Given the patient's history of immunoproliferative disorder, and the atypical presentation of her lesions, consideration was given to a vasculitic or vasculopathic etiology. A panel of additional laboratory studies was sent. Lupus anticoagulant was not detected, and anticardiolipin was also negative. Antinuclear antibodies (ANA) and antibodies to neutrophil cytoplasmic antigens (ANCA) were not detected. All hepatitis markers were negative, including for hepatitis C. The test for rheumatoid factor was negative. The cryoglobulin test was positive, and quantified as primarily immunoglobulin G (IgG). This was subsequently confirmed on a separate test several months later.
Cryoglobulins are single or mixed immunoglobulins that reversibly precipitate at low temperatures. Cryoglobulinemia is defined as the presence of cryoglobulins in the serum. This can lead to a syndrome of systemic inflammation caused by immune complexes associated with the cryoglobulins. The mechanism of precipitation is poorly understood. The solubility of cryoglobulins is partially related to the structure of the immunoglobulin heavy and light chains. Alteration in protein conformation resulting from temperature changes may cause decreased solubility and subsequent vasculitic damage. The ratio of antibody to antigen in circulating cryoglobulin aggregates affects the rate of clearance from the circulation and the resultant location of tissue deposition.[2,4]
Cryoglobulins are reported in otherwise healthy individuals, so their true prevalence is unknown. While cryoglobulinemia is thought to be rare, it may be underdiagnosed because of the diversity of clinical presentations. The prevalence of mixed cryoglobulinemia is approximately 1:100,000. The female-to-male ratio is 3:1. The mean age reported is 42-52 years.
Cryoglobulinemia is classified based on cryoglobulin type using the Brouet classification. Type I cryoglobulinemia is monoclonal, usually immunoglobulin M (IgM). Types II and III are immunocomplexes formed by monoclonal or polyclonal IgM, respectively. Types II and III have rheumatoid factor (RF) activity and bind to polyclonal immunoglobulins. These two types are referred to as "mixed cryoglobulinemia". Type I accounts for 10-15% of cases, type II is seen in 50-60%, and type 3 is found in 25-30%. Atypical cryoglobulins with a microheterogeneous composition that does not fit into any of the classifications have prompted suggestion of a classification called Type II-III variant.[2,3,4]
Type I cryoglobulinemia is usually related to an underlying lymphoproliferative disease and may be difficult to distinguish from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Type I cryoglobulinemia may result in hyperviscosity as a result of high levels of circulating monoclonal cryoglobulins, leading to physical obstruction of vessels. In addition, immune complex deposition may cause an inflammatory vasculitis. Specific clinical manifestations include acrocyanosis, retinal hemorrhage, Raynaud phenomenon with digital ulceration, livedo reticularis, purpura, and arterial thrombosis.[1,2,3,4]
Types II and III cryoglobulinemia are associated with chronic inflammatory states, such as systemic lupus erythematosus, Sjögren syndrome, and viral infections (particularly hepatitis C). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states. Tissue damage results from immune complex deposition and complement activation. Specific clinical manifestations associated with types II and III cryoglobulinemia include arthralgia (usually of the leg, ankle and foot), fatigue, myalgia, renal immune-complex disease, cutaneous vasculitis, and peripheral neuropathy. The Meltzer triad of purpura, arthralgia, and weakness is seen in 25-30% of patients.[1,2,4,5]
Mortality and morbidity in individuals with cryoglobulinemia often depends on the underlying associated disease, if present. The overall prognosis is worse in patients with associated disease. The mean survival is approximately 50% at 10 years after diagnosis. The risk of renal failure appears to be greater in those with hepatitis C virus—associated disease.[2,4]
Lymphoproliferative disease is more common in individuals with cryoglobulinemia. Patients with mixed cryoglobulinemia may develop benign lymphoid infiltrates in the spleen and bone marrow. Less frequently, patients may develop B-cell non-Hodgkin lymphoma. The incidence of malignant lymphoma in mixed cryoglobulinemia varies from 10-40%, with an onset of 5-10 years after disease diagnosis.[2,3]
Cutaneous manifestations are almost always present in cryoglobulinemia. Lesions are most often seen in dependent areas (especially the lower extremities), and they include erythematous macules and purpuric papules (90-95%), as well as ulcers (10-25%). Lesions in nondependent areas (head and mucosa) are more common in type I cryoglobulinemia, as are livedo reticularis, Raynaud phenomenon, and ulcers. Nail fold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.[1,3]
Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always seen in mixed cryoglobulinemia. Renal involvement is one of the most serious complications of cryoglobulinemia, and it typically manifests early in the course of the disease (within 3-5 years of diagnosis). This may progress to complete renal failure. Hypertension and nephritic-range proteinuria with resultant edema are characteristically seen in cryoglobulinemia.[2,4]
A reduction in forced expiratory flow rates and the presence of interstitial infiltrates are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic, with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare. Neuropathy is common in types II and III disease, affecting 70-80% of patients. Sensory neuropathy is more common than motor neuropathy (5% of patients). Abdominal pain has been reported in 2-22% of patients. Vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported. Splenomegaly may be seen in these patients.
