Discussion

This case illustrates a common and consequential pitfall: recurrent, dependent, antibiotic-unresponsive, lower-limb purpura misattributed to cellulitis. Cryoglobulinemic vasculitis arises when cold-precipitable immunoglobulins deposit in small vessels and activate complement, producing a leukocytoclastic small-vessel vasculitis [1,2]. In HCV infection, chronic B-cell stimulation drives the production of rheumatoid factor-containing immune complexes, and HCV is identified in the great majority of patients with mixed cryoglobulinemia, supporting a causal relationship [3,4]. Hepatitis C and mixed cryoglobulinemia synergistically decrease C4 levels, and C4 is disproportionately lowered relative to C3 in patients with immune complex-mediated disease as opposed to other disorders that consume complement [3,8].

Type III mixed cryoglobulinemia comprises only polyclonal immunoglobulins and is often associated with a lower cryoglobulin fraction. It may represent an earlier immunologic state along the spectrum toward type II, but the clinical features of the two mixed forms overlap [1,3]. The prototypical presentation is the Meltzer triad of purpura, weakness, and arthralgia, with cutaneous disease most common and renal (typically membranoproliferative glomerulonephritis) and peripheral nerve involvement representing major sources of morbidity [2,3,6]. Our patient demonstrated cutaneous disease together with hematuria and low-grade proteinuria at presentation, signaling renal involvement; however, repeated urine protein-to-creatinine ratio measurement after initiation of antiviral therapy was unremarkable, and active glomerulonephritis was not confirmed on follow-up. This evolution is consistent with the characteristic pattern of a depressed C4 with relatively preserved C3 (here C4 at the low end of normal) and underscores the value of serial renal monitoring rather than proceeding directly to immunosuppression when renal function is preserved [2,3].

Several diagnostic caveats deserve emphasis. Cryoglobulin testing is prone to false-negative results unless the sample is collected and transported at 37°C and allowed to clot while warm; so, repeated negative results may reflect pre-analytic handling rather than true absence [6]. Definitive confirmation may include a skin biopsy demonstrating leukocytoclastic vasculitis and, where renal involvement is suspected, a renal biopsy. Neither was performed in this patient, and the diagnosis rested on the combination of clinical findings and serology. Recurrence and failure to respond to antibiotics, as occurred here for more than a year, should prompt reconsideration of cellulitis and a vasculitis workup. The patient’s easy bruising and skin fragility broadened the differential to include nutritional causes, such as vitamin C deficiency, but the recurrent, inflammatory, purpuric picture with positive cryoglobulins pointed to vasculitis.

A key mimic in this patient was levamisole-adulterated cocaine vasculopathy, given her cocaine use. That entity classically produces retiform purpura favoring the ears, cheeks, and extremities, with neutropenia, high-titer antineutrophil cytoplasmic antibodies (frequently both myeloperoxidase and proteinase-3 specificities, plus anti-human neutrophil elastase), and a relative paucity of true autoimmune end-organ damage; lesions often improve with drug cessation [9]. Features favoring cryoglobulinemic vasculitis in our patient included positive cryoglobulins with a type III immunofixation pattern, chronic HCV as a defined driver, and the absence of the pathognomonic retiform or auricular lesions. Rheumatology considered anti-HNE antibody testing at the first follow-up visit to further evaluate levamisole vasculopathy as a concurrent contributor; when the two diagnoses overlap, antineutrophil cytoplasmic antibody testing and skin biopsy help to separate them and are advisable. The patient’s sustained cocaine abstinence after bronchoscopy cancellation removed an ongoing confound and supported clinical interpretation of her improving course.

Management and treatment response

Management of cryoglobulinemic vasculitis targets the underlying cause. HCV-directed direct-acting antivirals achieve high rates of sustained virologic response and can induce remission of vasculitis, with published data indicating cutaneous improvement in 60-90% of patients following viral eradication [3,4]. Our patient achieved undetectable HCV RNA after a two-month 100-40 mg Mavyret (three tablets daily) antiviral regimen, with complete resolution of cutaneous vasculitis on clinical examination. This outcome directly supports antiviral cure as the cornerstone of treatment and illustrates the principle that immunosuppression alone, without addressing the underlying driver, provides only temporary benefit. Corticosteroids served as a bridge to antiviral effect: prednisone was initiated with a 40 mg course daily for five days, transitioned to 20 mg daily, continued at 10 mg at rheumatology follow-up, and successfully tapered to 5 mg daily after viral cure was confirmed; the patient remains on this dose with ongoing taper. Active or severe vasculitis, particularly with significant renal involvement, may require B-cell depletion with rituximab, but the normalization of urine studies in this patient reduced the urgency for escalated immunosuppression [3,4].

Tobacco use represents an additional modifiable vascular risk factor. Smoking promotes endothelial dysfunction and compounds disease burden in small-vessel vasculitis. At the second rheumatology visit, tobacco cessation was counseled, and the patient had meaningfully reduced her smoking from approximately one pack per day to one to five cigarettes daily. Continued reduction to complete cessation remains an important therapeutic goal.

The incidentally discovered hypermetabolic pulmonary and pleural mass in this heavy smoker is concerning for malignancy and warrants tissue diagnosis. Although malignancy is itself an uncommon secondary cause of mixed cryoglobulinemia, HCV remained the established driver in this patient. Thoracentesis yielded pleural fluid with negative cytology, and cardiothoracic surgery referral for definitive biopsy has been made. The mass is best regarded as a separate, important finding requiring independent evaluation.

Limitations

Limitations include the single-patient design, the absence of confirmatory skin or renal biopsy, limited cryoglobulin quantification, incomplete documentation of antineutrophil cytoplasmic antibody and anti-HNE antibody status to fully exclude concurrent levamisole vasculopathy, and incomplete follow-up on the pulmonary mass. The ongoing corticosteroid taper and evolving pulmonary workup preclude a definitive long-term outcome assessment at this time.