What are the differential diagnoses for a patient who reports diffuse skin pain?

Differential Diagnoses for Diffuse Skin Pain

When a patient reports "my skin hurts all over," the most critical immediate consideration is to rule out severe cutaneous adverse drug reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS), which present with widespread skin pain, fever, and systemic toxicity and require immediate hospitalization. 1

Life-Threatening Conditions to Exclude First

Severe Cutaneous Adverse Drug Reactions (SCARs)

• Presenting symptoms include fever, widespread skin pain, facial or upper-extremity edema, blisters, erosions, or skin sloughing 1
• SJS/DRESS typically occur after the 6th week of drug exposure and may present with vesicles, skin detachment, pustules, purpura, or mucous ulcerations 1
• Obtain a detailed medication history documenting all drugs taken in the preceding 2 months, as antibiotics, nonsteroidal anti-inflammatory drugs, and antiepileptics are most frequently implicated 2, 3
• Immediate discontinuation of all suspected medications and emergency hospitalization are mandatory 1

Necrotizing Fasciitis

• Severe pain that is disproportionate to visible skin changes is the hallmark finding 4
• Look for systemic toxicity (altered mental status, fever >38°C or <36°C, heart rate >90 bpm, hypotension), skin necrosis, bullae, ecchymoses, or crepitus 4
• A hard "wooden" feel of subcutaneous tissue extending beyond erythematous margins suggests deep fascial involvement requiring immediate surgical exploration 4

Common Dermatologic Conditions Causing Diffuse Skin Pain

Drug-Induced Eczematous Dermatitis

• Interferon and ribavirin therapy cause diffuse erythematous, dry (xerotic), and painful skin in 10-30% of patients, often leading to diffuse prurigo with excoriations 1
• Protease inhibitor triple therapy (e.g., telaprevir) causes skin problems in 54% of cases, with over 90% being eczematous dermatitis presenting as diffuse erythema, xerosis, and poorly delimited vesicular lesions with pruritic excoriations 1
• The neck and axillary creases are particularly affected 1

Atopic Dermatitis with Severe Skin Pain

• Skin pain occurs in 42.7% of atopic dermatitis patients, with 13.8% reporting severe or very severe pain 5
• Patients describe pain as both part of their itch (16.8%) and from scratching (11.2%), with 72% attributing it to both mechanisms 5
• Skin pain prevalence increases significantly in patients with excoriations (72.6% vs 57.6% without excoriations) 5
• Look for diffuse eczematous lesions with erythema, papules, erosion, infiltration, or lichenification in a symmetrical, age-specific distribution 1

Urticarial Vasculitis

• Presents clinically as urticaria but with small vessel vasculitis on histology, causing painful rather than purely pruritic lesions 1
• Individual lesions last longer than typical urticaria (>24 hours) and may leave residual hyperpigmentation or purpura 1
• Joint and renal involvement may accompany skin findings 1

Erythroderma

• Diffuse erythema and scaling involving >90% of body surface area can cause significant skin pain and discomfort 3
• May result from drug reactions, psoriasis, atopic dermatitis, or cutaneous T-cell lymphoma 3

Diagnostic Approach Algorithm

Step 1: Assess for Red-Flag Features

• Document vital signs, mental status, and presence of fever, tachycardia, or hypotension 4
• Examine for skin necrosis, bullae, ecchymoses, crepitus, mucosal involvement, or Nikolsky sign (epidermal detachment with lateral pressure) 1, 4, 2
• Assess pain severity relative to visible skin changes; disproportionate pain suggests necrotizing infection 4

Step 2: Obtain Detailed Medication and Exposure History

• Document all medications taken in the past 2 months, including over-the-counter drugs and supplements 2, 3
• Identify recent initiation of antibiotics, anticonvulsants, NSAIDs, or immunotherapy agents 1, 3
• Note timing of symptom onset relative to drug exposure (SJS/DRESS typically occur after 6 weeks) 1

Step 3: Characterize Skin Lesion Morphology and Distribution

• Distinguish between macular, urticarial, maculopapular, vesiculobullous, pustular, petechial, or nodular patterns 6
• Document whether lesions are localized, diffuse (<50% body surface), or extensive (>50% body surface) 1
• Examine all mucosal surfaces for erosions, hemorrhagic crusting, or ulcerations 2
• Check for excoriations, xerosis, and involvement of skin folds (neck, axillae) 1, 5

Step 4: Laboratory and Imaging Evaluation

• Obtain complete blood count (looking for leukocytosis, leukopenia, or eosinophilia), comprehensive metabolic panel, ESR, and CRP 4, 7
• Collect blood cultures if systemic signs are present 4
• Plain radiographs are first-line to detect soft-tissue gas in suspected necrotizing infection 4
• Skin biopsy from lesional skin with perilesional biopsy for direct immunofluorescence is essential when diagnosis is uncertain or in immunocompromised patients 2, 3

Step 5: Risk Stratification and Specialist Consultation

• Immediate surgical consultation for any suspicion of necrotizing fasciitis based on red-flag findings 4
• Dermatology consultation is required for Grade 2 or higher drug-induced skin lesions (diffuse involvement <50% body surface) 1
• Infectious disease involvement for immunocompromised patients or failure to respond to initial therapy 4

Management Considerations by Diagnosis

For Drug-Induced Eczematous Dermatitis

• Grade 1 (localized) lesions can be managed with emollients and topical corticosteroids without drug discontinuation 1
• Grade 2 (diffuse <50% body surface) requires dermatology consultation; the offending drug may be continued with close monitoring 1
• Grade 3 (>50% body surface) mandates immediate discontinuation of the suspected drug 1

For Atopic Dermatitis with Skin Pain

• Frequent application of fragrance-free emollients immediately after lukewarm baths is integral to management 1
• Topical corticosteroids (low to medium potency for face/folds, higher potency for trunk/extremities) applied once or twice daily until significant improvement 1
• Proactive therapy with twice-weekly application of fluticasone or mometasone to previously affected areas may prevent relapses 1

For Suspected SJS/DRESS

• All treatments must be definitively stopped and the patient hospitalized immediately 1
• Supportive care in a burn unit or intensive care setting may be required for extensive epidermal detachment 1

Common Pitfalls to Avoid

• Do not attribute disproportionate pain to simple cellulitis or dermatitis; this is a hallmark of deeper necrotizing infection 4
• Do not await imaging results when necrotizing fasciitis is suspected; proceed with surgical consultation based on clinical judgment 4
• Do not continue suspected causative medications when Grade 2 or higher drug eruptions are present without dermatology consultation 1
• Do not dismiss skin pain in atopic dermatitis as purely psychogenic; it is a common and burdensome symptom that correlates with disease severity and quality of life impairment 5
• Recognize that bilateral or diffuse involvement should prompt evaluation for systemic causes such as drug reactions, vasculitis, or autoinflammatory syndromes rather than localized infection 4, 6