https://doi.org/10.1016/j.jdcr.2022.08.038

Shaw, K., Sanchez-Melendez, S., Taylor, D., Barker, J., LaChance, A., Shahriari, N., & Vleugels, R. A. (2023). Assessment of Clinical Response to Anifrolumab in Patients With Refractory Discoid Lupus Erythematosus. JAMA Dermatol, 159(5), 560-563. https://doi.org/10.1001/jamadermatol.2023.0175