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Cryoglobulinemic Vasculitis
Introduction
Cryoglobulinemic vasculitis (CryoVas) is an immune complex-mediated inflammation of the small and medium-sized blood vessels, involving complement activation.[1] In 1933, Wintrobe and Buell discovered “cryoprecipitate” in the blood from a patient suffering from multiple myeloma. In 1947, Lerner and Watson coined the term “cryoglobulin” and it applies to immunoglobulins that can precipitate in vitro, from plasma as well as serum when the temperature falls below 37 C and re-solubilize on warming.[2] CryoVas is famously associated with Hepatitis C (Hep-C) as well as some B-cell related blood dyscrasias.
Etiology
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Etiology
Cryoglobulins can be detectable in the serum of patients with several inflammatory conditions; however, they do not always lead to the disease. The real mechanism of cryoprecipitation is complicated and still not completely understood. It is sometimes attributed to the intrinsic properties of the Immunoglobulin components.[3][4] Cryoglobulinemic vasculitis can rarely occur by itself and is usually secondary to other diseases. Brouet classified cryoglobulins into 3 major groups based on the immunoglobulin type [5]:
- Type 1 cryoglobulins comprise monoclonal immunoglobulins, usually IgM, less frequently IgG, IgA, or light chains. Although rare, they are also found in plasma cell dyscrasias like multiple myeloma and monoclonal gammopathy of unknown significance, B cell diseases like Waldenstorms macroglobulinemia, lymphoproliferative diseases like Non-Hodgkin lymphoma and chronic lymphocytic leukemia.[6]
- Type 2 cryoglobulins consist of monoclonal IgM with rheumatoid factor (RF) activity and polyclonal IgG.
- Type 3 cryoglobulins involve polyclonal IgM with RF activity and polyclonal IgG.
- Newer techniques like immunoblotting have helped identify a novel mixed cryoglobulin, which is called type II to III (it is type II cryoglobulin with microheterogeneity) as it has a simultaneous presence of oligoclonal IgM and polyclonal IgG.[7] This type has not been studied in detail.
RF activity denotes the binding capacity of IgM to the Fc fragment of IgG. Type 2 and Type 3 are referred to as mixed cryoglobulins. They are commonly associated with infections, autoimmune diseases, and lymphoproliferative disorders:
- Among infections, Hepatitis C is the most common.[8][9] Other infections include Hepatitis B, Cytomegalovirus, Epstein B virus, Parvovirus B19, HIV, pyogenic bacterial infections, candidiasis, visceral leishmaniasis, and Coxiella burnetii.[10][11][12][13]
- Autoimmune conditions include systemic lupus erythematosus and Sjogren syndrome.[14][15] Giuggioli et al. have found that 2.8% of systemic sclerosis (SSc) cases can have cryoglobulins, of which 1.6% can have manifestations, and they are linked to HCV.[16][15] This overlap syndrome can cause severe vasculopathy symptoms like non-healing ulcers with gangrene.
