When the Body Attacks Itself: A Guide to Systemic Vasculitides

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

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Abstract

Systemic vasculitides represent a heterogeneous group of life-threatening disorders characterized by inflammation and necrosis of blood vessel walls. These conditions frequently present to intensive care units with multi-organ failure, rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage, or catastrophic vascular events. Early recognition and aggressive immunosuppressive therapy are critical to prevent irreversible organ damage and death. This review provides a practical approach to diagnosing and managing the most clinically significant systemic vasculitides encountered in critical care practice, with emphasis on ANCA-associated vasculitides, large vessel vasculitides, and cryoglobulinemic vasculitis. We discuss contemporary treatment strategies, including the evolving roles of cyclophosphamide and rituximab in induction and maintenance therapy.

Keywords: Vasculitis, ANCA, pulmonary-renal syndrome, giant cell arteritis, Takayasu arteritis, cryoglobulinemia, immunosuppression

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Introduction

Systemic vasculitides are uncommon but potentially catastrophic disorders that pose significant diagnostic and therapeutic challenges in critical care medicine. The annual incidence of ANCA-associated vasculitis (AAV) ranges from 13-20 cases per million population, with mortality rates approaching 20-25% at five years despite modern therapy.1,2 The classification of vasculitides has evolved significantly, with the 2012 Revised International Chapel Hill Consensus Conference (CHCC) nomenclature providing a framework based on vessel size and pathological features.3

Critical care physicians must maintain high clinical suspicion for vasculitis in patients presenting with:

Unexplained multi-organ dysfunction

Pulmonary-renal syndrome

Rapidly progressive glomerulonephritis (RPGN)

Diffuse alveolar hemorrhage (DAH)

Mononeuritis multiplex

Systemic inflammation with constitutional symptoms

Palpable purpura with systemic features

The cornerstone of management involves rapid diagnosis, assessment of disease severity, prompt initiation of immunosuppression, and meticulous supportive care. This review focuses on the vasculitides most relevant to intensive care practice and provides actionable guidance for the critical care physician.

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The ANCA-Associated Vasculitides (GPA, MPA, EGPA): The Pulmonary-Renal Syndrome

Clinical Overview

ANCA-associated vasculitides (AAV) comprise three distinct clinical syndromes: granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). These small-vessel vasculitides share the hallmark of anti-neutrophil cytoplasmic antibody (ANCA) positivity and pauci-immune necrotizing inflammation.4

GPA is characterized by necrotizing granulomatous inflammation affecting the upper and lower respiratory tracts, along with necrotizing glomerulonephritis. PR3-ANCA positivity occurs in 80-90% of generalized disease.5

MPA presents with necrotizing vasculitis affecting small vessels without granulomatous inflammation. MPO-ANCA is positive in 50-75% of cases, with prominent renal and pulmonary involvement.6

EGPA features asthma, peripheral eosinophilia, and vasculitis. Only 30-40% are ANCA-positive (usually MPO-ANCA), with ANCA-negative patients having more cardiac involvement.7

The Pulmonary-Renal Syndrome

The simultaneous occurrence of diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis defines pulmonary-renal syndrome—a medical emergency with mortality exceeding 50% without prompt treatment.8 AAV accounts for approximately 80% of pulmonary-renal syndrome cases presenting to ICU.

Clinical Presentation:

Hemoptysis (may be absent in 30-40% of DAH cases)

Progressive dyspnea and hypoxemic respiratory failure

Anemia disproportionate to visible blood loss

Ground-glass opacities or consolidation on chest imaging

Rapidly declining renal function (creatinine rise >0.5 mg/dL/day)

Active urinary sediment (dysmorphic RBCs, RBC casts)

Hematuria and proteinuria (usually sub-nephrotic)

Pearl: Serial hemoglobin measurements showing unexplained decline should prompt evaluation for DAH even without hemoptysis. The classic triad of hemoptysis, anemia, and infiltrates on chest X-ray is present in only 30% of DAH cases initially.9

Oyster: A normal hemoglobin does NOT exclude DAH. In acute presentations, intravascular hemoglobin may not have redistributed yet. Check hemoglobin 6-12 hours after presentation if clinical suspicion remains high.

Diagnostic Approach

Laboratory Evaluation:

ANCA testing: Both indirect immunofluorescence (IF) and antigen-specific ELISA (PR3 and MPO) should be performed

c-ANCA pattern with PR3-ANCA: highly specific for GPA (>95%)

p-ANCA pattern with MPO-ANCA: suggests MPA or EGPA

Sensitivity decreases with limited disease (60-70%)10

Urinalysis: Fresh urine microscopy is essential

Dysmorphic RBCs and RBC casts indicate glomerulonephritis

Protein-to-creatinine ratio (usually <3 g/g)

Complete blood count:

Eosinophilia >10% or >1,500/μL suggests EGPA

Anemia suggests chronic disease or DAH

Inflammatory markers: ESR and CRP are elevated (>90%) but non-specific

Complement levels: Normal C3 and C4 (helps exclude immune complex-mediated disease)

Imaging:

Chest CT: Ground-glass opacities, consolidation, nodules (cavitary in GPA), or infiltrates

Renal ultrasound: Usually normal-sized kidneys (helps exclude chronic kidney disease)

Bronchoscopy with bronchoalveolar lavage (BAL):

Progressively bloodier aliquots confirm DAH

Hemosiderin-laden macrophages (sensitivity ~90% after 48-72 hours)11

Essential to exclude infection and malignancy

Renal biopsy:

Gold standard for diagnosis when feasible

Pauci-immune necrotizing crescentic glomerulonephritis

Should not delay treatment in severely ill patients

Can be diagnostic even weeks after immunosuppression initiation

Hack: In critically ill patients with pulmonary-renal syndrome and positive ANCA serology (especially PR3-ANCA or MPO-ANCA), empiric treatment should be initiated immediately without waiting for biopsy confirmation. Biopsies can be obtained after stabilization. The specificity of PR3-ANCA in the appropriate clinical context approaches 95%.12

Disease Severity Assessment

The Birmingham Vasculitis Activity Score (BVAS) version 3 is the validated tool for assessing disease activity.13 For ICU management, pragmatic severity assessment includes:

Severe/Life-Threatening Disease:

Diffuse alveolar hemorrhage requiring mechanical ventilation

Rapidly progressive glomerulonephritis (creatinine >500 μmol/L or >5.7 mg/dL)

Cerebral vasculitis

Cardiac involvement

Mesenteric ischemia

Any organ-threatening or life-threatening manifestation

Five Factors Score (FFS) for EGPA: Predicts mortality and includes: cardiac symptoms, GI involvement, renal insufficiency, age >65 years, absence of ENT manifestations.14

Critical Care Management

1. Respiratory Support:

Early intubation for severe DAH (don't wait for complete respiratory failure)

Lung-protective ventilation strategies (tidal volume 6-8 mL/kg ideal body weight)

PEEP to recruit collapsed alveoli but avoid excessive airway pressures

Consider awake prone positioning or HFNC in milder cases

Pearl: Positive pressure ventilation may help tamponade alveolar hemorrhage

2. Renal Support:

Early nephrology consultation

Indications for emergent dialysis: refractory hyperkalemia, volume overload, uremia

Plasma exchange (see below) for severe renal disease

Avoid nephrotoxic medications

3. Hemodynamic Management:

Goal hemoglobin >7-8 g/dL (may need higher target with active bleeding)

Tranexamic acid has limited evidence but may be considered in severe DAH

Correct coagulopathy and thrombocytopenia before biopsy procedures

4. Infection Prophylaxis:

High index of suspicion for concurrent infection (present in 25-30% of AAV presentations)15

Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole or alternative)

Consider antifungal prophylaxis in high-risk patients

Oyster: Never assume infection and vasculitis are mutually exclusive. Obtain cultures before starting treatment, but do NOT delay immunosuppression if vasculitis is strongly suspected. Infections can trigger vasculitis flares and vice versa.

