Case presentation

History

A 61-year-old woman presented to a continuity clinic with recurrent left, then bilateral, lower-extremity eruptions. The lesions were red, intensely itchy and burning, associated with swelling, and accompanied by sharp pain radiating proximally. A similar episode approximately one year earlier had prompted exclusion of gout and an empiric antibiotic course with cephalexin 500 mg twice daily for 10 days for presumed cellulitis, without benefit; that rash later resolved spontaneously. At the index recurrence, she again received an antibiotic course for possible cellulitis. Over the following months, she also reported new, easy bruising with skin tearing after trivial trauma.

Her history included chronic HCV infection, chronic obstructive pulmonary disease (COPD), primary hypertension, chronic left knee and ankle pain, depression, and anxiety. Substance use included tobacco (approximately 23 pack-years) and cocaine. Outpatient medications included inhaled bronchodilator/corticosteroid therapy, gabapentin, amitriptyline, amlodipine, a proton-pump inhibitor, and as-needed analgesics.

Examination

Initially, she presented with an erythematous, macular, papular rash on the anterior right ankle (Figure 1).

Figure 1: Right ankle demonstrating lower extremity edema with arrow pointing to erythematous-to-violaceous, partly confluent, maculopapular rash.

On follow-up, the left lower limbs showed erythematous-to-violaceous, partly confluent macular and faintly papular lesions over the distal leg, ankle, and foot (Figures 2, 3). The patient would later develop bilateral lower extremity edema, bruising, and right ankle tenderness. The remainder of the examination was notable for an obese, chronically ill-appearing woman without acute distress. Cardiopulmonary examination was unremarkable at rest.

Figure 2: Left lower extremity demonstrating erythematous, macular, and papular lesions over the mid-distal anterior calf. Left and right arrows point to erythematous, maculopapular rash on the left and right sides of the lower extremity, respectively.

Figure 3: Clinical image of the left lower extremity. Upper arrows show macular and papular lesions over the distal calf and ankle. Lower arrows demonstrate violet discoloration and soft-tissue swelling of the left foot.

Laboratory studies

Inflammatory markers were elevated, with a C-reactive protein that rose on serial testing and a persistently elevated erythrocyte sedimentation rate. Serum cryoglobulins were qualitatively positive, and immunofixation of the cryoprecipitate demonstrated type III mixed cryoglobulinemia (polyclonal immunoglobulins); the cryoglobulin fraction was low (approximately 1%). Complement C3 was normal, and C4 was at the low end of normal. An extended antinuclear antibody panel was negative, with equivocal double-stranded DNA antibodies and negative extractable nuclear antigens, arguing against systemic lupus erythematosus or another defined connective tissue disease. Urinalysis showed hematuria and pyuria with low-grade proteinuria, and the spot urine protein-to-creatinine ratio was mildly elevated, indicating renal involvement. The hepatic panel showed mildly elevated alkaline phosphatase with previously elevated transaminases, HCV PCR 618,000 IU/mL, and HCV log10 5.791 log10 IU/mL, consistent with chronic HCV. Hepatitis C genotyping showed genotype 3 with METAVIR stage F2 hepatitis C. A urine drug screen was intermittently positive for cocaine (and at times fentanyl and benzodiazepines). Key laboratory results for the patient are reported in Table 1.