- Lymphoproliferative disorders like diffuse large B cell lymphoma and Non-Hodgkin lymphoma.[17]
Epidemiology
The prevalence of cryoglobulinemic vasculitis is rare (1:100,000) with significant geographic variations. It is commonly seen in patients aged 45 to 65 years with a maximum incidence in women (sex ratio is 2-3:1).[18] The disease is more common in southern Europe, which might be related to the endemic prevalence of hepatitis C.[19] 20% to 50% of patients with hepatitis C can have serum cryoglobulins; however, only up to one-third of these develop clinical cryoglobulinemic syndrome.[20]
Pathophysiology
Type 1 cryoglobulins usually cause hyperviscosity syndrome or vasculitis.[21]
Mixed cryoglobulins can be present in normal healthy individuals without causing symptoms.[22] It has been hypothesized that heavy chain glycosylation and other stereotactic properties can influence the activation of complement and Fc receptor of macrophage.[23] There is a role of genetic factors like the presence of BAFF (B-lymphocyte activating factor) and Fc receptor variants, especially in Hepatitis C infected individuals.[24] It is hypothesized that Hepatitis C envelope protein E2 can bind with the B lymphocyte CD81 receptor, thereby acting as an antigenic stimulus. This leads to the formation of antibodies and the resulting antigen-antibody complexes that get deposited in vessel walls.[25][26] Few cases of sustained vasculitis despite viral clearance indicate that the B cell clones persist despite antigen clearance.[27][28][29][30][31] It was also observed that B cell-activating factor (BAFF) levels increase despite the completion of antiviral treatment in patients with HCV leading to relapses.[32]
Histopathology
Among type 1 cryoglobulinemic vasculitis, occlusion of vessels can occasionally occur with eosinophilic precipitates. It can be distinguished from fibrin with periodic acid Schiff stain.[33] Leukocytoclastic vasculitis involving the small vessels is the major histopathology in Hep-C associated cutaneous lesions, and vessels from the dermis up to the subcutaneous fat layer can be affected.[26] Immunofluorescence in cryoglobulinemic vasculitis reveals complement and immunoglobulin deposition. The immunoglobulins identified on immunofluorescence vary for each type of cryoglobulinemic vasculitis, for example, in mixed cryoglobulinemic vasculitis, both IgG and IgM deposition along with complements will be seen, while in type I, deposition of a single type of immunoglobulin (most commonly IgM) with complements is seen. Agnello V et al. have demonstrated that the Hep-C virus is concentrated in the cryoprecipitate compared to its presence in the serum.[34] In another study, they have demonstrated the presence of HCV particles in the vascular endothelium of skin lesions.[35]
Membranoproliferative glomerulonephritis is the frequent type of kidney involvement in cryoVas whether or not related to Hep-C.[36][37] Mesangial proliferative glomerulonephritis and focal proliferative glomerulonephritis are occasionally found.[38] Luminal thrombi in capillary walls have also been seen.[39]
History and Physical
Identification of cryoglobulinemic vasculitis clinically is important because of its potential life-threatening and limb depriving complications.[38]
Type 1 cryoglobulinemia has frequent manifestations of skin like Raynaud’s phenomenon, ulcers, gangrene, and rarely involves kidneys.[6][40]
In mixed cryoglobulinemia, the skin, musculoskeletal system, and kidneys are frequently affected. Historically, Meltzer has described the triad of arthralgias, purpura, and weakness.[41]
- Cutaneous lesions include palpable purpura in dependent areas, digital ulcers, gangrene.[42]
- Musculoskeletal manifestations are arthralgias in hands and knees with no arthritis.
- Neurological symptoms are commonly bilateral and symmetrical. It can be distal sensory or sensorimotor polyneuropathy.[43][44]
- Renal involvement generally means worse prognosis and presents with hematuria, proteinuria, worsening renal function.
Other rare manifestations are:
- CNS vasculitis which can present with hemiplegia, coma, encephalopathy, or seizures.[38][45][38]
- Gastrointestinal - mesenteric vasculitis, duodenal vasculitis, or pancreatitis which present with abdominal pain.[29][38][29]
- Pulmonary hemorrhage can also be a rare presentation with hemoptysis, dyspnea, or respiratory failure as first signs.[38]
- Hypertrophic cardiomyopathy presents with dyspnea on exertion.[46]
- Pericarditis, coronary vasculitis, and heart failure.
- Hyperviscosity syndrome
- Dry eyes and dry mouth
- Parotitis, which is usually bilateral
Evaluation
Baseline complete blood counts, renal function, urinalysis, urine microscopy, and urine protein evaluation (urine protein by creatinine ratio, or 24-hour urine protein) should be performed in all patients with a suspicion of cryoglobulinemic vasculitis. Markers of inflammation, including erythrocyte sedimentation rate and C-reactive protein, may be elevated.