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Induction vs. Maintenance Therapy: The Roles of Cyclophosphamide and Rituximab

Treatment Paradigm

Management of AAV follows a two-phase approach: induction therapy to achieve disease remission (3-6 months) and maintenance therapy to prevent relapse (18-24 months minimum).16

Induction Therapy

1. Glucocorticoids: The backbone of induction therapy for all AAV patients.

Standard regimen:

Methylprednisolone 500-1000 mg IV daily × 3 days for severe/organ-threatening disease

Followed by oral prednisone 1 mg/kg/day (maximum 80 mg/day)

Taper beginning at 2 weeks: reduce by 10 mg weekly to 30 mg, then 5 mg weekly to 15 mg, then slower taper over months

Target discontinuation by 6-12 months if possible

Reduced-dose protocol (PEXIVAS trial): The PEXIVAS trial demonstrated non-inferiority of a reduced-dose glucocorticoid regimen (50-60% cumulative dose reduction) for death or end-stage renal disease, with significantly fewer serious infections.17

Reduced-dose regimen:

Methylprednisolone 500 mg IV daily × 3 days (if severe)

Oral prednisone 0.5 mg/kg/day (maximum 50 mg)

More rapid taper to 5 mg by week 23

Pearl: The PEXIVAS reduced-dose steroid regimen should be strongly considered for all AAV patients to minimize steroid toxicity without compromising efficacy. Serious infections decreased from 31% to 23% with the reduced regimen.17

2. Cyclophosphamide: A potent alkylating agent, cyclophosphamide was the gold standard for AAV induction for over 40 years following Fauci's landmark studies.18

Dosing:

IV pulse: 15 mg/kg (adjusted for age and renal function) every 2-3 weeks × 6 doses

Age >60: reduce by 2.5 mg/kg per decade

CrCl 10-30 mL/min: reduce by 2.5 mg/kg

CrCl <10 mL/min: reduce by 5 mg/kg

Daily oral: 2 mg/kg/day (adjusted for age and renal function) × 3-6 months

Higher relapse rates than IV in some studies

The CYCLOPS trial demonstrated non-inferiority of pulse IV cyclophosphamide compared to daily oral dosing, with reduced cumulative dose and leukopenia.19

Monitoring:

CBC with differential every 1-2 weeks (target nadir WBC 3,000-4,000/μL)

Mesna for hemorrhagic cystitis prophylaxis with high-dose IV

Aggressive hydration

Oncofertility counseling for reproductive-age patients

Toxicities:

Bone marrow suppression (neutropenia most common)

Hemorrhagic cystitis (5-15%)

Bladder cancer (5% at 10 years, 16% at 15 years with daily oral dosing)20

Infertility (nearly universal in women >30 years with cumulative dose >10 g)

Infections (20-30%)

Myelodysplasia/leukemia (<2%)

3. Rituximab: A chimeric anti-CD20 monoclonal antibody, rituximab has revolutionized AAV treatment based on two landmark trials.

RAVE trial (2010): Rituximab was non-inferior to cyclophosphamide for induction of remission in severe AAV (64% vs 53% remission, p=0.09), with superiority in relapsing disease subgroup.21

RITUXVAS trial (2010): Rituximab plus two IV cyclophosphamide doses was non-inferior to standard cyclophosphamide induction for severe renal AAV.22

Dosing:

375 mg/m² IV weekly × 4 doses (RAVE protocol), OR

1000 mg IV × 2 doses given 2 weeks apart (RA protocol, increasingly used)

Given with glucocorticoids as above

Advantages over cyclophosphamide:

Superior for relapsing disease

Preserves fertility

No bladder toxicity

Lower malignancy risk

Potentially lower infection risk

Monitoring:

CD19/CD20 B-cell depletion at 2 weeks (target: undetectable)

Immunoglobulin levels (risk of hypogammaglobulinemia with repeated courses)

Hepatitis B serology before treatment (risk of reactivation)

Infusion reactions (premedicate with acetaminophen, antihistamines)

Pearl: Rituximab is now considered first-line therapy for AAV by many experts, particularly for:

Relapsing disease (superior efficacy demonstrated)

Young patients desiring fertility preservation

PR3-ANCA positive disease (higher relapse risk with cyclophosphamide)

Patients at high risk for cyclophosphamide toxicity

Oyster: Complete B-cell depletion should be documented after rituximab. Approximately 10-15% of patients do not achieve complete depletion with standard dosing and may require additional doses or alternative therapy.23

4. Plasma Exchange (PLEX): PLEX removes circulating ANCA antibodies, immune complexes, and inflammatory mediators.

The MEPEX trial (2007): Demonstrated benefit of PLEX for severe renal AAV, reducing progression to ESRD (69% vs 49% renal survival at 3 months).24

The PEXIVAS trial (2020): The largest trial (704 patients) showed NO benefit of PLEX for the primary endpoint of death or ESRD in severe AAV, contradicting previous dogma.17

Current recommendations:

PEXIVAS suggests PLEX may not be routinely necessary

Consider PLEX for:

Dialysis-dependent renal failure with cellular crescents on biopsy (potentially salvageable kidneys)

Severe life-threatening DAH not responding to initial therapy

Concurrent anti-GBM antibody disease

Regimen: 60 mL/kg plasma exchange, 7 exchanges over 14 days

Replace with 5% albumin (avoid FFP unless bleeding/procedure planned)

Hack: In practice, most centers still use PLEX for dialysis-dependent AAV with crescents on biopsy and severe DAH, despite PEXIVAS results, as these represent salvageable organ-threatening scenarios. The decision should be individualized.

Maintenance Therapy

After remission induction (typically by 3-6 months), transition to maintenance therapy to prevent relapse. Relapse rates without maintenance therapy approach 50% at 5 years.25

1. Rituximab: Now preferred for maintenance based on superior efficacy.

MAINRITSAN trial (2014): Rituximab 500 mg every 6 months was superior to azathioprine for preventing relapse (5% vs 29% at 28 months, p<0.001).26

RITAZAREM trial (2019): Confirmed superiority of rituximab over azathioprine (23% vs 42% relapse at 36 months).27

Dosing strategies:

Fixed-interval: 1000 mg every 4-6 months (most common)

Biomarker-guided: Redose when CD19+ B-cells return or ANCA titer rises (experimental, may reduce cumulative dose)

Duration: Minimum 18-24 months; consider 36-48 months for high-risk patients (PR3-ANCA, relapsing disease, renal involvement)

Pearl: Patients maintained on rituximab have 80-85% lower relapse rates compared to azathioprine, establishing rituximab as the new standard of care for maintenance.26,27

2. Azathioprine: Second-line option when rituximab is unavailable or contraindicated.

Dosing: 2 mg/kg/day (maximum 200 mg/day)

Monitoring: CBC, LFTs monthly initially, then every 3 months

Adjust for TPMT deficiency if tested

Target WBC 4,000-5,000/μL

3. Methotrexate: Alternative for non-renal limited disease or when azathioprine is contraindicated.

Dosing: 20-25 mg weekly (oral or subcutaneous)

Contraindicated if CrCl <30 mL/min

Give with folic acid 1 mg daily

4. Mycophenolate mofetil: Less robust evidence; reserved for patients intolerant of other agents.

Dosing: 2000 mg daily in divided doses (2000-3000 mg/day)

Glucocorticoids during maintenance:

Taper to lowest effective dose (ideally ≤5 mg prednisone daily)

Attempt discontinuation by 12-18 months if possible

Some patients require low-dose maintenance (2.5-5 mg daily)

Monitoring for Relapse

Clinical surveillance:

Constitutional symptoms (fatigue, fever, weight loss)

Return of organ-specific manifestations

Regular urinalysis (monthly for first year, then quarterly)

Serum creatinine

Serological monitoring:

ANCA titers: Rising titers may precede clinical relapse by weeks to months

Sensitivity for predicting relapse: ~40-60%

Specificity: ~80-90%

Oyster: Do NOT treat rising ANCA titers alone without clinical evidence of active disease. Many patients have persistently positive ANCA in remission.

