BOTTOM LINE

Immune complex mediated vasculitis is a group of small vessel vasculitis caused by deposition of immunoglobulin and/or complement on vessel walls. Common features include purpuric skin rash, neuropathy, and renal impairment. Pathology commonly reveals leukocytoclasic vasculitis (LCV) and fibrinoid necrosis with immune complex deposition on immunofluorescence. Specific vasculitis included under immune-complex mediated vasculitis include: anti-glomerular basement membrane disease, IgA vasculitis (Henoch-Schonlein purpura),  hypo-complementemic urticarial vasculitis, and Cryoglobulinemic vasculitis (aka: mixed cryoglobulinemia).
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ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE

AKA: Anti-GBM disease, Goodpasture Disease

—Epidemiology

• Population (Rare)
  • Incidence: <2/1,000,000 annually (European populations)
  • Prevalence: 10/1,000,000 hospitalized patients; 10-15% of crescentic GN in large biopsy series
  • Ethnicity: more commonly reported in Caucasian and Asian populations; rarer in African populations
• Age, sex
  • Bimodal age: 30’s and 60-70’s
  • Male predominance in younger patients, more pulmonary-renal syndrome
  • Female predominance in older patients, more renal-only involvement
• Risk factors
  • Genetic: HLA-DRB1*1501, -DRB1*0401, -DRB1*01
  • Environmental: smoking, possibly prodromal infection, alemtuzumab (used for multiple sclerosis)

—Clinical Manifestations

• Systemic
  • Weeks of malaise, weight loss, fever
• Renal
  • Acute glomerulonephritis 90%, ~ 50% require renal replacement therapy at diagnosis
• Respiratory
  • Diffuse alveolar hemorrhage, DAH (40-60%): dyspnea, cough/hemoptysis, or overt respiratory failure
  • Small minority may present with DAH without glomerulonephritis.
• Variants
  • Overlap Anti-GBM and ANCA-associated vasculitis
  • Anti-GBM with membranous nephropathy
  • Anti-GBM without circulating anti-GBM antibodies (but seen on biopsy)
  • Post-transplant anti-GBM

—Investigations

• Creatnine, urinalysis
  • Acute renal failure with red cell casts
• Serology
  • Anti-GBM antibody; all should be screened for ANCA as well
  • Also ANA, rheumatoid factor/cryoglobulins, blood cultures etc. as indicated for differential diagnosis
• Imaging
  • X-ray chest, if symptomatic or abnormal X-ray, CT chest
  • Consider bronchoscopy with serial lavage to diagnose pulmonary hemorrhage and for cultures
• Biopsy
  • Light microscopy: crescentic GN
  • Immunofluorescence: linear deposition IgG along glomerular capillaries

—Diagnosis

Suspect anti-GBM in patient presenting with acute GN (AKI, hematuria/proteinuria, casts), particularly if concomitant pulmonary hemorrhage. Confirm with anti-GBM serology and renal biopsy. Screen for infection, other vasculitis.

::: Differential Diagnosis

• ANCA-associated vasculitis, IgA-vasculitis, Mixed Cryoglobulinemia, lupus nephritis, phospholipid antibody syndrome (as a mimic, does not cause GN), pulmonary infection with associated AKI

—Treatment

Treat urgently with plasma exchange (PLEX) combined with prednisone and cyclophosphamide

• PLEX:
  • Daily 4 L exchange for 5% albumin solution until antibodies negative or for 14 days
• Glucocorticoid
  • Methylprednisolone 1g IV x 3 days then prednisone 1mg/kg/d (max 60 mg), taper to 20mg by 6 weeks, taper to discontinuation by month 6-9
• Cyclophosphamide IV or PO
  • Dosing similar to ANCA vasculitis; remember to adjust dose for renal function
• Alternative:
  • Rituximab, mycophenolate mofetil (less evidence than cyclophosphamide)
• Transplant:
  • Some may be candidates if progress to end stage renal disease

Overlap Anti-GBM/ANCA vasculitis: require longer maintenance after PLEX and cyclophosphamide; maintenance is similar to ANCA vasculitis (see ANCA vasculitis chapter)

IgA VASCULITIS (IgA-V)

