Residency · Residency · Rheumatology

IgA Vasculitis and Cryoglobulinemic Vasculitis

Introduction

IgA vasculitis, formerly known as Henoch-Schonlein purpura, and cryoglobulinemic vasculitis are immune complex-mediated small-vessel vasculitides that share the common pathogenic mechanism of complement activation and immune complex deposition in vessel walls. IgA vasculitis is characterized by IgA-dominant immune deposits and represents the most common systemic vasculitis in children. Cryoglobulinemic vasculitis involves cryoglobulin-containing immune complexes and is strongly associated with hepatitis C virus infection.

IgA Vasculitis (Henoch-Schonlein Purpura)

Epidemiology

IgA vasculitis is the most common systemic vasculitis in children, with peak incidence between 3 and 10 years of age. Adult IgAV is less common but tends to be more severe, particularly with respect to renal involvement. The incidence is 10 to 20 per 100,000 in children and 0.8 to 1.8 per 100,000 in adults. There is a mild male predominance with a ratio of approximately 1.5 to 1. The disease shows a seasonal predilection for autumn and winter and often follows an upper respiratory infection.

Pathogenesis

The central pathogenic event is the deposition of IgA1-containing immune complexes in small vessel walls and the renal mesangium. Aberrantly glycosylated IgA1, specifically galactose-deficient IgA1, is the key pathogenic molecule and is the same molecule implicated in primary IgA nephropathy, highlighting the shared pathobiology of these conditions. Triggers include upper respiratory infections with Streptococcus and various viral agents, as well as medications, vaccinations, and certain foods. Complement activation proceeds via the lectin and alternative pathways rather than the classical pathway, resulting in C3 deposition without C1q involvement. Genetic susceptibility involves familial clustering and reported HLA-DRB1 associations.

Clinical Manifestations

IgA vasculitis classically presents with a tetrad of palpable purpura, arthritis or arthralgia, abdominal pain, and renal involvement.

Skin (100%)

Palpable purpura is mandatory for diagnosis and is non-thrombocytopenic, distinguishing it from thrombotic causes of purpura. The distribution is characteristically gravity-dependent, affecting the lower extremities and buttocks, with rare involvement of the upper extremities or trunk. The rash may be preceded by urticarial or maculopapular lesions. Skin biopsy demonstrates leukocytoclastic vasculitis with IgA deposits on direct immunofluorescence.

Musculoskeletal (60-80%)

Arthritis and arthralgia are oligoarticular, most commonly affecting the knees and ankles. The joint involvement is non-erosive, non-deforming, and self-limited. Periarticular swelling is common.

Gastrointestinal (50-75%)

Colicky abdominal pain results from submucosal hemorrhage and edema in the bowel wall. Gastrointestinal hemorrhage manifests as melena or hematochezia. Intussusception occurs in 1 to 5 percent of cases, characteristically ileoileal in location, which differs from the ileocolic pattern typical of idiopathic intussusception in children. Bowel perforation and pancreatitis are rare complications. Endoscopy reveals purpuric lesions predominantly in the duodenum and proximal jejunum.

Renal (20-60%)

Renal involvement is the most important prognostic determinant and determines long-term outcome. Manifestations range from microscopic hematuria, the most common renal finding, to proteinuria, nephrotic syndrome, and rapidly progressive glomerulonephritis. Renal involvement usually appears within 1 to 3 months of disease onset but may develop up to 6 months later, necessitating prolonged monitoring. Histology reveals IgA-dominant mesangial deposits that are indistinguishable from primary IgA nephropathy, with grading performed using the ISKDC classification or the Oxford MEST-C classification. Adult IgAV nephritis is more severe, with 10 to 20 percent progressing to end-stage renal disease, while pediatric disease is usually self-limited with fewer than 5 percent progressing to ESRD.

Diagnosis

The 2012 EULAR/PRINTO/PRES criteria for children require purpura as a mandatory criterion plus at least one of diffuse abdominal pain, IgA on biopsy, arthritis or arthralgia, or renal involvement. The 2022 ACR/EULAR criteria for adults employ a similar weighted approach. Serum IgA is elevated in approximately 50 percent of patients but is not diagnostic. Complement levels including C3 and C4 are usually normal, which distinguishes IgAV from SLE and cryoglobulinemic vasculitis. Coagulation studies show a normal platelet count, distinguishing the condition from TTP and ITP. Skin biopsy with direct immunofluorescence demonstrating leukocytoclastic vasculitis with IgA deposits in vessel walls represents the gold standard for diagnosis.