Pearl: The combination of rising ANCA titer + urinary abnormalities (hematuria, proteinuria) has high positive predictive value for impending relapse and should prompt consideration of treatment intensification.28

Management of Refractory Disease

Definition: Failure to achieve remission despite 4-6 weeks of standard induction therapy, or disease progression on treatment.

Strategies:

Switch induction agent: Cyclophosphamide ↔ Rituximab

Repeat PLEX: Consider if not used initially or inadequate response

Higher-dose rituximab: 1000 mg × 2 doses or 375 mg/m² × 4 weekly

Intravenous immunoglobulin (IVIG): 2 g/kg divided over 2-5 days (limited evidence)

Avacopan: C5a receptor antagonist, FDA-approved for AAV in 2021

ADVOCATE trial (2021): Avacopan (30 mg PO BID) was non-inferior to prednisone taper for remission and superior for sustained remission at 52 weeks (72% vs 70% remission; 66% vs 55% sustained remission), with significantly better glucocorticoid-sparing effects.29

Emerging therapies:

Tocilizumab (anti-IL-6): Ongoing trials

Abatacept (CTLA-4-Ig): Some efficacy in refractory cases

Complement inhibitors beyond avacopan

6. Clinical Scenario Approach:

Scenario 1: 62-year-old woman, dialysis-dependent acute renal failure, DAH requiring intubation, PR3-ANCA positive

Management:

Methylprednisolone 1000 mg IV daily × 3

Rituximab 1000 mg × 2 (weeks 0 and 2) OR cyclophosphamide 15 mg/kg IV (reduced for age)

Consider PLEX if renal biopsy shows cellular crescents

Lung-protective ventilation

PCP prophylaxis

Scenario 2: 45-year-old man, relapsing GPA (third episode), serum creatinine 2.1 mg/dL

Management:

Prednisone 0.5-1 mg/kg/day

Rituximab 1000 mg × 2 (preferred for relapsing disease)

Transition to rituximab maintenance 1000 mg every 4-6 months

Scenario 3: 28-year-old woman, newly diagnosed severe MPA, desires future fertility

Management:

Reduced-dose prednisone protocol (PEXIVAS)

Rituximab 1000 mg × 2 (fertility-sparing)

Oncofertility consultation

Avoid cyclophosphamide

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Giant Cell Arteritis: Beyond the Headache - The Risk of Permanent Blindness

Clinical Overview

Giant cell arteritis (GCA), also known as temporal arteritis, is the most common primary systemic vasculitis in adults, affecting individuals over 50 years of age with peak incidence in the 7th-8th decades.30 Annual incidence ranges from 15-25 cases per 100,000 persons over age 50 in Northern European populations, with a 2-3:1 female predominance.31

GCA is a granulomatous vasculitis affecting large and medium-sized arteries, with predilection for the cranial branches of the aorta (hence "cranial arteritis"). The temporal arteries are involved in approximately 90% of cases, but GCA is fundamentally a systemic disease that can affect any large artery, including the aorta itself.

Critical point: GCA is a medical emergency because of the risk of permanent, irreversible blindness, which can occur suddenly and without warning. Visual loss occurs in 15-20% of untreated patients and is the most feared complication.32

Pathophysiology

GCA involves transmural inflammation of arterial walls with:

Lymphocytic and macrophage infiltration

Giant cell formation (present in only 50% of positive biopsies)

Intimal hyperplasia and luminal stenosis

Disruption of internal elastic lamina

The inflammatory process leads to vascular stenosis, occlusion, and rarely aneurysm formation. Anterior ischemic optic neuropathy (AION) from involvement of posterior ciliary arteries is the mechanism of blindness.

Clinical Presentation

Classic manifestations:

1. Cranial symptoms (60-90%):

New-onset headache (most common, 60-90%)

Temporal, frontal, or occipital

Unilateral or bilateral

Often described as boring, burning, or lancinating

Scalp tenderness (40-50%)

Jaw claudication (40-50%): pain/fatigue in jaw muscles while chewing—highly specific (>95%)

Tongue claudication (rare but specific)

Abnormal temporal artery: thickened, tender, nodular, reduced or absent pulse (40-50%)

2. Visual symptoms (25-50%):

Transient visual loss (amaurosis fugax): Fleeting episodes of monocular vision loss lasting seconds to minutes—a red flag for impending permanent loss

Permanent visual loss: Sudden, painless, monocular (can become bilateral in 30-50% without treatment)

Anterior ischemic optic neuropathy (AION): most common mechanism

Central retinal artery occlusion (CRAO)

Posterior ischemic optic neuropathy

Diplopia (5-15%): extraocular muscle ischemia

Visual field defects

Pearl: Jaw claudication has the highest positive likelihood ratio (4.2-4.6) for GCA diagnosis and should prompt immediate treatment.33

3. Systemic symptoms (40-50%):

Fever (15-50%), typically low-grade

Weight loss

Malaise, fatigue

Anorexia

Night sweats

Depression

4. Large vessel involvement (30-60%):

Upper extremity claudication

Asymmetric blood pressures (>10 mmHg difference)

Absent pulses

Arterial bruits (subclavian, axillary, carotid)

Aortic aneurysm/dissection (late complication)

5. Polymyalgia rheumatica (PMR):

Occurs in 40-60% of GCA patients

Bilateral shoulder and hip girdle pain and stiffness

Morning stiffness >45 minutes

Elevated inflammatory markers

Note: PMR can occur without GCA (but always screen PMR patients for GCA symptoms)

Atypical presentations in ICU:

Fever of unknown origin

Stroke or TIA (carotid or vertebrobasilar involvement)

Mental status changes (rare: brain stem or cerebral ischemia)

Myocardial infarction (rare: coronary arteritis)

Aortic dissection

Mesenteric ischemia (very rare)

Respiratory symptoms (cough, sore throat from large vessel involvement)

Oyster: GCA should be considered in any patient over 50 with new-onset headache, unexplained fever, or elevated inflammatory markers, even without classic temporal artery findings. Many patients have "occult" GCA without cranial symptoms.

Diagnostic Approach

Clinical suspicion is paramount. GCA is primarily a clinical diagnosis supported by laboratory and imaging findings.

Laboratory evaluation:

1. Inflammatory markers:

ESR: Usually markedly elevated (>50 mm/hr, often >100 mm/hr)

Sensitivity: ~85%

<1% of GCA patients have normal ESR34

CRP: Elevated in >95% of cases

More sensitive than ESR in some studies

Consider CRP when ESR is borderline

Pearl: The combination of normal ESR AND CRP makes GCA extremely unlikely (<1% probability)

2. Complete blood count:

Normocytic anemia (60-75%)

Thrombocytosis (40-60%)

3. Liver function tests:

Elevated alkaline phosphatase (30-40%)

Mild transaminase elevation

4. Creatine kinase:

Should be normal (elevated CK suggests alternative diagnosis like polymyositis)

Imaging:

1. Temporal artery ultrasound:

"Halo sign": Hypoechoic wall thickening ≥0.3 mm (edema of arterial wall)

Sensitivity: 55-80%

Specificity: 78-95%35

Operator-dependent

Advantages: Non-invasive, rapid, point-of-care

Limitations: Cannot image extracranial vessels, operator expertise required

Hack: Can be performed at bedside in ICU by trained personnel; a positive halo sign in the right clinical context can expedite treatment

2. Contrast-enhanced MRI/MR angiography:

Arterial wall enhancement and thickening

Useful for large vessel assessment

Sensitivity: 70-85% for cranial vessel involvement

Can detect large vessel GCA missed by temporal artery biopsy

3. PET-CT (FDG-PET):

Identifies large vessel inflammation (aorta, subclavian, carotid)

