What causes a skin rash or lesion?

What Causes Skin Rash or Lesions

Skin rashes and lesions arise from three primary mechanisms: immune-mediated reactions (including drug-induced, autoimmune, and checkpoint inhibitor-related), infectious etiologies, and inflammatory dermatoses, with the specific cause determined by morphology, distribution, associated symptoms, and exposure history.

Immune-Mediated and Drug-Induced Causes

Checkpoint Inhibitor Therapy

• Cutaneous toxicities are the most common immune-related adverse events, occurring in up to 71.5% of patients receiving immune checkpoint inhibitors, with rash typically appearing within 3-6 weeks of treatment initiation 1.
• The proinflammatory microenvironment created by checkpoint inhibitor immune-mediated activity and unrestrained T-cell activity drives these cutaneous manifestations 1.
• CTLA-4 inhibitors cause cutaneous reactions more frequently than anti-PD-1 agents, with combination therapy carrying the highest risk 1.
• Presentations include inflammatory dermatitis (eczematous, lichenoid, psoriasiform, morbilliform patterns), bullous dermatoses, and severe cutaneous adverse reactions 1.
• Vitiligo occurs in up to 25% of checkpoint inhibitor-treated patients and presents as completely painless, well-demarcated depigmented macules 2.

Radiation-Associated Reactions

• Radiation dermatitis develops when radiotherapy is combined with EGFR inhibitors like cetuximab, creating a synergistic inflammatory effect 1.
• The median onset is 4 weeks but can range from 2 to 150 weeks after treatment initiation 1.
• Topical products applied before radiation create a bolus effect, artificially increasing epidermal radiation dose and worsening dermatitis 1.

Anti-TNF Therapy

• Paradoxical psoriatic and eczematous lesions occur in approximately 22% of patients receiving anti-TNF therapy for inflammatory bowel disease 2.

Autoimmune Dermatoses

Lichen Sclerosus

• This autoimmune inflammatory dermatosis presents as painless porcelain-white papules and plaques with follicular delling, most commonly affecting anogenital skin 2.
• 60% of patients have at least one autoimmune-related phenomenon, with 22% having concurrent autoimmune disease and 42% having autoantibodies 2.
• The most commonly associated conditions include alopecia areata, vitiligo, and thyroid disease 2.
• Genital involvement follows a characteristic "figure-of-eight" distribution around vulva and anus, with vagina and cervix always spared 2.
• Extragenital lesions most commonly affect inner thighs, submammary area, neck, shoulders, and wrists 2.

Systemic Lupus Erythematosus

• Specific cutaneous lesions include "butterfly" rash in acute form, annular or psoriasiform photosensitive lesions in subacute form, and discoid lesions in chronic form 3.
• Nonspecific lesions such as exanthema, vasculitis, and alopecia can occur during SLE flares 3.

Dermatomyositis

• Cutaneous lesions (Gottron's papules and sign, heliotrope rash, dystrophic cuticles, nailfold capillary abnormalities) may precede muscular or systemic organ involvement 3.
• Anti-MDA-5 antibodies associate with life-threatening interstitial lung disease, while anti-TIF1-γ antibodies confer higher malignancy risk 3.

Infectious Causes

Life-Threatening Tickborne Infections

• Rocky Mountain Spotted Fever carries a 5-10% case-fatality rate, with 50% of deaths occurring within 9 days of illness onset, requiring immediate empiric doxycycline without waiting for laboratory confirmation 4.
• The rash typically appears 2-4 days after fever onset as small blanching pink macules on ankles, wrists, or forearms, progressing centrally while initially sparing the face 4.
• Up to 20% of RMSF patients never develop a rash, and less than 50% have rash in the first 3 days 4.
• 40% of patients do not report tick exposure history 4.

Fungal Infections

• Tinea corporis presents as pruritic, annular, erythematous patches that grow centrifugally, diagnosed through potassium hydroxide examination of scrapings 5.
• Dimorphic fungi (Blastomyces, Coccidioides, Histoplasma, Paracoccidioides) can mimic autoimmune lesions, particularly in immunocompromised patients 1.

Parasitic Infections

• Cutaneous larva migrans causes characteristic self-limiting itchy, serpiginous rash migrating at 1-2 cm per day from dog/cat hookworm larvae penetrating skin 1.
• Onchocerciasis presents with diffuse dermatitis, severe pruritus, and eventual skin depigmentation ("river blindness") 1.
• Schistosomiasis can cause urticarial rash and pruritus during acute infection 1.

Viral Infections

• Pityriasis rosea typically starts with a herald patch (erythematous lesion with elevated border and depressed center), followed by generalized rash along Langer lines two weeks later 6.
• Erythema migrans is pathognomonic for Lyme disease and requires prompt antibiotic initiation 5.

Inflammatory and Hypersensitivity Reactions

Atopic Dermatitis

• Food allergies are present in some patients, but effective treatment centers on good skin care and topical therapies regardless of food allergy status 1.
• Aeroallergen sensitization increases with age, with higher rates in moderate to severe atopic dermatitis 1.
• Allergic contact dermatitis (type IV delayed hypersensitivity) has high prevalence in individuals with atopic dermatitis 1.

Urticaria and Vasculitis

• Urticaria results from histamine release, appearing as well-circumscribed, erythematous lesions with raised borders and blanched centers 5.
• Non-pruritic urticarial lesions suggest anti-C1q-associated urticarial vasculitis, Still's disease, or hereditary autoinflammatory syndromes 3.
• Schnitzler syndrome presents with chronic urticarial rash that is typically non-pruritic and painless, associated with monoclonal gammopathy 2.

Other Inflammatory Patterns

• Erythema multiforme presents with annular, raised lesions with central clearing due to hypersensitivity reaction 5.
• Nummular eczema appears as coin-shaped papulovesicular erythematous lesions related to skin dryness 5.
• Lichen planus characteristically presents as planar, purple, polygonal, pruritic papules and plaques 5.

Critical Diagnostic Pitfalls

• Never exclude autoimmune disease based solely on positive autoantibodies, as nonspecific autoantibodies can be transiently present at low levels 1, 2.
• Always exclude infection first, particularly in immunocompromised patients where fungal infections mimic autoimmune lesions 2.
• Do not wait for serologic confirmation before starting doxycycline if RMSF is suspected, as antibodies are not detectable before the second week of illness 4.
• Asymptomatic lichen sclerosus may still have active disease with ongoing scarring and malignant potential 2.

Algorithmic Approach to Diagnosis

1. Assess for life-threatening causes first: If fever + rash + headache + tick exposure (or endemic area residence), thrombocytopenia, hyponatremia, or elevated transaminases are present, start doxycycline 100 mg twice daily immediately 4.

2. Classify rash morphology: Categorize as petechial/purpuric, maculopapular, vesiculobullous, diffusely erythematous with desquamation, or nodular 4.

3. Document distribution pattern: Anogenital (lichen sclerosus), "figure-of-eight" perianal (lichen sclerosus), facial butterfly (SLE), extensor surfaces (dermatomyositis), or along Langer lines (pityriasis rosea) 2, 3, 6.

4. Obtain medication history: Checkpoint inhibitors, anti-TNF therapy, radiation therapy, or other immunomodulators 1, 2.

5. Perform targeted laboratory evaluation: Complete blood count with differential, comprehensive metabolic panel, skin biopsy if diagnosis unclear, and pathogen-specific testing based on clinical suspicion 4, 7.

6. Consider autoimmune workup only after excluding infection: Document presence of other autoimmune conditions, as 60% of lichen sclerosus patients have autoimmune-related phenomena 2.