Management

Mild disease limited to skin and joints is managed with supportive care and NSAIDs for arthritis. The condition is self-limited in most children, with 90 percent resolving within 4 to 6 weeks. Gastrointestinal involvement, when severe, is treated with glucocorticoids at prednisone 1 to 2 milligrams per kilogram per day for 1 to 2 weeks followed by a taper, with surgical consultation for intussusception or perforation. Renal involvement is stratified by severity: mild disease with isolated hematuria and mild proteinuria is monitored with ACE inhibitors or ARBs for proteinuria management; moderate to severe disease with nephrotic-range proteinuria, declining GFR, or crescents on biopsy warrants glucocorticoids plus immunosuppression. No high-quality randomized controlled trial data exist specifically for IgAV nephritis, and treatment is largely extrapolated from IgA nephropathy and lupus nephritis trials. Options include glucocorticoids plus mycophenolate mofetil, or glucocorticoids plus cyclophosphamide for severe crescentic disease, with KDIGO guidelines suggesting immunosuppression for crescentic IgAV nephritis. The PREDNOS trial demonstrated that early prophylactic glucocorticoids in children did not prevent the development of nephritis. Recurrence occurs in 30 to 40 percent of children, though recurrent episodes are usually milder. Adult recurrence is less common.

<image>A clinical presentation diagram of IgA vasculitis showing the classic tetrad on a child figure. (1) Skin: Palpable purpura distributed on the lower extremities and buttocks, with magnified view showing raised, non-blanching, violaceous papules; inset of skin biopsy showing leukocytoclastic vasculitis with neutrophilic infiltration of small vessel walls and IgA deposits on direct immunofluorescence (green fluorescence in vessel walls). (2) Joints: Swollen knees and ankles with periarticular edema. (3) Abdomen: Cross-section showing submucosal hemorrhage and edema in the small bowel wall; inset of intussusception diagram. (4) Kidneys: Glomerulus showing mesangial IgA deposits on immunofluorescence and mesangial proliferation on light microscopy. Include a timeline at bottom showing typical disease course: infection trigger → purpura onset → joint/GI symptoms → renal involvement (up to 3 months later).</image>

Cryoglobulinemic Vasculitis

Cryoglobulin Classification (Brouet)

The Brouet classification divides cryoglobulins into three types. Type I consists of a monoclonal immunoglobulin, either IgM or IgG, and is associated with lymphoproliferative disorders including Waldenstrom macroglobulinemia, myeloma, and chronic lymphocytic leukemia. Type I causes hyperviscosity syndrome and thrombosis but not true vasculitis. Type II consists of monoclonal IgM with rheumatoid factor activity plus polyclonal IgG and is the most common type, strongly associated with HCV in 80 to 90 percent of cases. Type II produces true immune complex vasculitis. Type III consists of polyclonal IgM with rheumatoid factor activity plus polyclonal IgG and is associated with autoimmune diseases and infections, causing vasculitis less commonly.

Epidemiology

Among HCV-infected patients, 40 to 60 percent have detectable cryoglobulins, though only 5 to 10 percent develop clinically significant vasculitis. Non-HCV causes include hepatitis B, HIV, systemic lupus erythematosus, Sjogren syndrome, and lymphoproliferative disorders. Essential or idiopathic mixed cryoglobulinemia is rare and diagnosed only after excluding all secondary causes. The female-to-male ratio is approximately 3 to 1.

Pathogenesis

Hepatitis C virus drives B cell activation and clonal expansion, producing monoclonal IgM with rheumatoid factor activity. Immune complexes composed of IgM, IgG, and HCV RNA deposit in small vessel walls. Complement activation proceeds through the classical pathway, consuming C4 while C3 remains normal or only mildly decreased, a pattern that is diagnostically useful. The rheumatoid factor activity of the IgM cryoglobulin, which binds to the Fc portion of IgG, produces false-positive rheumatoid factor on serologic testing. Cryoprecipitation, the temperature-dependent precipitation of immune complexes below 37 degrees Celsius, causes vessel occlusion and contributes to clinical manifestations.

Clinical Manifestations

The Meltzer triad of purpura, arthralgias, and weakness is present in approximately 30 percent of patients.

Skin (80-95%)

Palpable purpura predominantly affecting the lower extremities may be ulcerating. Livedo reticularis is common. Cold-induced acrocyanosis produces Raynaud-like symptoms. Chronic, painful leg ulcers typically located on the ankles and shins are a characteristic and often debilitating feature. Urticaria occurs less commonly.

Musculoskeletal (50-80%)

Arthralgias are symmetric, affecting both large and small joints, and are usually non-inflammatory. True arthritis is less common and non-erosive.

Renal (20-35%)

Membranoproliferative glomerulonephritis type I is the most characteristic renal manifestation. Biopsy reveals mesangial and subendothelial immune complex deposits containing IgM, IgG, and C3. The clinical presentation includes proteinuria that is often in the nephrotic range, hematuria, hypertension, and renal insufficiency. "Pseudothrombi" in glomerular capillaries, representing intracapillary cryoglobulin deposits, are a distinctive histologic finding. Without treatment, progression to end-stage renal disease may occur.

Neurologic (30-70%)

Peripheral neuropathy is the most common neurologic manifestation, presenting as a symmetric distal sensory or sensorimotor polyneuropathy. Mononeuritis multiplex occurs less commonly than in PAN. Central nervous system involvement with stroke and cognitive impairment is rare.

Other

Hepatic involvement reflects the underlying HCV infection, with chronic hepatitis and cirrhosis. Sicca syndrome with dry eyes and mouth overlaps with Sjogren syndrome. The risk of B cell lymphoma, including MALT lymphoma and diffuse large B cell lymphoma, is increased.