Helpful for detecting large vessel GCA

Not routinely available emergently

False negatives after steroid initiation (within 3-10 days)

4. CT angiography:

Less sensitive than MRI for wall inflammation

Useful for detecting stenoses, aneurysms, dissection

Radiation exposure consideration

5. Temporal artery biopsy:

Gold standard for diagnosis

Sensitivity: 70-87% (false negatives due to skip lesions)

Specificity: nearly 100%

Should be performed bilaterally if possible

Minimum 1-2 cm length per side

Pathological features: transmural inflammation, giant cells (50%), intimal hyperplasia, fragmentation of internal elastic lamina

Critical timing considerations:

Biopsy remains positive for up to 2-4 weeks after steroid initiation36

Do NOT delay treatment waiting for biopsy

Obtain biopsy within 7-10 days of starting steroids if possible

Negative biopsy does NOT exclude GCA (sensitivity 70-80%)

Pearl: The 2016 ACR/EULAR provisional diagnostic criteria for GCA provide a clinical decision tool but are not validated for individual patient diagnosis:

Age ≥50 years

New temporal headache

Temporal artery abnormality on exam

Elevated ESR or CRP

Positive temporal artery biopsy

A score ≥3 is highly suggestive of GCA.37

The Ophthalmologic Emergency

Visual loss in GCA is an ophthalmologic emergency.

Mechanisms of visual loss:

1. Anterior ischemic optic neuropathy (AION): ~80% of cases

Sudden, painless monocular vision loss

Optic disc swelling, pallor, edema on fundoscopy

Afferent pupillary defect (APD)

2. Central retinal artery occlusion (CRAO): ~15% of cases

Pale, edematous retina with "cherry red spot" at macula

Severely reduced or absent vision

3. Posterior ischemic optic neuropathy: ~5% of cases

Normal optic disc initially (later atrophy)

Ischemia of retrolaminar optic nerve

4. Occipital lobe infarction: Rare

Posterior cerebral artery involvement

Bilateral vision loss with preserved pupillary reflexes

Risk factors for visual loss:

Delayed treatment (>1 week from symptom onset)

History of amaurosis fugax

Jaw claudication

Marked ESR elevation (>100 mm/hr)

Diabetes mellitus

Cardiovascular disease

Natural history without treatment:

30-60% of patients with initial monocular loss develop bilateral involvement within days to weeks

Once visual loss occurs, it is usually permanent

Treatment initiated after vision loss has low success in restoring vision (10-15% improvement)38

Oyster: Any patient with confirmed or suspected GCA who develops sudden visual symptoms requires immediate high-dose IV corticosteroids, even if outpatient treatment has already been initiated. Do not wait for ophthalmology evaluation.

Hack: If a patient with suspected GCA reports "curtains" or "shades" coming over their vision (amaurosis fugax), this is a dire warning of impending permanent vision loss—initiate IV corticosteroids immediately and obtain emergent ophthalmology consultation.

Treatment

The primary goal is prevention of visual loss and other vascular complications. Treatment should be initiated based on clinical suspicion BEFORE biopsy confirmation.

**

Treatment (continued)

Initial Therapy:

1. For typical GCA without visual symptoms/complications:

Oral prednisone:

Dose: 40-60 mg daily (1 mg/kg/day for patients <60 kg)

Initiate immediately upon clinical suspicion

Do NOT wait for biopsy confirmation

Clinical response typically dramatic within 24-48 hours (resolution of headache, normalization of inflammatory markers)

Lack of response within 72 hours should prompt reconsideration of diagnosis

Pearl: A rapid clinical response to corticosteroids (within 24-48 hours) is so characteristic of GCA that it has diagnostic value. The absence of improvement should raise concern about alternative diagnoses.39

2. For GCA with visual symptoms or other complications:

High-dose IV methylprednisolone:

Dose: 500-1000 mg IV daily × 3-5 days

Followed by oral prednisone 1 mg/kg/day (60-80 mg/day)

Evidence supports better visual outcomes with IV pulse therapy40

May reduce risk of second-eye involvement

Indications for IV pulse therapy:

Any visual symptoms (current or recent)

Amaurosis fugax

Diplopia

Large vessel complications (stroke, limb ischemia)

CNS involvement

Extensive large vessel disease

Aspirin:

Low-dose aspirin (75-100 mg daily) should be initiated in all GCA patients

Reduces risk of visual loss and vascular events by ~70% in meta-analyses41

Continue indefinitely unless contraindicated

Pearl: Aspirin is a critical adjunctive therapy often overlooked—ensure all GCA patients receive it unless contraindications exist

Steroid Taper:

GCA requires prolonged corticosteroid therapy (12-24 months typical, some patients longer).

Suggested taper schedule:

Maintain initial dose (40-60 mg prednisone) until symptom resolution and ESR/CRP normalization (typically 2-4 weeks)

Reduce by 10 mg every 2 weeks to 20 mg/day

Reduce by 2.5 mg every 2-4 weeks to 10 mg/day

Reduce by 1 mg every 1-2 months below 10 mg/day

Target discontinuation at 12-24 months if possible

Monitoring during taper:

Clinical symptoms (headache, visual symptoms, jaw claudication)

ESR/CRP every 2-4 weeks initially, then monthly

Rising inflammatory markers or recurrent symptoms indicate relapse

30-50% of patients experience relapse during taper42

Oyster: Many patients require low-dose prednisone (5-7.5 mg daily) for years. Do not force aggressive tapering that results in repeated relapses—cumulative steroid toxicity from multiple relapses and re-escalations may exceed the toxicity of low-dose maintenance.

Hack: If ESR or CRP rises during taper but patient remains asymptomatic, consider holding taper and monitoring closely rather than automatically increasing dose. Some patients have mild fluctuations without clinical relapse. However, any recurrent symptoms mandate dose increase.

Steroid-Sparing Agents:

Given prolonged steroid exposure and associated toxicities, steroid-sparing agents are often needed.

1. Tocilizumab (IL-6 receptor antagonist):

GiACTA trial (2017): The first randomized controlled trial to demonstrate efficacy of steroid-sparing therapy in GCA43

Tocilizumab 162 mg subcutaneously weekly or every other week + 26-week prednisone taper vs. 52-week prednisone taper alone

Results: 56% (weekly) and 53% (every-other-week) sustained remission vs. 14% (placebo + 52-week taper)

Significantly reduced cumulative steroid dose

FDA approved for GCA in 2017

Indications:

Relapsing disease (most common indication)

Inability to taper steroids

Significant steroid-related complications

Consider as initial therapy in high-risk patients (debated)

Dosing:

162 mg subcutaneously weekly, OR

162 mg subcutaneously every 2 weeks (slightly less efficacious)

Given for 12-24 months typically

Adverse effects:

Infections (monitor closely)

GI perforation (rare but serious—avoid in patients with diverticulitis)

Hepatotoxicity (monitor LFTs)

Lipid abnormalities

Neutropenia, thrombocytopenia

Pearl: Tocilizumab suppresses acute phase reactants (CRP, ESR) even in the presence of active disease. Monitor for clinical relapse symptoms rather than relying solely on inflammatory markers in patients on tocilizumab.44

2. Methotrexate:

Older steroid-sparing option with modest efficacy

Meta-analyses show ~35% reduction in relapse risk and reduced cumulative steroid dose45

Dose: 15-25 mg weekly (oral or subcutaneous)

Less effective than tocilizumab but more accessible and less expensive

Useful when tocilizumab unavailable or unaffordable

3. Other agents (limited evidence):

Azathioprine: inconsistent evidence

Leflunomide: small studies suggest benefit

TNF inhibitors (infliximab, etanercept): failed trials, NOT recommended

Abatacept: ongoing trials

Steroid Toxicity Prophylaxis:

Given prolonged high-dose steroid therapy, all GCA patients require:

1. Osteoporosis prevention:

Calcium 1200-1500 mg daily + Vitamin D 800-1000 IU daily

Bisphosphonate therapy (alendronate, risedronate) for:

All patients ≥40 years on prednisone ≥7.5 mg daily for ≥3 months

Consider DEXA scan baseline and monitoring

2. Pneumocystis jirovecii prophylaxis:

Trimethoprim-sulfamethoxazole DS 3× weekly, OR

Daily single-strength tablet

For patients on prednisone ≥20 mg daily for ≥1 month

3. Gastric protection:

Proton pump inhibitor if risk factors for peptic ulcer disease

4. Diabetes screening:

Monitor glucose, consider diabetes screening

Manage steroid-induced hyperglycemia aggressively

5. Ophthalmologic monitoring:

Screen for cataracts and glaucoma

Annual eye exams while on steroids

Large Vessel GCA

Increasingly recognized, large vessel GCA involves the aorta and its major branches in 30-80% of cases depending on imaging modality.46

Clinical features:

May occur with or without cranial symptoms

Upper extremity claudication

Asymmetric pulses and blood pressures

Arterial bruits

Constitutional symptoms (fever, weight loss) may predominate

Diagnosis:

Temporal artery biopsy may be negative (sampling error)

MRI/MRA, CTA, or PET-CT needed for diagnosis

FDG-PET showing aortitis or large vessel uptake supports diagnosis

Complications:

Aortic aneurysm: 17-fold increased risk, may occur years after diagnosis47

Aortic dissection

Stenotic lesions causing limb or organ ischemia

Management:

Same corticosteroid regimen as cranial GCA

Tocilizumab may be particularly beneficial

Surveillance imaging (MRA, CTA, or PET-CT) annually or biannually for aortic complications

Long-term follow-up essential (aneurysms can develop years later)

Hack: Check bilateral arm blood pressures in all GCA patients at presentation. A difference >10-15 mmHg suggests large vessel involvement and should prompt vascular imaging.

ICU Considerations

GCA patients may require ICU admission for:

1. Acute visual loss:

High-dose IV methylprednisolone 1000 mg daily × 3-5 days

Emergent ophthalmology consultation

Aspirin if not already on it

Consider hyperbaric oxygen (limited evidence, case reports only)

2. Stroke/TIA:

IV corticosteroids

Standard stroke management (consider thrombolysis if within window and eligible)

Neurology consultation

Imaging to document large vessel involvement

3. Aortic dissection/rupture:

Vascular surgery consultation

Surgical intervention as appropriate

High-dose steroids once hemorrhage controlled

4. Fever of unknown origin:

Consider GCA in elderly patients with FUO and elevated ESR

Temporal artery biopsy if diagnosis unclear

Empiric steroids if high suspicion (after infections ruled out)

Oyster: Do not withhold corticosteroids in suspected GCA patients pending infectious workup unless there is strong evidence of infection. The risk of irreversible blindness from delayed treatment far exceeds the risk of brief steroid exposure.

________________________________________

Takayasu's Arteritis: The "Pulseless Disease" in Young Women

Clinical Overview

Takayasu's arteritis (TAK) is a chronic granulomatous large-vessel vasculitis predominantly affecting the aorta and its major branches. Named after Japanese ophthalmologist Mikito Takayasu who first described the retinal findings in 1908, TAK is also known as "pulseless disease" due to the characteristic finding of absent or diminished peripheral pulses.48

Epidemiology:

Age: Typically onset between 10-40 years (mean age 25-30 years)

Sex: 80-90% female predominance

Geographic distribution: Most common in Asia, Middle East, South America; less common in North America and Europe

Incidence: 1-3 cases per million per year in Western populations, up to 10× higher in endemic regions49

Pathophysiology

TAK involves granulomatous inflammation of the arterial media and adventitia, leading to:

Early phase: Arterial wall inflammation, edema, infiltration by lymphocytes and giant cells

Late phase: Fibrosis, intimal hyperplasia, stenosis or occlusion

Aneurysm formation in 10-30% (due to weakening of arterial wall)

Vessel distribution:

Aorta and major branches (100%)

Subclavian arteries (93%)

Carotid arteries (58%)

Renal arteries (38%)

Vertebral arteries (35%)

Coronary arteries (15%)

Pulmonary arteries (50% on imaging, usually asymptomatic)50

Classification

Numano Classification (based on angiographic findings):

Type I: Branches of aortic arch

Type IIa: Ascending aorta and arch

Type IIb: Ascending aorta, arch, and descending thoracic aorta

Type III: Descending thoracic and abdominal aorta

Type IV: Abdominal aorta and renal arteries

Type V: Combination of IIb and IV (entire aorta)

"Plus": Coronary or pulmonary artery involvement added to any type51

Clinical Presentation

TAK typically evolves through two phases:

1. Early inflammatory phase ("pre-pulseless phase"):

Constitutional symptoms (60-80%):

Fever, night sweats

Weight loss

Fatigue, malaise

Myalgias, arthralgias

Often misdiagnosed as infection, malignancy, or connective tissue disease

May last weeks to months

Elevated inflammatory markers

2. Late occlusive/stenotic phase ("pulseless phase"):

Vascular insufficiency symptoms from stenosis/occlusion:

Upper extremity (most common):

Arm claudication (44-73%)

Absent or diminished pulses (96%)

Blood pressure discrepancies (>10 mmHg between arms)

Coolness, paresthesias

Pearl: Check bilateral arm and leg blood pressures in all suspected cases—BP differences are nearly universal

Neurological/Cerebrovascular:

Dizziness, syncope (postural, effort-induced)

Visual disturbances (blurred vision, diplopia, amaurosis)

TIA or stroke (10-20%)

Seizures (rare)

Takayasu retinopathy: Microaneurysms, arteriovenous anastomoses (rare with modern treatment)

Cardiovascular:

Hypertension (33-83%):

Renovascular hypertension from renal artery stenosis (most common cause)

Aortic coarctation

Oyster: Hypertension may be underdiagnosed if BP only measured in affected (stenotic) arm—always check all four limbs

Aortic regurgitation (7-55%): from aortic root dilatation

Heart failure

Myocardial ischemia/infarction: coronary artery involvement (10-25%)

Pericarditis (rare)

Renal:

Renovascular hypertension (most common renal manifestation)

Renal artery stenosis (28-75%)

Renal infarction

Glomerulonephritis (rare)

Pulmonary:

Pulmonary artery involvement (50-80% on imaging)

Usually asymptomatic

Pulmonary hypertension (10-50% when symptomatic)52

Dyspnea, chest pain

Gastrointestinal:

Abdominal angina (mesenteric ischemia)

Nausea, vomiting, diarrhea

Abdominal pain after eating

Cutaneous:

Erythema nodosum (3-16%)

Pyoderma gangrenosum (rare)

Pearl: The classic triad of absent pulses + hypertension + vascular bruits is present in only 50% of patients at presentation. Maintain high suspicion in young women with constitutional symptoms and vascular findings.

Hack: In any young woman presenting with hypertension, stroke, or unexplained systemic symptoms, obtain bilateral arm blood pressures and auscultate for bruits (carotid, subclavian, abdominal). These simple bedside findings can trigger appropriate workup.

Diagnostic Approach

Diagnosis requires high clinical suspicion combined with imaging evidence of large vessel vasculitis.

Laboratory Evaluation:

1. Inflammatory markers:

ESR elevated in 72-78% during active disease

CRP elevated in 63-89%

Oyster: Normal inflammatory markers do NOT exclude active disease—up to 30% of patients with active disease have normal ESR/CRP53

2. Other labs:

Anemia of chronic disease (50%)

Thrombocytosis

Hypergammaglobulinemia

Positive ANA (low titer) in 10-20% (non-specific)

ANCA, anti-dsDNA: negative (helps exclude other vasculitides)

3. Biomarkers under investigation:

Pentraxin-3, MMP-9, IL-6: correlate with disease activity in some studies but not routinely available

Imaging:

Imaging is essential for diagnosis, disease monitoring, and assessing complications.