Formerly known as Henoch Schonlein Purpura

—Epidemiology

• Population
  • Incidence: 3-26/100,000 children, 0.1-1.6/100.000 adults.
  • All ethnic groups described; lower incidence in African versus Caucasian or Asian children
• Age, Sex
  • Adults: age onset 50 years; Children: age onset 4-7 years;
  • M>F, 1.5-5.0 : 1.0
• Risk factor
  • Environmental: children typically present fall/winter; adults presentation is less seasonal though may be more common summer and winter

—Clinical Manifestations

Classic tetrad of pupura, arthritis, abdominal pain, renal disease

• Skin
  • Purpura (lower limb > upper limb > abdomen) 100%.
  • Skin necrosis (25%), hemorrhagic blisters (8%)
• MSK
  • Arthralgias 100%, arthritis; 15%. Lower > upper extremity migratory oligoarticular
• GI
  • GI symptoms often onset ~7 days after rash.
  • Pain 100%; bleed 31%, diarrhea 25%, Nausea 20%, perforation. Intussusception rare in adults.
• Renal
  • Prevalence 45-85% of IgAV
  • Renal failure present in 30% of adult IgAV, onset within 4 months of presentation
  • Clinically ranges from asymptomatic hematuria/proteinuria ±casts to progressive crescentic glomerulonephritis or nephrotic syndrome
  • Chronic renal failure in 80% and end stage renal disease in 10-30% of adult patients over follow-up
• Other
  • GU: testicular pain (orchitis)
  • Neuro: headache, seizures, encephalopathy, deficits, ataxia, peripheral neuropathy (rare)
  • Resp: Alveolar hemorrhage rare but reported
  • Ocular: rare uveitis, keratitis, scleritis
  • Cardiac: rare myocarditis, dysrhythmias

—Investigations

• CBC
  • Anemia, micro/normocytic, if bleeding. Leukocytosis, thrombocytosis (nonspecific)
• ESR, CRP
  • Elevated (non-specific)
• Creatinine, Urinalysis
  • Creatinine may be elevated; urinalysis may show varying degrees of hematuria or proteinuria
• C3, C4
  • May be low, particularly if post-infectious (ex: post-streptococcal infection) IgA vasculitis
• Serum IgA
  • Elevated serum IgA 50%, not specific for IgAV
• Biopsy
  Not always necessary; adults may need biopsy due to lower incidence IgAV and more atypical rash
  • Skin
    • Leukocytoclasic vasculitis. IgA and C3 deposition on immunofluorescence.
    • IgA deposition on skin biopsy: Sensitivity 81%, Specificity 83% PPV 84%, NPV 81% for IgAV
  • Renal
    • Consider if nephrotic or nephritic syndrome, persistent proteinuria >1g/d at 6 months despite RAAS blockade, or diagnostic uncertainty.
    • Biopsy findings range from mild mesangial hypercellularity to proliferative glomerulonephritis.
• Imaging
  • CT abdomen if abdominal pain to consider alternate diagnoses, may show lymphadenopathy
• Screening
  • Including: ANCA, ANA, RF, serologies (Hep B, C, HIV), cryoglobulins, blood cultures

—Diagnosis

Suspect IgA vasculitis in adult patient (more often pediatric) presenting with compatible purpuric skin rash with  joint pain, abdominal pain, and new renal disease with active urine sediment. Consider biopsy of rash; some may require renal biopsy if nephrotic/nephritic syndrome, persistent proteinuria, or diagnostic uncertainty. Differential includes other small-vessel vasculitis, infection and acute renal injury, other systemic rheumatic disease.

—Treatment

• Most cases resolve and only need supportive care or short course of steroids.
• Prednisone 0.5-1.0 mg/kg/d (max 40-60mg/d) if severe GI or renal manifestations tapered over 6 months
• Refractory: rare, reports of colchicine, dapsone, rituximab, MMF, azathioprine, calcineurin inhibitors, IVIG, cyclo.
• Limited data guide treatment discussed below