Test | Value | Reference range
Inflammatory markers
C-reactive protein | 15 mg/L (H) | <5 mg/L
Erythrocyte sedimentation rate | 41 mm/hr (H) | 0-20 mm/hr
Cryoglobulins and complement
Serum cryoglobulin, qualitative | Positive | Negative
Cryoprecipitate immunofixation | Type III (polyclonal) | -
Cryoglobulin fraction (cryocrit) | 1.0% (H) | <0.5%
Complement C3 | 109 mg/dL | 82-167 mg/dL
Complement C4 | 18 mg/dL (low-normal) | 16-48 mg/dL
Viral serology
HCV RT-PCR HCV log 10 | 5.791 log IU/mL | Undetected
Hepatitis C quantitation | 618,000 IU/mL | Undetected
Hepatitis C virus antibody | Reactive | Non-reactive
Hepatitis A virus, IgM | Negative | Negative
Hepatitis B core, IgM | Negative | Negative
Hepatitis B surface antigen | Negative | Negative
Autoimmune serology
ANA comprehensive panel† | Negative | Negative
Hepatic panel
AST (peak 70 H, 2025) | 13 U/L | 13-39 U/L
ALT (peak 66 H, 2025) | 6 U/L (L) | 7-52 U/L
Alkaline phosphatase | 139 U/L (H) | 30-105 U/L
Albumin | 3.7 g/dL | 3.5-5.7 g/dL
Renal
Creatinine | 0.74 mg/dL | 0.60-1.30 mg/dL
eGFR | >60 mL/min/1.73 m² | >60 mL/min/1.73 m²
Urinalysis | Hematuria, pyuria, trace protein | Negative
Urine protein/creatinine ratio | 131 mg/g (H) | <150 mg/g
Hematology
Hemoglobin | 13.8 g/dL | 12.0-16.0 g/dL
White blood cells | 6.7 ×10³/µL | 4.5-12.5 ×10³/µL
Platelets | 309 ×10³/µL | 150-450 ×10³/µL
Toxicology
Urine drug screen | Cocaine positive‡ | Negative

Imaging and other studies

Lower-extremity venous duplex ultrasonography was negative for deep vein thrombosis, excluding DVT as a cause of the unilateral swelling. Screening mammography was negative. Incidentally, cross-sectional imaging identified an approximately 2.6-3.1 cm enhancing, hypermetabolic mass at the mediastinal border of the right middle lobe (maximum standardized uptake value 7.9 on positron-emission tomography), with a small left pleural effusion, pleural thickening, healing left rib fractures, and cardiomegaly for which CT-guided biopsy was recommended (Figures 4, 5).

Figure 4: Incidental thoracic mass. Contrast-enhanced axial CT chest demonstrating a solid enhancing mass (green arrow points to the mass) at the mediastinal border of the right middle lobe adjacent to the right atrium.CT: computed tomography

Figure 5: Panels A, B, C, and D show positron emission tomography (PET) scans demonstrating a solid hypermetabolic mass at the mediastinal border of the right middle lobe adjacent to the right atrium (arrow points to the mass), with a small left pleural effusion (A: PET axial view, B: PET coronal view, C: computerized tomography (CT)-fused axial view, D: CT-fused coronal view).

Pulmonary function testing showed a severe (stage III) obstructive pattern with a significant bronchodilator response and mildly reduced lung volumes, consistent with COPD (Table 2).

Parameter | Pre-BD | Post-BD | % Predicted
FEV1 (L) | 1.41 | 1.64 | 52
FVC (L) | 2.13 | 2.33 | 57
FEV1/FVC (%) | 66 | 70 | -
TLC (L) | 5.03 | - | 76
RV (L) | 2.73 | - | 117
RV/TLC (%) | 54 | - | -

Diagnosis, management, and clinical course

Initial Diagnosis and Management

The constellation of recurrent dependent purpura, systemic inflammation, positive serum cryoglobulins with a type III immunofixation pattern, low-normal C4, a negative ANA panel, and chronic HCV established HCV-associated type III mixed cryoglobulinemic vasculitis with cutaneous and probable renal involvement. The patient’s cocaine use mandated consideration of levamisole-adulterated cocaine vasculopathy as a mimic. After symptomatic improvement with 100-40 mg glecaprevir/pibrentasvir (Mavyret) and a five-day course of 40 mg prednisone tablets, she was started on 20 mg prednisone tablets for 10 days (with a planned taper) and referred to rheumatology, with HCV-directed antiviral therapy as the cornerstone of treatment for the underlying driver.

