What is the differential diagnosis for a patient with a chronic pruritic (itchy) rash on the lower extremities, worse on the left side, with intense itching at night and partial relief from over-the-counter cortisone (corticosteroid) cream, who has a benign biopsy result and no relief from triamcinolone (triamcinolone) cream?

Differential Diagnosis for Chronic Pruritic Rash on Lower Extremities

Most Likely Diagnosis

This presentation is most consistent with prurigo nodularis, a chronic neurodermatosis characterized by firm, hyperkeratotic pruritic nodules on the bilateral lower extremities that develops from persistent scratching and represents a self-perpetuating itch-scratch cycle. 1

Key Diagnostic Features Supporting Prurigo Nodularis

• Chronic duration (>1 year) with bilateral lower extremity involvement is the classic distribution pattern for prurigo nodularis, which typically presents symmetrically on extensor surfaces 1
• "Ingrown bump-like lesions" matches the firm, hyperkeratotic nodular appearance that defines this condition 2, 1
• Nocturnal pruritus predominance is characteristic, as nighttime scratching perpetuates the lesions 3, 4
• Benign biopsy result is expected, as prurigo nodularis shows nonspecific findings (hyperkeratosis, acanthosis, neural hyperplasia) without malignant features 1
• Partial response to OTC cortisone but failure of triamcinolone reflects the notoriously difficult-to-treat nature of established prurigo nodularis, where the itch-scratch cycle becomes independent of initial triggers 2, 1

Critical Differential Diagnoses to Exclude

Systemic Causes of Chronic Pruritus Without Primary Rash

Before accepting prurigo nodularis as the final diagnosis, you must exclude underlying systemic disease that may be driving the pruritus:

• Hematological disorders account for approximately 2% of generalized pruritus cases and require complete blood count with peripheral smear, lactate dehydrogenase, and ESR 3, 4
• Iron deficiency causes pruritus in 25% of patients with chronic itch and should be evaluated with serum ferritin in all cases 3, 4
• Polycythemia vera presents with aquagenic pruritus (water-induced itching) and requires JAK2 V617F mutation testing if hemoglobin/hematocrit is elevated 3, 4
• Hodgkin lymphoma should be suspected if there is weight loss, fever, or night sweats accompanying the nocturnal pruritus 3, 4
• Chronic kidney disease requires basic metabolic panel and urinalysis 3
• Thyroid dysfunction and hepatic disease should be screened with TSH and liver function tests 3

Dermatologic Conditions

• Atopic dermatitis typically involves flexural areas (antecubital/popliteal fossae) rather than isolated lower extremities, and usually responds better to topical corticosteroids 3, 2
• Contact dermatitis would have identifiable triggers and more acute flares rather than chronic stable nodules 3
• Cutaneous T-cell lymphoma can present with pruritus and normal-appearing skin initially, but the benign biopsy makes this unlikely unless inadequate sampling occurred 3
• Scabies should be considered with nocturnal pruritus, but typically involves web spaces, wrists, and genitalia with burrows visible 3

Management Algorithm

Step 1: Complete Systemic Workup (Do Not Skip This)

Order the following laboratories to exclude treatable systemic causes: 3, 4

• Complete blood count with differential and peripheral smear
• Serum ferritin
• Comprehensive metabolic panel (renal and hepatic function)
• Thyroid-stimulating hormone
• Lactate dehydrogenase and ESR

Step 2: Escalate Topical Therapy

Since medium-potency triamcinolone 0.1% failed, escalate to high-potency topical corticosteroids: 3, 5

• Clobetasol propionate 0.05% ointment or betamethasone dipropionate 0.05% ointment applied once to twice daily for 2-4 weeks 3, 5
• Apply under occlusion (plastic wrap overnight) to enhance penetration into thick nodules 3
• Critical caveat: High-potency steroids on lower extremities carry lower risk of atrophy than intertriginous areas, but still monitor for telangiectasia and striae 3, 5

Step 3: Break the Itch-Scratch Cycle

Antihistamines are essential for nocturnal pruritus control: 3

• First-generation sedating antihistamines at bedtime: hydroxyzine 25-50 mg or diphenhydramine 25-50 mg specifically for nighttime use 3
• Non-sedating second-generation antihistamines during daytime: loratadine 10 mg daily or cetirizine 10 mg daily 3, 5
• Avoid long-term sedating antihistamines except for nighttime use due to dementia risk 4

Step 4: Consider Second-Line Agents if High-Potency Steroids Fail

Antiepileptic agents modulate peripheral and central itch pathways: 3

• Gabapentin 900-3600 mg daily or pregabalin 25-150 mg daily as second-line treatment 3
• These agents reduce calcitonin gene-related peptide release peripherally and modulate μ-opioid receptors centrally 3

Topical tacrolimus as steroid-sparing alternative: 5

• Tacrolimus 0.1% ointment twice daily can be used long-term without atrophy risk 5

Step 5: Dermatology Referral Indications

Refer to dermatology if: 5

• No response to optimized high-potency topical therapy within 4-6 weeks despite documented adherence
• Need for intralesional corticosteroid injections into individual nodules (triamcinolone 5-10 mg/mL)
• Consideration of phototherapy (narrowband UVB) or systemic immunosuppression (cyclosporine, methotrexate)
• Diagnostic uncertainty requiring repeat biopsy from different sites

Common Pitfalls to Avoid

• Never assume treatment failure means wrong diagnosis without first confirming adequate application technique and duration (twice daily for minimum 2-4 weeks to all affected areas) 5
• Do not continue ineffective medium-potency corticosteroids indefinitely when high-potency options remain untried 5
• Never overlook systemic workup in chronic pruritus, as 25% respond to iron replacement alone and 2% have hematological malignancy 3, 4
• Do not attribute all chronic pruritus to atopic disease without excluding neurologic, psychiatric, and systemic causes 6
• Recognize that prurigo nodularis has guarded long-term prognosis and requires realistic patient counseling about chronicity and relapsing nature 1