What is the appropriate workup and treatment for a patient presenting with a rash of suspected autoimmune origin?

Autoimmune Workup for Rash

Begin with a focused history examining joint pain, recent infections, family history of autoimmune disorders, and medication exposures (especially immune checkpoint inhibitors), followed by physical examination documenting rash distribution, body surface area involvement, mucosal surfaces, joint swelling, and splenomegaly. 1, 2

Initial Clinical Assessment

History and Physical Examination

• Document rash characteristics including distribution pattern, duration of individual lesions (crucial: <24 hours suggests urticaria, >24 hours suggests vasculitis), presence of blisters or erosions, and body surface area (BSA) involvement 3, 4
• Assess for systemic symptoms: fever, joint pain, muscle weakness, dyspnea, and constitutional symptoms 1, 2
• Identify recent viral illnesses (particularly COVID-19), exposure to immunosuppressive therapies, or immune checkpoint inhibitors (nivolumab, durvalumab, pembrolizumab) which can trigger autoimmune bullous disorders 5, 6
• Examine all mucosal surfaces (oral, ocular, genital) as involvement suggests severe disease requiring immediate intervention 3
• Evaluate for joint involvement, muscle tenderness, and organomegaly 1, 2

Essential Laboratory Workup

First-Line Testing

Order the following tests immediately for all patients with suspected autoimmune rash: 1, 2

• Complete blood count with differential to detect cytopenias (anemia, thrombocytopenia, lymphopenia) and eosinophilia 1, 2
• Inflammatory markers: ESR and CRP to quantify inflammatory activity 1, 2
• Comprehensive metabolic panel including liver function tests (AST, ALT), kidney function (creatinine, BUN), and electrolytes 1, 2
• Antinuclear antibody (ANA) as the primary screening tool for systemic autoimmune diseases 1, 2

Disease-Specific Testing Based on Clinical Presentation

For suspected systemic lupus erythematosus or connective tissue disease:

• Anti-dsDNA, anti-Smith, anti-RNP, anti-SSA (Ro), anti-SSB (La) antibodies 1
• Complement levels (C3, C4, CH50) 1

For suspected dermatomyositis/polymyositis (rash with muscle weakness):

• Creatine kinase (CK), AST, ALT, LDH, aldolase 1, 2, 5
• Troponin to evaluate myocardial involvement 1, 2
• Anti-aminoacyl tRNA synthetase antibodies (anti-Jo-1, anti-PL-7, anti-PL-12) and anti-MDA-5 antibodies 5, 7

For urticaria (wheals lasting <24 hours):

• Most cases require no routine laboratory testing if mild and responsive to antihistamines 3, 4
• For chronic urticaria (>6 weeks) not responding to antihistamines: CBC with differential, ESR, thyroid function tests, and thyroid autoantibodies 3, 4
• Consider autologous serum skin test (ASST) in specialized centers for autoimmune urticaria 3

For suspected urticarial vasculitis (lesions lasting >24 hours):

• Lesional skin biopsy is mandatory to confirm small-vessel vasculitis 3, 4
• Full vasculitis screen including C3, C4, and CH50 to distinguish normocomplementemic from hypocomplementemic disease 3, 4

For angioedema without wheals:

• Serum C4 as initial screening test (high sensitivity for C1 inhibitor deficiency) 3, 4
• If C4 is low, proceed with quantitative and functional C1 inhibitor assays 3

For bullous or blistering rashes:

• Skin biopsy with direct immunofluorescence to distinguish bullous pemphigoid, pemphigus vulgaris, Stevens-Johnson syndrome/toxic epidermal necrolysis, and other autoimmune blistering disorders 3, 6
• Consider serum indirect immunofluorescence for circulating autoantibodies 6

Skin Biopsy Indications

Perform skin biopsy in the following scenarios: 3

• Lesions lasting >24 hours (to rule out vasculitis) 3, 4
• Any blistering or erosive lesions 3
• Rash covering >10% BSA with systemic symptoms 3
• Suspected autoimmune blistering disease 3
• Diagnostic uncertainty or failure to respond to initial therapy 3

Imaging Studies

• Chest imaging (chest X-ray or high-resolution CT) if respiratory symptoms present, as interstitial lung disease can accompany dermatomyositis and anti-synthetase syndrome 5, 7
• Joint radiographs for suspected inflammatory arthritis 2
• Muscle MRI for suspected inflammatory myopathies 2

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting complete autoantibody results in severe presentations with systemic symptoms, extensive BSA involvement, or mucosal involvement 1, 2
• Do not rely solely on autoantibody testing without clinical correlation, as positive ANA occurs in up to 15% of healthy individuals 2
• Do not perform extensive laboratory workup for acute urticaria or mild chronic urticaria responsive to antihistamines, as this is low-yield and not cost-effective 3, 4
• Do not miss infectious screening (HIV, hepatitis B and C, tuberculosis) before initiating immunosuppressive therapy 2

Initial Management Approach

For Mild Rash (<10% BSA, no systemic symptoms)

• Continue monitoring and treat symptomatically with topical emollients and mild-to-moderate potency topical corticosteroids 3
• For urticaria: initiate second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine) at standard or up to 4-times standard doses 3

For Moderate-to-Severe Rash (>10% BSA or systemic symptoms)

• Initiate systemic corticosteroids promptly without delaying for complete workup: 1, 2
  • Prednisone 0.5-1 mg/kg/day orally for moderate disease 1, 2
  • Prednisone 1-2 mg/kg/day or IV methylprednisolone for severe disease 1, 2
• Refer to dermatology within days for biopsy, definitive diagnosis, and management guidance 3, 1, 2
• Refer to rheumatology urgently if systemic autoimmune disease suspected 1, 2

For Life-Threatening Presentations

• Immediately discontinue any suspected causative agents (especially immune checkpoint inhibitors) 3
• Admit to hospital or burn center for mucosal involvement, blistering >30% BSA, or suspected Stevens-Johnson syndrome/toxic epidermal necrolysis 3
• Initiate IV methylprednisolone 1-2 mg/kg/day 3
• Consider IVIG, plasmapheresis, or rituximab for refractory autoimmune blistering diseases 3, 8

Monitoring and Follow-up

• Serial monitoring of CBC, inflammatory markers (ESR, CRP), and organ function tests based on systems involved 1, 2
• Clinical photography to document progression or improvement 3
• Consider second-line immunosuppression (rituximab, methotrexate, mycophenolate) if no improvement after 2-4 weeks of corticosteroids or if symptoms worsen 1, 2, 8