1. CT Angiography (CTA):

Advantages: Widely available, rapid, excellent visualization of stenoses, occlusions, aneurysms

Findings:

Arterial wall thickening (>2 mm)

Luminal stenosis or occlusion

Aneurysmal dilatation

Mural calcification (chronic disease)

Limitations: Radiation exposure, contrast nephropathy risk, doesn't assess wall inflammation well

2. MR Angiography (MRA) with vessel wall imaging:

Advantages: No radiation, excellent for wall inflammation assessment

Findings:

Arterial wall thickening

Mural edema (T2 hyperintensity)

Wall enhancement on post-contrast images (indicates active inflammation)

Luminal stenosis/occlusion

Pearl: MRA with vessel wall imaging is superior to conventional MRA and can distinguish active inflammation from chronic fibrosis54

Becoming the preferred modality for diagnosis and monitoring

3. PET-CT (FDG-PET):

Advantages: Whole-body assessment, excellent for detecting active inflammation

Findings: Increased FDG uptake in affected vessel walls

Limitations:

False negatives after corticosteroid therapy (within 7-10 days)

Radiation exposure

Atherosclerosis can cause false positives in older patients

Hack: If PET-CT planned, perform BEFORE initiating steroids if possible

4. Conventional angiography:

Gold standard for luminal assessment historically

Now largely replaced by CTA/MRA (non-invasive alternatives)

Findings:

Stenoses (most common)

Occlusions

Post-stenotic dilatation

Aneurysms

"Rat-tail" appearance of branch vessels

Collateral circulation

Reserved for cases requiring intervention (angioplasty, stenting)

5. Doppler ultrasound:

Useful for carotid and subclavian arteries

Operator-dependent

Cannot assess aorta or deep vessels

"Macaroni sign": homogeneous concentric wall thickening

6. Echocardiography:

Assess for:

Aortic regurgitation

Left ventricular hypertrophy (hypertension)

Pulmonary hypertension

Regional wall motion abnormalities (coronary involvement)

Biopsy:

Rarely performed (vessels involved are not easily accessible)

Pathology: granulomatous inflammation similar to GCA, giant cells, medial destruction

Consider only when diagnosis uncertain and vessel surgically accessible

Diagnostic Criteria

1990 ACR Classification Criteria (requires ≥3 of 6):

Age at onset ≤40 years

Limb claudication

Decreased brachial artery pulse

Blood pressure difference >10 mmHg between arms

Bruit over subclavian arteries or aorta

Angiographic abnormalities (stenosis or occlusion of aorta or major branches)

Sensitivity: 90.5%, Specificity: 97.8%55

Note: These are classification criteria for research, not diagnostic criteria for individual patients.

Disease Activity Assessment

Clinical indicators:

New/worsening vascular symptoms

New bruits or pulse deficits

Worsening hypertension

Constitutional symptoms

Laboratory:

Rising ESR/CRP (but remember 30% of active disease has normal markers)

Imaging:

New or progressive stenosis

New aneurysm formation

Arterial wall enhancement and edema on MRI

Increased FDG uptake on PET-CT

NIH Criteria for Active Disease (requires ≥2 of 4):

Systemic features (fever, musculoskeletal symptoms, ESR >20 mm/hr)

Elevated acute phase reactants

New vascular lesion on angiography

Typical histopathologic features56

Oyster: Distinguishing active inflammation from chronic vascular damage is challenging. Vessel wall enhancement on MRI or FDG uptake on PET-CT can help identify active inflammation requiring treatment intensification vs. chronic damage requiring surgical intervention.

Treatment

Goals:

Induce and maintain remission

Prevent vascular progression

Manage complications (hypertension, stenoses, aneurysms)

Medical Management:

1. Glucocorticoids (first-line):

Induction:

Prednisone 1 mg/kg/day (40-60 mg/day, maximum 80 mg)

Pulse IV methylprednisolone 500-1000 mg daily × 3 days for severe disease

Taper:

Once remission achieved (typically 4-12 weeks)

Reduce by 10 mg every 2 weeks to 20 mg

Reduce by 2.5-5 mg every 2-4 weeks to 10 mg

Slow taper below 10 mg (1-2.5 mg every 4-8 weeks)

Goal: lowest dose maintaining remission (often 5-10 mg long-term)

Response rate: 60-100% initially, but:

50-80% relapse during taper

50% become steroid-dependent

Only 20-50% achieve steroid-free remission57

2. Steroid-sparing agents (most patients require):

Methotrexate:

Most commonly used steroid-sparing agent

Dose: 15-25 mg weekly (oral or subcutaneous)

Efficacy: Reduces relapse rates and steroid doses in observational studies

Monitor: CBC, LFTs, creatinine

Give with folic acid 1 mg daily

Azathioprine:

Alternative to methotrexate

Dose: 2 mg/kg/day

Similar efficacy to methotrexate in retrospective studies

Mycophenolate mofetil:

Dose: 2-3 g/day in divided doses

Increasingly used, especially when methotrexate/azathioprine fail or are contraindicated

May be superior to azathioprine in some studies58

Leflunomide:

Dose: 20 mg daily

Alternative option with some efficacy data

3. Biologic therapies:

Tocilizumab (IL-6 receptor antagonist):

Most promising biologic for TAK

Multiple case series and retrospective studies show efficacy

GIACTA trial (2022): First RCT in TAK, showed trend toward benefit but did not meet primary endpoint (likely underpowered)59

Real-world data strongly supports efficacy

Dose: 162 mg subcutaneously weekly or 8 mg/kg IV monthly

Pearl: Consider early for:

Relapsing/refractory disease

Steroid-dependent patients

Unable to taper steroids due to recurrent activity

Severe disease at presentation

Tumor necrosis factor inhibitors:

Infliximab, adalimumab, etanercept

Mixed results in small studies and case series

Less consistent efficacy than tocilizumab

Consider when tocilizumab fails or unavailable

Rituximab:

Limited data in TAK

Some case reports of benefit in refractory disease

Not first-line

4. Antiplatelet/anticoagulation:

Aspirin 75-100 mg daily recommended for all patients

Reduces thrombotic complications

Consider anticoagulation for:

Documented thrombosis

Severe stenoses

Aneurysms (controversial)

5. Cardiovascular risk management:

Aggressive hypertension control:

Target BP <130/80 mmHg

ACE inhibitors or ARBs preferred (especially with renovascular hypertension)

Beta-blockers if aortic regurgitation

Measure BP in unaffected limb

Statin therapy (high atherosclerosis risk)

Diabetes management

Smoking cessation (critical)

Hack: In TAK patients with renovascular hypertension, medical management with ACE inhibitors/ARBs should be tried first before considering revascularization, as inflammation control may improve renal perfusion. However, monitor creatinine carefully (may worsen initially).

Surgical/Endovascular Management

Revascularization procedures should be performed during inactive disease when possible (lower complication rates).

Indications:

Absolute:

Critical limb ischemia

Uncontrolled renovascular hypertension despite maximal medical therapy

Critical coronary stenosis

Severe aortic regurgitation with heart failure

Symptomatic cerebrovascular insufficiency

Mesenteric ischemia

Relative:

Moderate-severe aortic regurgitation

Aneurysm >5-6 cm or rapidly enlarging

Timing:

Preferred: During remission (lower restenosis rates)

Disease activity at time of procedure associated with 50% restenosis rate vs. 20% in quiescent disease60

In emergencies, operate and intensify immunosuppression perioperatively

Options:

Percutaneous transluminal angioplasty (PTA) ± stenting:

Less invasive

Preferred for:

Short-segment stenoses

Renal artery stenosis

Subclavian stenosis

Limitations:

High restenosis rates (17-74% depending on vessel and disease activity)

May require repeat procedures

Bypass grafting:

More durable than PTA

Preferred for:

Long-segment occlusions

Aneurysm repair

Multiple sequential lesions

Failed PTA

Types: Anatomic (aorto-femoral, carotid-subclavian) or extra-anatomic (axillo-axillary) bypasses

Oyster: Surgical outcomes are significantly better when performed during disease remission. Whenever possible, defer elective procedures until inflammatory markers normalized and imaging shows no active inflammation.