Cryoglobulin Detection
Accurate detection of cryoglobulins can be difficult, and false-positive and false-negative values are not uncommon. The blood shall be drawn into preheated tubes at 37°C until coagulated followed by centrifugation after which, it should be stored at 4°C for 7 days. A white precipitate indicates the presence of cryoglobulins at the bottom of the tube, which dissolves when the tube is rewarmed to 37°C. Quantification of cryoglobulins shall be determined by measuring the percentage of cryoglobulins. Cryoglobulins shall be then characterized by immunologic methods, including immunofixation and immunodiffusion, which help identify the type of immunoglobulin involved. As noted above, false-positive and false-negative test results are common and repeated testing increases accuracy.
Serologic Testing
Rheumatoid factor testing shall be pursued in all patients with a suspicion of cryoglobulinemic vasculitis. Complement levels shall be tested as well and will usually indicate low serum C4 and normal C3. Serological workup including ANA, Anti-SSA, Anti-SSB, Anti-Ds-DNA, Anti-Smith, and other autoantibodies to detect underlying autoimmune diseases such as systemic lupus erythematosus or Sjogren syndrome shall be considered based on the patient's clinical presentation.
Infection Workup
Viral hepatitis screening, including anti-hepatitis C viral antibody, hepatitis C viral RNA PCR, hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody, shall be performed to detect underlying viral hepatitis. Workup for other potential infectious etiology can be considered on an individual basis.
Malignancy Workup
Complete blood count with differential, peripheral smear, flow cytometry for evaluation of underlying leukemia or lymphoma should be considered. Serum protein electrophoresis and quantitative immunoglobulins shall be considered to rule out multiple myeloma or monoclonal gammopathy of unknown significance. Bone marrow or lymph node biopsy may be needed in some cases.
Pathological Workup
Skin biopsy of cutaneous lesions can be done (and is recommended if initial presentation). Skin biopsy shall be sent for histopathology and for immunofluorescence to identify immune-complexes. In cases of suspicion of renal involvement, renal biopsy shall be considered.
Treatment / Management
Treatment of cryoglobulinemic vasculitis can require combined inputs from different specialties like hepatologists, rheumatologists, and hematologists, depending on the underlying disease present and the severity of the illness.[47]. The treatment is dictated by the underlying associated etiology, disease severity, and organ involvement. Treatment should be aimed at suppressing B-cell proliferation, eradicating hepatitis C viral infection when present, and reducing circulating immune complex-mediated damage.(B3)
Immunosuppressive Therapy
In patients with life-threatening or severe manifestations such as mesenteric vasculitis, pulmonary hemorrhage, and rapidly progressing glomerulonephritis, treatment with plasmapheresis and high dose corticosteroids is the first-line therapy. Immunosuppression with rituximab or cyclophosphamide in combination with plasmapheresis and high-dose corticosteroids reduces the risk of relapse. Antiviral therapy for hepatitis C virus is not considered first-line in life-threatening manifestations as the immune process can become independent of viral antigen triggering. Milder manifestations, including skin rash/ulcers, glomerulonephritis, and peripheral neuropathy all respond well to corticosteroids and rituximab with resolution in the symptoms within 6 months of starting rituximab.[48][49] However, repeat courses of rituximab may be needed to maintain remission.[47] Regimens containing cyclophosphamide and corticosteroids were also tried in this group. Patients who have associated other autoimmune diseases such as systemic lupus erythematosus or Sjogren syndrome also usually respond well to corticosteroids. Immunosuppressive therapy, such as cyclophosphamide for more serious manifestations, methotrexate for milder manifestations, and mycophenolate mofetil for refractory cases, can be used.[50][51] (B2)
Antiviral therapy:
In patients with cryoglobulinemic vasculitis associated with hepatitis C infection who have milder manifestation, simultaneous treatment of immunosuppressive therapy, as documented above with antiviral therapy (for hepatitis C viral infection), has been shown to be effective and is the cornerstone of management. Antiviral therapy involving a combination of ribavirin with direct-acting agents like sofosbuvir has shown to be effective.[52][53] Rituximab, in combination with antiviral therapy involving interferon, seemed to show better clinical outcomes compared to antiviral treatment alone in some trials.[54][55] Rituximab also showed quicker response rates and better renal relapse rates compared to antiviral therapy alone.[56] It has helped achieve remission in cases where antiviral therapy has failed.[57][58] Although sustained virologic response seems to correlate well with remission of cryoglobulinemic vasculitis, there are rare instances of persistent cryoglobulins and related symptoms despite viral clearance.[31][30][59][30] This has been attributed to the B cell clonal stimulation, and therefore long term follow-up is essential.(A1)
Other Therapeutic Considerations
Cryoglobulinemic vasculitis associated with B-cell dyscrasias and lymphoproliferative diseases can be treated with the disease-specific chemotherapy and occasionally requires immunosuppression. Cyclophosphamide, dexamethasone, and thalidomide can treat cutaneous symptoms (with no renal involvement).[60] Bortezomib has been successfully used to treat cryoglobulinemic vasculitis related to multiple myeloma and MGUS.[6][61] It was found to be effective in treating patients with concomitant cryoglobulinemic vasculitis and cold agglutinin disease.[62] It was also used in rituximab resistant disease with favorable results.[63] Plasmapheresis is done in life-threatening complications like renal failure or severe cutaneous necrosis.[21](B3)
In patients with cryoglobulinemic vasculitis and hepatitis B infection, treatment with rituximab alone without antiviral therapy can lead to severe reactivation of hepatitis B. It is recommended that antiviral therapy be started before or concomitantly with immunosuppressive therapy (especially rituximab) in these patients.[64][65](B3)
Other infections causing mixed CryoVas can be treated with specific antimicrobial therapy for sustained remission, immunosuppression is to be used only in refractory cases.[10](B3)
IV immunoglobulin treatment is contraindicated in CryoVas as it can cause immune complex precipitation leading to multi-organ failure.[66]
TNF-alpha inhibitors are not to be used in CryoVas as they have shown to cause early relapses and occasional worsening of neuropathy and skin ulcers.[67][68](B3)
Differential Diagnosis
Systemic lupus erythematosus can cause cutaneous vasculitis, cytopenias, arthralgias, positive RF, and glomerulonephritis. Further, there can be overlap with patients with underlying systemic lupus erythematosus developing cryoglobulinemic vasculitis. Systemic lupus erythematosus is usually associated with low complements, both C3 and C4, and not just isolated C4 depletion. Serum cryoglobulin detection and pathological evaluation are critical in differentiating these two conditions.
Rheumatoid arthritis is associated with joint pain and a positive RF. Rarely, leukocytoclastic vasculitis can be seen in rheumatoid arthritis as well. However, rheumatoid arthritis is associated with the presence of inflammatory arthritis and synovitis, which is usually absent in cryoglobulinemic vasculitis, where patients have arthralgias but usually lacks true synovitis. Further, anti-CCP antibodies are specific for rheumatoid arthritis and are not seen in cryoglobulinemic vasculitis. Renal involvement is rare in rheumatoid arthritis. Complements are usually normal in rheumatoid arthritis. Cryoglobulins will be absent.
Systemic sclerosis can cause cutaneous manifestations like digital ulcers and gangrene. However, other clinical features of systemic sclerosis, including sclerodactyly, calcinosis, interstitial lung disease, gastrointestinal dysmotility, are not seen in cryoglobulinemic vasculitis. Renal involvement in systemic sclerosis is rare and is manifested as scleroderma renal crisis which is different from cryoglobulinemic vasculitis induced glomerulonephritis. Both of these can be differentiated by kidney biopsy.
