Cutaneous Clues to Systemic Disease: A Rheumatology Overview for Dermatologists

Amanda Mixon, PA-C, a physician assistant with 18 years of experience in rheumatology and co-founder of the Rheumatology Advanced Practice Providers (RAPP) organization, shared a comprehensive overview of cutaneous findings in connective tissue diseases (CTDs) at SDPA Fall 2025.¹ Her goal was to help dermatology attendees recognize rashes that may signal systemic autoimmune disease, understand the appropriate laboratory work-up, and know when to refer or start treatment before rheumatology evaluation.

Systemic Lupus Erythematosus (SLE)

Mixon began with lupus, a multisystem autoimmune disease caused by autoantibody production and immune complex deposition. Environmental triggers such as UV light, infections, or stress can activate disease in genetically predisposed individuals. When clinicians encounter a rash on sun-exposed skin, she advised thinking beyond dermatology alone—systemic clues like fatigue, anemia, or renal findings may suggest SLE.

She also noted that a positive antinuclear antibody (ANA) test occurs in over 95% of lupus patients. A negative ANA makes systemic lupus unlikely, though ANA is sensitive rather than specific. Specific antibodies help refine diagnosis:

• Anti–double-stranded DNA (dsDNA): correlates with disease activity and lupus nephritis risk, especially at high titers.
• Anti-Smith (Sm): highly specific but less sensitive (20–30%).
• SSA/SSB: linked with subacute cutaneous lupus, photosensitivity, Sjögren’s overlap, and neonatal lupus; SSA positivity in women of childbearing age requires high-risk obstetric care.
• RNP antibodies: suggest mixed connective tissue disease (MCTD) when strongly positive.
• Histone antibodies: associated with drug-induced lupus.

Cutaneous lupus presents in several forms. Acute cutaneous lupus manifests as the classic but uncommon butterfly (malar) rash. Subacute cutaneous lupus shows annular or psoriasiform plaques on sun-exposed areas, often linked to SSA antibodies and mild systemic symptoms. Chronic (discoid) lupus features scarring plaques and alopecia but rarely progresses to systemic disease. Lupus panniculitis and chilblain lupus are rarer deep or cold-induced variants.

Management centers on hydroxychloroquine (Plaquenil), recommended for all lupus patients unless contraindicated. It benefits both systemic and cutaneous disease but requires baseline and annual eye exams for retinal monitoring. For refractory cases, immunosuppressants such as methotrexate, azathioprine, or mycophenolate are used. New biologics—belimumab and anifrolumab—have revolutionized lupus care, particularly for difficult cutaneous disease. Amanda shared personal experiences highlighting how improved therapies have dramatically changed outcomes over her career.

Dermatomyositis and Myositis Spectrum Disorders

Mixon then covered dermatomyositis (DM). Some patients have “amyopathic” DM—cutaneous features without muscle weakness. Typical rashes include the heliotrope rash on eyelids, Gottron’s papules over knuckles, and the shawl sign on the upper back. She emphasized ordering a myositis antibody panel and evaluating for malignancy, since certain antibodies (MDA5, NXP2, TIF-1γ) are strongly cancer-associated. Patients with these markers require full-body imaging (CT chest/abdomen/pelvis), mammography or pelvic ultrasound, and ongoing cancer surveillance for at least 3 years.

Treatment begins with corticosteroids, often combined with methotrexate, azathioprine, or mycophenolate. IVIG is effective for severe skin disease but requires screening for IgA deficiency due to reaction risk. Mixon also described antisynthetase syndrome, featuring myositis, Raynaud’s, “mechanic’s hands,” arthritis, and interstitial lung disease, commonly linked to Jo-1 antibodies.

Scleroderma (Systemic Sclerosis)

Finally, Mixon discussed scleroderma, marked by fibrosis, vasculopathy, and autoimmunity. It occurs in two main forms: limited (CREST syndrome) and diffuse. Limited scleroderma, associated with anticentromere antibodies, primarily affects distal extremities and carries a risk for pulmonary hypertension. Diffuse disease, linked to Scl-70 or RNA polymerase III antibodies, involves proximal skin and internal organs, including lungs, kidneys, and heart. She warned that steroids can precipitate scleroderma renal crisis in patients with RNA polymerase antibodies, an emergency she once encountered early in her career.

Treatment is organ-targeted: mycophenolate for interstitial lung disease, vasodilators (calcium channel blockers, sildenafil) for Raynaud’s, and proton pump inhibitors and lifestyle modifications for reflux. Emerging CAR-T cell therapies show early promise in reversing fibrosis.

Mixon concluded her talk by emphasizing multidisciplinary collaboration between dermatology and rheumatology. Early recognition of skin clues, appropriate antibody testing, and timely referral can prevent irreversible organ damage and improve survival in patients with connective tissue diseases.

Reference

1. Mixon, A. Connective Tissue Diseases. Presented at: Society of Dermatology Physician Associates Fall 2025 Conference; November 5-9, 2025; San Antonio, Texas.