Rheumatology Follow-Up

Rheumatology co-management spanned two visits. At the first visit, approximately six weeks into antiviral therapy, the diagnosis was confirmed clinically and serologically. The left lower extremity bore the predominant disease burden: circumferential erythema, pitting edema, and tenderness to palpation, with bilateral petechiae of the legs and dorsal forearm ecchymoses. Creatinine was normal; urine studies and CRP were ordered to monitor for renal involvement. Prednisone was continued at 10 mg daily as a bridge to antiviral effect, 40 mg pantoprazole tablets daily were added, and anti-human neutrophil elastase antibody (anti-HNE antibody) testing was considered to evaluate concurrent levamisole vasculopathy. At the second visit, the patient had completed the two-month antiviral regimen with 100-40 mg glecaprevir/pibrentasvir (Mavyret) three tablets daily with lunch, and HCV RNA was undetectable, confirming sustained virologic response. Cutaneous disease had resolved: no purpura or ulcerations on examination, with only residual distal left leg hyperpigmentation markedly improved from baseline. Urine protein-to-creatinine ratio was unremarkable, excluding active glomerulonephritis. Prednisone was tapered to 5 mg daily, where it remains with ongoing taper. For the pulmonary mass, thoracentesis cytology was negative, and the patient was referred to cardiothoracic surgery for biopsy. Tobacco use had decreased from one pack to one to five cigarettes daily; cocaine abstinence was maintained. A summary of the clinical course is shown in Table 3.

Visit | Key findings | Management | Response/status
Initial presentation | Recurrent lower-extremity (LE) rash with macular-papular eruption, pruritus, and edema | 10-day course of cephalexin, ibuprofen (200 mg), and acetaminophen (325 mg) as needed | No improvement during antibiotic course; rash spontaneously resolved after several months
Six-month follow-up | Bilateral LE pain, forearm abrasions and bruising, recurrent rash and bruising in all extremities | Topical mupirocin 2%; CMP, PT/INR, aPTT, and hepatitis panel obtained to evaluate liver function | Hepatitis C virus RNA detected; informed the patient's gastroenterologist for treatment; genotyping confirmed HCV genotype 3 with METAVIR stage F2; glecaprevir-pibrentasvir (Mavyret) 100/40 mg initiated
Six-week follow-up | Recurrent LE purpura, bilateral bruising and edema, severe LE tenderness, HCV-positive, reported cocaine use | Prednisone (40 mg) PO × five days, oxycodone (5 mg) twice daily as needed × five days, CT angiography of the aorta with bilateral iliofemoral runoff, urinalysis, protein/creatinine ratio, cryoglobulin, C3, C4 ordered | Right middle lobe mass identified on CT, symptoms improved with prednisone (40 mg), cryoglobulin elevated
Two-week follow-up | Recurrent LE purpura, positive cryoglobulins (type III), hematuria/proteinuria, right middle lobe mass, HCV therapy ≈ 8 weeks underway | Prednisone (20 mg) daily, rheumatology referral, dedicated chest CT followed by PET-CT | Type III cryoglobulinemia diagnosis established, symptoms improved on prednisone (20 mg) and glecaprevir-pibrentasvir 100/40 mg, pulmonology referral placed
Rheumatology visit, one month later | LE circumferential erythema with pitting edema, bilateral petechiae, creatinine normal | Prednisone continued at 10 mg daily, proton-pump inhibitor prescribed, urine studies and CRP ordered, anti-HNE antibody considered, cocaine abstinence reinforced | Disease is clinically active but stable, renal function preserved
Two-month rheumatology follow-up | HCV RNA undetectable (sustained virologic response), rash resolved, LE swelling cleared, urine protein/creatinine ratio unremarkable, residual LE hyperpigmentation | Pulmonary mass evaluation ongoing; thoracentesis performed (cytology negative), CT-surgery referral for biopsy, tobacco cessation counseled | Cutaneous vasculitis in remission, no active glomerulonephritis, prednisone taper in progress