ICU Considerations

TAK patients may require critical care for:

1. Hypertensive emergency/urgency:

Renovascular hypertension often severe and difficult to control

IV agents: nicardipine, labetalol, enalaprilat

Identify and address underlying cause (renal artery stenosis)

Avoid precipitous BP drops (may worsen cerebral/limb ischemia)

2. Acute stroke/TIA:

Carotid or vertebrobasilar involvement

Standard stroke protocols (consider thrombolysis if eligible)

Blood pressure management challenging (cerebral perfusion dependent on collaterals)

High-dose steroids if active vasculitis suspected

3. Acute coronary syndrome:

Coronary arteritis or atherosclerotic disease

PCI or CABG as indicated

Intensify immunosuppression if active disease

4. Acute limb ischemia:

Emergent vascular surgery evaluation

Anticoagulation (if no contraindications)

Revascularization (PTA, bypass, or thromboembolectomy)

5. Aortic dissection/rupture:

Medical stabilization

Emergent surgical repair

Mortality high in TAK-associated dissection

6. Heart failure:

Due to aortic regurgitation, hypertension, or myocardial ischemia

Medical management

Urgent surgery for severe symptomatic AR

7. Pulmonary hypertension crisis:

Pulmonary artery involvement

Supportive care, pulmonary vasodilators

Treat underlying inflammation

Prognosis

Modern era outcomes:

5-year survival: 91-97%

10-year survival: 85-90%61

Significant improvement from historical cohorts (pre-steroid era <50% 5-year survival)

Predictors of poor outcome:

Major complications at diagnosis (stroke, MI, AR, aneurysm)

Refractory disease/frequent relapses

Pulmonary artery hypertension

Progressive renal insufficiency

Cardiac involvement

Causes of death:

Heart failure (most common)

Myocardial infarction

Stroke

Aneurysm rupture

Renal failure

Pearl: Most patients with TAK require lifelong monitoring and treatment. The disease is chronic and relapsing in the majority. Regular surveillance with imaging (every 6-12 months) is essential to detect progression even in apparent clinical remission.

________________________________________

Cryoglobulinemic Vasculitis: The Link to Hepatitis C and Cold-Triggered Purpura

Clinical Overview

Cryoglobulinemic vasculitis is a small-vessel vasculitis caused by circulating immune complexes (cryoglobulins) that precipitate in cold temperatures and deposit in small to medium-sized vessels, particularly affecting skin, joints, kidneys, and peripheral nerves.62

Cryoglobulins are immunoglobulins that precipitate at temperatures below 37°C (98.6°F) and redissolve upon rewarming. The precipitation of these proteins in vessel walls triggers complement activation and inflammatory vasculitis.

Classification

Type I (Monoclonal):

Single monoclonal immunoglobulin (usually IgM or IgG)

Associated with hematologic malignancies (10-15% of cases):

Multiple myeloma

Waldenström's macroglobulinemia

Chronic lymphocytic leukemia

NOT true vasculitis (hyperviscosity syndrome)

Not covered in detail here

Type II (Mixed, monoclonal):

Monoclonal IgM with rheumatoid factor activity + polyclonal IgG

50-60% of cryoglobulinemia cases

80-90% associated with HCV infection

True vasculitis

Type III (Mixed, polyclonal):

Polyclonal IgM + polyclonal IgG

25-30% of cases

Often HCV-associated

True vasculitis

Also associated with autoimmune diseases (Sjögren's, SLE, RA)

Pearl: When discussing cryoglobulinemic vasculitis, we typically refer to mixed cryoglobulinemia (Types II and III), which cause true immune complex-mediated vasculitis. Type I causes hyperviscosity, not vasculitis.

The Hepatitis C Connection

The association between HCV and mixed cryoglobulinemia is one of the strongest virus-disease links in medicine.

Epidemiology:

40-60% of HCV patients have detectable cryoglobulins

Only 5-10% of HCV patients with cryoglobulins develop symptomatic vasculitis (so ~2-5% of all HCV patients develop vasculitis)63

Conversely, 80-90% of mixed cryoglobulinemia patients have HCV infection

Pathophysiology:

HCV directly infects B-lymphocytes

Chronic antigenic stimulation leads to B-cell clonal expansion

Production of IgM with rheumatoid factor (RF) activity

Formation of immune complexes (HCV RNA + anti-HCV antibodies + RF-IgM)

Immune complex deposition in vessels triggers complement activation and vasculitis

Other associations (10-20% of mixed cryoglobulinemia):

Hepatitis B (less common than HCV)

HIV

Autoimmune diseases: Sjögren's syndrome (most common), SLE, RA

Chronic infections: EBV, CMV, bacterial endocarditis

Lymphoproliferative disorders

Oyster: Always test for HCV in any patient with mixed cryoglobulinemia. With effective direct-acting antiviral (DAA) therapy, HCV-associated cryoglobulinemic vasculitis can now be cured in most patients.

Clinical Presentation

Classic Triad (Meltzer's triad, present in ~30%):

Purpura (palpable, non-blanching)

Arthralgias/Arthritis

Weakness/Fatigue

Cutaneous manifestations (70-100%):

Palpable purpura: Most characteristic finding

Lower extremities predominantly (orthostatic distribution)

Cold-triggered or exacerbated

May ulcerate in severe cases

Healing leaves hyperpigmentation

Urticaria (cold-induced)

Livedo reticularis

Raynaud's phenomenon

Acral necrosis (severe cases, rare)

Clinical Presentation (continued)

Pearl: The purpura in cryoglobulinemic vasculitis is characteristically "cold-triggered"—patients often report worsening in cold weather or after cold exposure. Ask about seasonal variation in symptoms.

Musculoskeletal (40-80%):

Non-erosive polyarthralgias (most common)

Symmetric, involving small joints (hands, knees, ankles)

Rarely true arthritis with swelling

Myalgias

Diffuse weakness and fatigue

Renal involvement (20-35%):

Membranoproliferative glomerulonephritis (MPGN): Most characteristic

Clinical spectrum:

Asymptomatic hematuria/proteinuria (mild)

Nephrotic syndrome (moderate)

Rapidly progressive glomerulonephritis (severe, ~10%)

Active urinary sediment (RBCs, RBC casts, proteinuria)

Oyster: Unlike ANCA vasculitis, cryoglobulinemic renal disease often presents with NEPHROTIC-range proteinuria (>3.5 g/day), not just nephritic features

Renal involvement is the major predictor of mortality

Peripheral nervous system (30-70%):

Distal sensory or sensorimotor polyneuropathy: Most common pattern

"Glove and stocking" distribution

Paresthesias, dysesthesias, pain

Distal weakness (if motor involved)

Mononeuritis multiplex: Less common but more severe

Acute onset

Asymmetric

Stepwise progression

Foot drop, wrist drop

Typically axonal neuropathy on EMG/NCS

May be first manifestation in some patients

Gastrointestinal (rare, 2-5%):

Mesenteric vasculitis (can be life-threatening)

Abdominal pain, often postprandial

GI bleeding

Perforation, infarction (severe cases)

Central nervous system (very rare, <5%):

Stroke (usually small vessel)

Encephalopathy

Seizures

Cranial neuropathies

Pulmonary (rare):

Alveolar hemorrhage (very rare, <1%)

Interstitial lung disease

Pulmonary hypertension (extremely rare)

Hepatic:

Related to underlying HCV infection

Chronic hepatitis, cirrhosis in some patients

HCV-related hepatocellular carcinoma (long-term risk)

Other:

Sicca symptoms (overlap with Sjögren's syndrome in 10-15%)

Lymphadenopathy

Splenomegaly

Risk of B-cell lymphoma (5-10% over 10 years, related to chronic B-cell stimulation)64

Diagnostic Approach

Clinical suspicion:

Purpura + arthralgias + weakness in patient with HCV

Peripheral neuropathy + renal disease + purpura

Cold-triggered symptoms

Unexplained systemic vasculitis (check for HCV)

Laboratory Evaluation:

1. Cryoglobulin detection:

Critical pre-analytical requirements:

Blood must be drawn into pre-warmed tube (37°C)

Keep at 37°C during transport and processing

Allow to clot at 37°C

Separate serum at 37°C

Then refrigerate at 4°C for 7 days to allow precipitation

Hack: Many negative cryoglobulin tests are false negatives due to improper collection/handling. If clinical suspicion is high and test is negative, repeat with meticulous attention to collection technique.