The differential diagnosis of cryoglobulinemia includes antiphospholipid syndrome, chronic lymphocytic leukemia, Churg-Strauss syndrome, cirrhosis, giant cell arteritis, glomerulonephritis, Goodpasture syndrome, hemolytic-uremic syndrome, hepatitides, non-Hodgkin lymphoma, microscopic polyangiitis, multiple myeloma, polyarteritis nodosa, sarcoidosis, serum sickness, systemic lupus erythematosus, and Waldenström hypergammaglobulinemia.[2,3]
Key lab studies include evaluation for serum cryoglobulins. The specimen must be obtained in warm tubes (98.6°F or 37°C) without anticoagulants and then allowed to clot before centrifugation. The serum is then incubated at 39.2°F (4°C). Type I tends to precipitate within 24 hours. Type III may require 7 days to precipitate. Specific immunologic assays may be used to identify cryoglobulin components (immunoglobulins, light chains, clonality).
Urinalysis, serum creatinine, and electrolytes are important to evaluate for evidence of renal disease. A complete blood cell (CBC) count should be done to screen for infection, anemia, or leukemia. Abnormal liver function studies and transaminases may suggest underlying hepatitis. If so, hepatitis serologies are indicated. If hepatitis C virus test results are negative and clinical suspicion remains high, serologies may be performed on the cryoprecipitate. Rheumatoid factor is positive in types II and III. ANA is indicated upon clinical suspicion of underlying connective-tissue disease. ESR elevation is nonspecific, and it may occur in the presence of a number of associated inflammatory disorders. Patients may display hypocomplementemia (especially low C4 levels). The clinician should consider serum protein electrophoresis, urine protein electrophoresis, and quantitative immunoglobulin if there is suspicion for underlying gammopathy.[3]
Clinical imaging should be ordered as warranted based on suspected underlying disease. Tissue biopsy may be required for diagnosis in patients with vasculitis and/or renal disease. Purpura is characterized by dermal vasculitis that extends variably to the subcutaneous tissue. Hepatitis C virus—associated proteins have been found in vasculitic skin biopsy specimens. Although samples generally exhibit inflammatory vascular changes, intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli.
The management of cryoglobulinemia should be focused on treating underlying conditions, as well as limiting the precipitation of cryoglobulins and the resultant inflammatory effects. Asymptomatic cryoglobulinemia does not require treatment. When treatment is required, it is based on suppression of the immune response.[2]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in patients with arthralgia and fatigue, but may be contraindicated in patients with renal disease. Immunosuppressive medications (eg, corticosteroids, cyclophosphamide, azathioprine) are indicated in cases with evidence of organ involvement, such as vasculitis, renal disease, progressive neurologic findings, or severe skin manifestations.[2]
Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for the reduction of immunoglobulin production.[2]
Pegylated interferon alfa combined with ribavirin has been demonstrated to be effective in patients with cryoglobulinemia associated with hepatitis C, and efficacy in patients with chronic myelogenous leukemias and low-grade lymphomas has been reported.
Rituximab (anti-CD20 chimeric monoclonal antibody) has shown promise in controlling vasculitis, peripheral neuropathy, arthralgias, low-grade B-cell lymphomas, renal disease, and fever, specifically in patients with hepatitis C virus—related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral therapy. Studies have not yet been published on its efficacy and safety in the setting of other types of cryoglobulinemia.[2,4]
The patient in this case was referred to rheumatology and prescribed a course of oral corticosteroids. She was also referred to dermatology and had azathioprine added to her treatment. The lesions began to slowly shrink and lift at the edges (see Figure 2). Serial debridements were performed. Appropriate wound care was provided by her caregiver under instruction and supervision of the wound center. Following this care plan, the patient has had nearly complete resolution of most of her lesions (see Figure 3). She developed a persistent pancytopenia despite discontinuation of the azathioprine. She was referred to a hematologist and now has evidence of multiple myeloma based on bone marrow biopsy, with continued positive cryoglobulins.
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