Henoch Schlein purpura (HSP) causes palpable purpura in lower extremities but can be differentiated by immunofluorescence of skin biopsy. In HSP, immunofluorescence usually shows the deposition of IgA and not immune complexes.
Prognosis
Mortality rates for cryoglobulinemic vasculitis are higher compared to the general population.[69] Most deaths occur due to renal involvement or widespread vasculitis, especially gastrointestinal involvement. The use of antiviral treatment results in better outcomes; however, several poor prognostic factors have been documented.
Poor prognostic features of cryoglobulinemic vasculitis in association with hepatitis C viral infection include:
- Presence of severe liver fibrosis at the time of diagnosis
- In the absence of liver fibrosis, five-factor score (FFS) developed by Guillevin et al., which takes into account- proteinuria greater than 1 g/day, serum creatinine greater than 150 micromol/L, cardiomyopathy, gastrointestinal and CNS involvement, seemed to correlate with prognosis.[70][71]
- Gastrointestinal vasculitis seemed to have a poor prognosis.[29][72]
The prognostic factors in non-infectious mixed cryoglobulinemic vasculitis include CryoVas score (age greater than 65, pulmonary and gastrointestinal involvement, and renal failure).[73][74]
Poor prognostic features in type 1 cryoglobulinemia are old age and renal involvement. Sign of neuropathy on presentation was also found to be one of the poor prognostic indicators in a retrospective study.[75]
Complications
- B-cell lymphomas are commonly found in mixed cryoglobulinemic vasculitis patients.[76] Treatment is directed against B-cell lymphoma.
- The presence of mixed cryoglobulinemic vasculitis in Hep-C infected individuals is associated with increased mortality, whereas, in other infections, prognosis relies on the infection itself.[42]
- The major causes of death include Hep-C related hepatopathy and severe infections related to immunosuppressive therapy used.
- Multiorgan involvement can occur, which is always a poor prognostic sign.[66][77][38]
Deterrence and Patient Education
Cryoglobulinemic vasculitis can result in debilitating symptoms like painful neuropathy or complications like gangrene requiring amputations. It is also associated with an increase in mortality and sometimes has many relapses throughout the disease process. Hence it is important to initiate appropriate treatment early in the disease course and have a long term follow up.
Pearls and Other Issues
Cryoglobulins in the serum can interfere with other lab detection tests like troponin assays and should be kept in mind when there are no clinical features.[78]
A patient with fever, valvular heart disease, negative cultures in the setting of mixed cryoglobulinemia must be evaluated for Q fever.
Enhancing Healthcare Team Outcomes
Although cryoglobulinemic vasculitis is predominantly associated with Hepatitis C virus infection, various specialties are involved in the management of these patients. Gastroenterologists play a role in initiating antiviral therapy along with monitoring the viral load for hepatitis C. Dermatologists are involved when a skin biopsy is needed. The pathologist also plays a role as he could suggest the diagnosis based on labs and biopsies. Rheumatologists are frequently involved in managing severe or resistant cases as they have more experience with immunosuppressive therapies. When cryoglobulinemic vasculitis is related to non-Hepatitis C infections, we need appropriate antibiotic therapy to treat the infection, which may be acting as a trigger. Pharmacists help adjust the doses of medications based on renal function and in monitoring drug interactions. Patients can have complications like multiorgan failure, requiring critical care, and the nursing role is immense in taking care of these patients and in educating the families. Wound care is important as the patients frequently have nonhealing ulcers and gangrene when general surgeons help salvaging the limbs. Hematologists play a major role in treating hematologic malignancies and when complications like lymphoma arise. Primary care physicians play a major role in identifying the disease, as it frequently presents with common outpatient complaints like a purpuric rash, arthralgias, and neuropathic pain. They also play a key role as a mediator between the various specialties, while advocating for the patient and keeping them well-informed. [Level 5]
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