• Musculoskeletal
  • Analgesia, avoid NSAID is renal or GI involvement; colchicine 1.2 mg/d if needed
• Gastrointestinal
  • Benign
    • Mild abdominal pain
    • Symptomatic treatment, or dapsone, colchicine, low-dose prednisone
  • Severe
    • Ex: massive bleeding, perforation
    • Surgical evaluation ± surgery, Prednisone 1mg/kg/d ± pulse IV steroids ± cyclophosphamide 
• Renal
  • Mild
    • Hematuria, proteinuria <0.5 g/d, normal GFR: observe for 3-6 months.
      If persistent, add ACE-inhibitor
  • Moderate
    • Hematuria, proteinuria >0.5g/d, normal GFR: ACE-inhibitor0
  • Moderate-severe
    • Proteinuria >1g/d at 3-6month, acute/rapidly progressive renal failure, crescents on biopsy:
      • Prednisone 1mg/kg/d ± pulse IV steroids ± Cyclophosphamide similar to AAV
      • If failure of cyclophosphamide, may consider cyclosporine or rituximab

—Prognosis

• Relapses in 20% of adult cases
• 10-30% develop end-stage renal disease (ESRD), usually within 3 years of disease onset
• Factors associated with relapse
  • Disease onset at age > 30, persistent rash, abdominal pain, and hematuria
• Factors associated with ESRD
  • Baseline renal function impairment or proteinuria >1 or 1.5 g/day
  • Macroscopic hematuria
  • Hypertension
  • Proteinuria ≥1 g/day during follow-up
  • On renal biopsy: degree of interstitial fibrosis, sclerotic glomeruli and fibrinoid necrosis

URTICARIAL VASCULITIS (UV)

—Terminology

• Urticarial Vasculitis (UV)
  • Continuum of disease from urticaria with minimal skin vasculitis to life/organ threatening systemic vasculitis (hypocomplementemia associated with worse disease severity)
• Hypocomplementemic Urticarial Vasculitis (HUV)
  • · UV with hypocomplementemia, but only few or no systemic manifestations
• Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
  • 6 months urticaria with systemic symptoms, typically: arthritis, mild GN, uveitis/episcleritis, and recurrent
  • abdominal pain. Complement and Cq1 often low and biopsy shows small vessel vasculitis with deposits of immunoglobulins, complement or fibrin

—Epidemiology

• Epidemiology of HUV:
  • Unclear epidemiology: changing terminology, rare disease
  • Age: 40-55 years. Sex: F >> M.
  • Incidence: 0.7/1,000,000 annually; Prevalence: 9.5/1,000,000

—Clinical

• Skin
  • Urticaria in UV lasts >24h, more painful/burning/pruritic, resolves leaving purpura or hyperpigmentation.
  • Common benign urticaria: lasts <24 hours, mostly  pruritic, no residual skin changes
  • Other findings: angioedema (51%), purpura (35%), livedo (14%), target lesions, annular lesions, bullae
• Systemic
  • Fatigue, fever, weight loss (50%)
• Musculoskeletal (82%)
  • Inflammatory arthritis in 50%: migratory transient hand/elbow/feet/ankle/knees. Jaccoud’s arthropathy
  • Inflammatory arthritis more common in HUV rather than NUV
  • Myositis reported, may resemble idiopathic inflammatory myopathy
• Gastrointestinal (33%)
  • Abdominal pain, nausea, vomiting diarrhea
  • GI bleeding not noted as feature of UV
• Renal (14%)
  • Microscopic proteinuria/hematuria
  • Histology varies: Proliferative necrotizing GN, membranoproliferative GN, tubulointerstitial nephritis
• Respirological
  • Most common: COPD or asthma 20-50%.
  • Also: hemoptysis, pleuritis, pleural effusions, tracheal stenosis
  • Leading cause of morbidity and mortality
• Rare manifestations
  • Cardiac:
    • Pericarditis, pericardial effusion, cardiac tamponade, valvulopathy
  • Ophthalmologic:
    • Conjunctivitis, episcleritis, uveitis
  • Neurological:
    • Pseudotumor cerebri, cranial nerve palsies, axonal neuropathy, aseptic meningitis, peripheral neuropathy
• Associated Conditions
  • Systemic Lupus Erythematosus
    • Both UV and SLE can cause inflammatory arthritis, GN, low complement, ANA+
    • HUV more likely if angioedema, COPD/asthma, uveitis/episcleritis; should have no specific lupus rash
    • Some patients can present with overlap SLE/UV
  • Sjogren’s disease
    • · Sjogren’s more likely to be anti-Ro/SSA positive
  • Infection
    • Prodromal Hep B, Hep C, Lyme, infectious mononucleosis, or after vaccination
  • Other
    • Complement deficiency, IgM monoclonal gammopathy (Schnitzler’s syndrome), IgG/A/D gammopathy
    • Hematologic malignancy (leukemia, lymphoma), solid malignancy (adenocarcinoma, teratoma)
    • Drug-induced UV: including diltiazem, fluoxetine, Etanercept, Methotrexate, Cimetidine