Diagnosis

Cryoglobulin detection requires meticulous pre-analytical handling: blood must be drawn in pre-warmed tubes at 37 degrees Celsius, transported at 37 degrees Celsius, and serum separated at 37 degrees Celsius. The serum is then incubated at 4 degrees Celsius for at least 72 hours and up to 7 days for low-level cryoglobulins. False negative results are common with improper handling, making careful specimen processing essential. A cryocrit above 1 to 2 percent is usually significant. Immunofixation is used to type the cryoglobulin, with monoclonal IgM indicating Type II. Complement testing characteristically reveals low C4, often markedly so, with normal or mildly decreased C3, and low CH50. Rheumatoid factor is positive at high titer because the IgM cryoglobulin possesses intrinsic RF activity. HCV testing with anti-HCV and HCV RNA is mandatory in all patients with cryoglobulinemic vasculitis. Biopsy of skin reveals leukocytoclastic vasculitis with immune complex deposits of IgM, IgG, and C3, while renal biopsy demonstrates a type I MPGN pattern.

<image>A pathogenesis and clinical features diagram of HCV-associated cryoglobulinemic vasculitis. Top panel: Show the pathogenesis pathway - HCV infects hepatocytes and stimulates B lymphocyte clonal expansion via CD81 binding, producing monoclonal IgM with rheumatoid factor activity that binds polyclonal IgG, forming cryoglobulin-containing immune complexes that precipitate at <37°C and deposit in small vessel walls, activating complement (C4 consumption). Bottom panel: Show clinical manifestations on a female body figure - palpable purpura and leg ulcers on lower extremities, MPGN in kidneys (glomerulus showing mesangial proliferation, capillary wall thickening, subendothelial deposits, intracapillary pseudothrombi), peripheral neuropathy (stocking distribution), and arthralgias. Include laboratory findings box: positive cryoglobulins, low C4, positive RF, positive HCV RNA.</image>

Management

HCV-Associated Cryoglobulinemic Vasculitis

For mild to moderate disease presenting with purpura, arthralgias, and neuropathy, direct-acting antiviral therapy for HCV is the first-line treatment. Sofosbuvir-based regimens achieve sustained virologic response in more than 95 percent of patients, and cryoglobulinemic vasculitis often improves or resolves with SVR, though improvement may take months. Vasculitis can persist despite SVR in some patients due to an established, autonomous B cell clone.

For severe or life-threatening disease including rapidly progressive glomerulonephritis, severe neuropathy, GI vasculitis, or widespread skin ulcers, rituximab combined with DAA therapy is the preferred approach. Rituximab depletes the pathogenic B cell clone while DAA therapy eliminates the viral trigger. The CRYOVAS-RITUX trial demonstrated rituximab superiority over conventional immunosuppression for renal and overall response. Glucocorticoids are used for acute severe manifestations. Plasma exchange is indicated for hyperviscosity or severe renal or neurologic disease as it directly removes cryoglobulins. Cyclophosphamide should be avoided in HCV-positive patients because it may increase HCV viremia and lymphoma risk.

Non-HCV Cryoglobulinemic Vasculitis

Treatment is directed at the underlying cause: lymphoproliferative disease is treated with chemotherapy, and autoimmune diseases are treated according to their primary management. Rituximab is effective for non-HCV cryoglobulinemic vasculitis by depleting the pathogenic B cell clone. Glucocorticoids plus conventional immunosuppression are used for severe disease. Essential mixed cryoglobulinemia follows a rituximab-based approach.

Type I Cryoglobulinemia

Management targets the underlying lymphoproliferative disorder. Plasma exchange addresses acute hyperviscosity syndrome. Chemotherapy is directed at the underlying malignancy, whether diffuse large B cell lymphoma, Waldenstrom macroglobulinemia, or myeloma.

Comparison of IgAV and CryoVas

Key Clinical Pearls

• IgA deposits on skin or kidney biopsy are essential for distinguishing IgAV from other vasculitides
• Adult IgAV has worse renal prognosis than childhood IgAV; monitor urinalysis for up to 6 months after diagnosis
• Cryoglobulin sample handling is critical: blood must be collected and transported at 37°C to avoid false negatives
• Low C4 with positive RF and HCV should raise immediate suspicion for cryoglobulinemic vasculitis
• DAA therapy for HCV has transformed CryoVas outcomes; SVR can lead to vasculitis remission
• Rituximab is the preferred immunosuppressive agent for severe CryoVas; avoid cyclophosphamide in HCV-positive patients

References

1. Pillebout E, et al. IgA vasculitis (Henoch-Schonlein purpura) in adults. Autoimmun Rev. 2017;16(7):693-700.
2. De Vita S, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012;64(3):843-853.
3. Cacoub P, et al. Cryoglobulinemia vasculitis. Am J Med. 2015;128(9):950-955.
4. Ozen S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis. Ann Rheum Dis. 2010;69(5):798-806.
5. Gragnani L, et al. Directly acting antivirals in HCV-related mixed cryoglobulinemia: long-term effects. Medicine (Baltimore). 2018;97(51):e13516.

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