What is the differential diagnosis for a chronic itchy morbiliform rash in an adult?

Differential Diagnosis for Chronic Itchy Morbiliform Rash in Adults

The differential diagnosis for a chronic itchy morbiliform rash in adults must distinguish between primary dermatologic conditions (most commonly chronic urticaria or drug eruptions) and systemic diseases presenting with cutaneous manifestations, with the critical first step being to determine whether individual lesions persist beyond 24 hours, which mandates skin biopsy to exclude urticarial vasculitis or cutaneous lymphoma. 1, 2

Primary Dermatologic Causes

Chronic Urticaria

• Chronic ordinary urticaria (COU) presents with wheals lasting more than 6 weeks, with individual lesions typically present for 2-24 hours 1
• At least 30% of cases have an autoimmune etiology, often remaining idiopathic after excluding allergic, infectious, physical, and drug-related triggers 1
• Critical distinction: If individual wheals last longer than 24 hours, urticarial vasculitis must be excluded via skin biopsy 1
• Prognosis varies: 50% of patients with wheals alone clear by 6 months, but over 50% with wheals plus angioedema have active disease beyond 5 years 1

Drug-Induced Morbilliform Eruptions

• Low-risk drug exanthems are the most common cause of morbilliform eruptions in the inpatient setting 2
• Drug-induced pruritus accounts for 12.5% of drug reactions presenting with pruritus without prominent rash 3
• A complete medication review is essential, with particular attention to recently started medications within the past 2-4 weeks 4
• High-risk drug eruptions that can present with morbilliform patterns include Stevens-Johnson syndrome/toxic epidermal necrolysis, DRESS syndrome, and acute generalized exanthematous pustulosis—these require immediate recognition and different management 2

Systemic Diseases Presenting with Chronic Pruritic Rash

Hematologic Malignancies

• Hodgkin lymphoma should be suspected when nocturnal pruritus occurs with weight loss, fever, night sweats, or palpable adenopathies 1
• Polycythemia vera characteristically presents with aquagenic pruritus (water-induced itching) 1, 3
• Nocturnal pruritus with or without visible rash strongly suggests these hematologic malignancies and mandates investigation 1

Cutaneous Lymphoma

• Persistent unexplained pruritic rash requires skin biopsy to evaluate for cutaneous lymphoma 3
• This diagnosis should be considered when standard treatments fail and the rash persists despite appropriate management 1

Autoimmune/Inflammatory Conditions

• Dermatomyositis presents with a persistent photosensitive rash including heliotrope rash, Gottron papules, and poikiloderma over weeks to months 1
• Adult-Onset Still's Disease presents with an evanescent salmon-pink maculopapular rash (72.7% of cases) accompanying high-spiking fevers 1

Systemic Diseases Causing Pruritus Without Primary Rash (But May Have Secondary Changes)

Hepatic Causes

• Cholestatic liver disease is a major cause of generalized pruritus, predominantly affecting palms and soles, worsening at night 3
• Primary biliary cholangitis should be considered if antimitochondrial antibodies are present 3
• Drug-induced cholestatic hepatitis (e.g., from statins) can cause severe pruritus 3

Renal Causes

• Uremic pruritus occurs in 42% of patients on hemodialysis 5
• Chronic kidney disease may be asymptomatic other than pruritus 5
• Symptoms vary from mild intermittent irritation to intractable itch with poor sleep 5

Hematologic Disorders

• Iron deficiency causes generalized pruritus, with 25% of patients with systemic pruritus responding to iron replacement 1, 3
• Iron overload can also cause pruritus 3

Endocrine/Metabolic

• Thyroid disorders (both hyperthyroidism and hypothyroidism) can be associated with pruritus, though routine screening is not recommended unless clinical features suggest endocrinopathy 5, 3
• Diabetes should be considered in the differential 6

Infectious Causes

• HIV infection can present with pruritus, often correlating with viral load 5
• Hepatitis A, B, C, and E are associated with cholestatic pruritus 5
• Scabies should always be considered, particularly as it can present with severe pruritus and minimal skin signs 5

Neuropathic Causes

• Small fiber neuropathy should be suspected in cases of persistent unexplained pruritus and confirmed by skin biopsy 4
• Localized cutaneous pruritus is indicative of a neuropathic cause 6

Psychogenic/Functional

• Psychogenic pruritus (functional itch disorder) is a diagnosis of exclusion after ruling out physical causes 5
• Stress and emotional factors can trigger or worsen pruritus 5
• Significant psychosocial morbidity develops in up to one-third of individuals with chronic pruritus 5

Essential Diagnostic Workup

Initial laboratory panel for all patients with chronic pruritic morbilliform rash: 4, 3

• Complete blood count with differential and peripheral smear (to detect polycythemia vera, lymphoma, eosinophilia)
• Ferritin level (iron deficiency is treatable and common)
• Liver function tests, total bilirubin, and serum bile acids
• Urea and electrolytes (renal function)
• LDH and ESR (hematological disease screening)

Additional testing based on clinical suspicion: 4, 3

• JAK2 V617F mutation if polycythemia vera suspected (positive in up to 97% of cases)
• Antimitochondrial antibodies if liver disease suspected
• HIV and hepatitis A, B, C serology if risk factors present
• Thyroid function tests only if clinical features suggest thyroid disease
• Skin biopsy if wheals last >24 hours, or if cutaneous lymphoma or small fiber neuropathy suspected

Critical Pitfalls to Avoid

• Do not dismiss nocturnal pruritus without investigation—it may herald hematologic malignancy 1
• Do not delay skin biopsy when individual lesions persist beyond 24 hours, as this distinguishes urticarial vasculitis from benign urticaria 1
• Do not use long-term sedating antihistamines due to dementia risk, except in palliative care settings 5, 4, 1
• Do not continue empiric treatment indefinitely—if no improvement after 2 weeks of appropriate therapy, escalate workup or refer to dermatology 1
• Do not overlook medication review—drug-induced eruptions are extremely common and cessation may be curative 4, 3
• Remember that ferritin may be falsely normal in iron deficiency with concurrent inflammation; check serum iron and TIBC if clinical suspicion remains 1