—Investigations

• CBC
  • May see anemia, leukocytosis
• Creatinine, urinalysis
  • Send for baseline in case of renal involvement
• ESR, CRP
  • Elevated, nonspecific
• C3, C4
  • If HUV, low C3, C4. Low complement is a sensitive marker for systemic disease.
  • Also low C1, C2 and CH50 (evidence of classical pathway activation)
• C1q
  • Low C1q, positive anti-C1q antibodies (these antibodies also seen in SLE, indicate lupus-nephritis risk)
• ANA, ENA
  • ANA positive in many UV; may be challenging to differentiate with SLE; but ENA usually negative in UV
• Other
  • If systemic disease, for differential consider if indicated: ANCA, cryoglobulins, rheumatoid factor
• Infection
  • Screen for hepatitis B or C; consider Borrelia serologies if indicated on history
• Biopsy
  • Histology:
    Leukocytoclastic skin vasculitis (LCV)
  • Immunofluorescence
    Perivascular and/or basement membrane deposits of immunoglobulin or complement

—Diagnosis

Suspect HUVS in patients with painful urticaria lasting >24h and symptoms of systemic disease like angioedema, abdominal pain, renal injury, and arthritis. Low complement suggests systemic disease. ANA is positive in many, though ENA should be negative. Seek supportive skin biopsy showing LCV and perivascular and/or basement membrane deposits of immunoglobulin and complement.

::: Differential Diagnosis

• Benign chronic spontaneous urticaria, bullous pemphigoid, IgA vasculitis, Auto-inflammatory disease (Muckle-Wells Schnitzler’s, CAPS), allergic contact dermatitis, cutaneous mastocytosis, acquired angioedema

—Treatment

No standardized treatment. Treat according to clinical assessment of disease severity, based on case reports/series

• Mild
  • Symptomatic treatment with antihistamines, NSAIDs
• Moderate
  • Prednisone, dapsone, colchicine, hydroxychloroquine
• Severe Systemic
  • Mycophenolate mofetil, methotrexate, azathioprine, Rituximab, cyclosporine
  • Anakinra, Canakinumab, omalizumab

ERYTHEMA ELEVATUM DIUTINUM (EED)

• Epidemiology
  • Adults 40-60 years, all ethnicities. Presents earlier in those co-infected with HIV
• Clinical Manifestations
  • Eruption of violaceous red-brown/yellow papules, plaques, or nodules on extensor elbows, knees, ankles, hands and fingers. Less common face, trunk, axillae, buttocks, genitalia, palms, soles
  • Photographic examples
  • Differential diagnosis: Sweet’s syndrome, pyoderma gangrenosum, granuloma annulare, Kaposi’s sarcoma
• Disease Associations
  • Infection:
    • HIV, streptococcal, hepatitis B/C, tuberculosis
  • Hematologic:
    • Plasma cell dyscrasias, myelodysplasia, myeloproliferative/lymphoproliferative  disease
  • Autoimmune:
    • IBD, RA, relapsing polychondritis, SLE, GPA, dermatomyositis
• Biopsy
  • Leukocytoclastic vasculitis; immunofluorescence (not necessary) may show perivascular fibrin, complement, and immunoglobulins
• Treatment
  • Steroids and Dapsone 50mg/d titrated usually to 100mg/d (can go up to 300mg/d); get baseline G6PD
  • Other: Methotrexate, hydroxychloroquine IVIG, surgical excision, treating underlying disease (ex: GPA, Cancer)

REFERENCES

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Maritati, F., Canzian, A., Fenaroli, P., & Vaglio, A. (2020). Adult-onset IgA vasculitis (Henoch-Schönlein): Update on therapy. Presse medicale (Paris, France : 1983), 49(3), 104035. https://doi.org/10.1016/j.lpm.2020.104035

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