What is the differential diagnosis and treatment approach for a patient presenting with a vasculitic pruritic rash, considering potential underlying autoimmune disorders, infections, and allergic reactions?

Differential Diagnosis for Vasculitic Pruritic Rash

The differential diagnosis for a vasculitic pruritic rash must distinguish urticarial vasculitis from chronic urticaria, autoimmune conditions (particularly Adult-Onset Still's Disease and systemic lupus erythematosus), IgA vasculitis, drug-induced vasculitis, and autoinflammatory diseases, with lesion duration >24 hours being the single most critical diagnostic discriminator. 1, 2

Primary Diagnostic Approach

Key Clinical Discriminators

Lesion duration is the most important clinical feature:

• Urticarial vasculitis lesions persist >24 hours (often days to weeks), while ordinary urticaria resolves within 2-24 hours 1, 2
• Individual lesions that leave residual hyperpigmentation, purpura, or ecchymosis strongly suggest vasculitis rather than simple urticaria 3, 4
• Painful or burning lesions (rather than purely pruritic) favor vasculitis over allergic urticaria 4

Essential Diagnostic Confirmation

Skin biopsy is mandatory when vasculitis is suspected:

• A deep punch biopsy extending to the subcutis must be performed on the most tender, reddish, or purpuric lesion 5, 6
• Superficial biopsies are inadequate and will miss diagnostic vascular changes 5
• Histopathologic features confirming vasculitis include leucocytoclasia, endothelial cell damage, perivascular fibrin deposition, and red cell extravasation 1, 2
• Direct immunofluorescence distinguishes IgA vasculitis (Henoch-Schönlein purpura) from IgG/IgM-associated vasculitis, which has prognostic significance 6

Differential Diagnosis Categories

1. Urticarial Vasculitis (Primary Consideration)

Two distinct subtypes with different prognoses:

• Normocomplementemic urticarial vasculitis: Minimal systemic involvement, better prognosis 4
• Hypocomplementemic urticarial vasculitis: Propensity for severe multi-organ involvement, worse prognosis 4

Required laboratory evaluation:

• Full blood count with differential, ESR (usually elevated in urticarial vasculitis), serum complement assays (C3, C4) to distinguish subtypes 3, 1
• C4 levels <30% of mean normal suggest complement-mediated disease 3

2. Autoimmune Connective Tissue Diseases

Adult-Onset Still's Disease (AOSD):

• Presents with salmon-pink maculopapular rash that can be mildly pruritic and is often confused with drug allergy 3
• A vasculitic purpuric rash variant has been described in AOSD with association to mixed cryoglobulinemia 3
• Characteristic triad: high-spiking quotidian fevers (>39°C), evanescent rash, and arthritis/arthralgias 3
• Rash typically appears on proximal limbs and trunk, sparing face and distal extremities 3

Systemic Lupus Erythematosus:

• Thyroid autoimmunity is more prevalent in chronic urticaria (14%) than controls (6%), suggesting autoimmune overlap 3
• Full blood count may reveal leucopenia characteristic of SLE 3
• Urticarial vasculitis can occur in the context of SLE, with C1q autoantibodies present in both conditions 4

3. IgA Vasculitis (Henoch-Schönlein Purpura)

Clinical presentation:

• Occurs in adults in only 10% of cases but must be considered 7
• Presents with palpable purpura, abdominal pain, and potential renal involvement 7
• Direct immunofluorescence showing perivascular IgA, C3, and fibrin deposition is diagnostic 7

4. Drug-Induced Vasculitis

Common culprits to identify and discontinue:

• Aspirin, NSAIDs, and codeine can cause or aggravate urticaria through leukotriene formation and histamine release 3
• ACE inhibitors cause angioedema through inhibition of kinin breakdown 3
• Drug-induced vasculitis should be studied as a pathogenetically separate entity from primary vasculitis 3

5. Autoinflammatory Diseases

Emerging recognition:

• Leukocytoclastic vasculitis can be a major presenting symptom of autoinflammatory diseases 8
• Consider autoimmune polyendocrine syndrome type 1, where cutaneous vasculitis may represent an early sign appearing years before classic components 9
• Autoinflammatory diseases should be included in the differential diagnosis of vasculitis 8

6. Infection-Associated Vasculitis

Specific considerations:

• Helicobacter pylori: Meta-analysis shows resolution of chronic urticaria more likely when antibiotic therapy successfully eradicates H. pylori 3
• Hepatitis C-associated cryoglobulinemic vasculitis and hepatitis B-associated polyarteritis nodosa should be studied separately 3
• Occult infections (dental abscess, gastrointestinal candidiasis) have little evidence supporting association with chronic urticaria 3

Critical Pitfalls to Avoid

Never dismiss non-blanching petechial rash without thorough evaluation:

• Meningococcemia can present similarly to viral illness initially but requires urgent treatment 5
• Use glass slide or clear plastic to compress lesions and assess for non-blanching quality 5

Do not perform superficial punch biopsy:

• Inadequate depth will miss diagnostic vascular changes and result in false-negative biopsy with delayed diagnosis 5

Avoid indiscriminate laboratory testing:

• No investigations are required for mild chronic urticaria responding to H1 antihistamines 3
• Screening profile for severe nonresponders should include: full blood count with differential, ESR, thyroid autoantibodies, thyroid function tests, and complement levels 3, 1

Do not assume malignancy association:

• There is no statistical association between malignancy and urticaria, though individual case reports exist 3
• Urticarial vasculitis as paraneoplastic syndrome is rare 4

Systematic Evaluation Algorithm

1. Assess lesion duration: >24 hours strongly suggests vasculitis rather than urticaria 1, 2
2. Evaluate for systemic symptoms: Fever, arthritis, abdominal pain, or renal involvement indicate systemic disease 3, 7
3. Perform deep punch biopsy extending to subcutis with direct immunofluorescence 1, 5, 6
4. Order complement levels (C3, C4) to distinguish normocomplementemic from hypocomplementemic disease 1, 4
5. Screen for autoimmune disease: ESR, full blood count, thyroid autoantibodies if autoimmune etiology likely 3, 1
6. Consider drug history: Discontinue potential triggers (NSAIDs, ACE inhibitors, aspirin) 3
7. Evaluate for infection: H. pylori testing if chronic urticaria present 3