Quantification: Cryocrit (volume of precipitated cryoglobulins)

<1%: minimal

1-5%: mild-moderate

5%: significant

10%: severe (correlates with worse outcomes)

Characterization: Immunofixation to determine type (II vs III)

2. Serologies:

Hepatitis C:

Anti-HCV antibody (screening)

HCV RNA by PCR (confirms active infection, quantifies viral load)

HCV genotype (guides treatment selection)

Hepatitis B: HBsAg, anti-HBc, anti-HBs

HIV testing

Rheumatoid factor (RF): Positive in 70-100% (Type II always has monoclonal RF)

High-titer RF typical (>1:1000 not uncommon)

3. Complement levels:

Low C4: Hallmark finding (80-90% of cases)

Often profoundly low (<5 mg/dL; normal 10-40)

Low C3 in 30-40% (usually moderate reduction)

Normal C2

Pearl: Markedly depressed C4 with relatively preserved C3 is characteristic of cryoglobulinemic vasculitis65

Serial C4 levels may correlate with disease activity

4. Complete blood count:

Anemia (chronic disease, renal disease)

Leukopenia (HCV-associated)

Thrombocytopenia (HCV-associated, hypersplenism)

5. Renal function tests:

Serum creatinine, BUN

Urinalysis: hematuria, proteinuria, RBC casts

24-hour urine or spot protein-to-creatinine ratio

6. Liver function tests:

Transaminases (elevated with HCV)

Assess for cirrhosis (albumin, bilirubin, PT/INR, platelets)

7. Other tests:

ESR/CRP: Elevated during active vasculitis

Serum protein electrophoresis (SPEP): May show monoclonal spike (Type II)

Immunoglobulins: Often elevated (polyclonal or monoclonal)

ANA, anti-dsDNA, anti-SSA/SSB: If autoimmune disease suspected

ANCA: Should be negative

Biopsy:

Skin biopsy (if purpura present):

Leukocytoclastic vasculitis of small vessels

Neutrophilic infiltration

Nuclear debris (leukocytoclasis)

Fibrinoid necrosis

Direct immunofluorescence: IgM and C3 deposition (immune complex-mediated)

Pearl: Skin biopsy has high diagnostic yield in cryoglobulinemic vasculitis (>80% positive)

Renal biopsy (if renal involvement):

Membranoproliferative glomerulonephritis (MPGN): Classic finding

Type I MPGN most common

Mesangial proliferation

Capillary wall thickening ("tram-track" appearance)

Subendothelial deposits

Immunofluorescence: IgM, IgG, C3 deposition (granular pattern)

Electron microscopy: Organized deposits with "fingerprint" or "cylindrical" structures (pathognomonic for cryoglobulinemia)66

Indications for renal biopsy:

Significant proteinuria (>1 g/day)

Declining renal function

Active urinary sediment

Nephrotic syndrome

Nerve biopsy (rarely performed):

Vasculitis of vasa nervorum

Axonal degeneration

Reserve for atypical cases where diagnosis uncertain

Oyster: Remember that cryoglobulinemia may be detected incidentally in asymptomatic patients. The presence of cryoglobulins alone does NOT equal vasculitis—clinical manifestations must be present. Conversely, negative cryoglobulin testing does not exclude the diagnosis if collection was improper.

Disease Severity Assessment

Several prognostic scoring systems exist:

Factors associated with severe disease and poor prognosis:

Renal involvement (especially RPGN)

Gastrointestinal involvement

CNS involvement

Extensive skin ulceration

High cryocrit (>10%)

Older age

Low C4

Liver cirrhosis

Clinical severity categories:

Mild:

Purpura alone

Arthralgias

Mild peripheral neuropathy (sensory only)

No organ-threatening disease

Moderate:

Extensive purpura with ulceration

Moderate renal involvement (proteinuria, stable creatinine)

Disabling peripheral neuropathy (motor involvement)

Severe/Life-threatening:

Rapidly progressive glomerulonephritis

Mesenteric vasculitis

Extensive skin necrosis

CNS involvement

Severe mononeuritis multiplex

Treatment

Treatment approach differs based on whether HCV is present and on disease severity.

For HCV-associated cryoglobulinemic vasculitis:

Paradigm shift: With the advent of highly effective direct-acting antivirals (DAAs), HCV eradication is now the cornerstone of treatment for HCV-associated cryoglobulinemic vasculitis.

Treatment algorithm:

1. Mild to moderate disease (no organ-threatening manifestations):

First-line: HCV DAA therapy alone

Goal: Viral eradication → immune complex clearance → vasculitis resolution

Regimens (based on genotype, prior treatment, cirrhosis):

Genotype 1: Ledipasvir/sofosbuvir, Glecaprevir/pibrentasvir, Elbasvir/grazoprevir

Genotype 2: Sofosbuvir/velpatasvir, Glecaprevir/pibrentasvir

Genotype 3: Sofosbuvir/velpatasvir, Glecaprevir/pibrentasvir

Genotypes 4-6: Sofosbuvir/velpatasvir, Glecaprevir/pibrentasvir

Duration: 8-12 weeks (pangenotypic regimens preferred)

SVR (sustained virological response) rates: >95%

Outcomes with DAA therapy:

Complete clinical response: 60-80%

Partial response: 15-25%

No response: 5-10%

Cryoglobulin clearance lags behind viral clearance (may take 6-12 months post-SVR)67

Renal outcomes generally good (stabilization or improvement in 60-80%)

Pearl: Low-dose corticosteroids (5-10 mg prednisone daily) may be used for symptomatic relief during DAA treatment but are not required. Avoid high-dose immunosuppression if possible to preserve immune-mediated HCV clearance.

2. Severe/organ-threatening disease:

Combined approach: Immunosuppression + HCV DAA therapy

The dilemma: Need rapid disease control with immunosuppression, but immunosuppression may interfere with HCV clearance.

Current recommendations:

Initiate immunosuppression immediately for disease control

Start DAA therapy simultaneously or shortly after (1-2 weeks)

Taper immunosuppression rapidly as HCV responds (4-8 weeks)

Immunosuppressive regimens:

High-dose corticosteroids:

Methylprednisolone 500-1000 mg IV daily × 3 days (pulse therapy) for severe disease

Then prednisone 0.5-1 mg/kg/day

Rapid taper over 6-12 weeks as DAA takes effect

Rituximab:

Most effective immunosuppressive agent for cryoglobulinemic vasculitis68

Depletes B-cells (source of cryoglobulin production)

Dose: 375 mg/m² weekly × 4 doses OR 1000 mg × 2 doses (2 weeks apart)

Particularly effective for:

Severe renal disease

Severe peripheral neuropathy

Refractory disease

Can be used with or without corticosteroids

Pearl: Rituximab is now considered first-line for severe HCV-associated cryoglobulinemic vasculitis, used in combination with DAA therapy

Cyclophosphamide:

Reserved for life-threatening disease or rituximab failure

Dose: IV pulse 500-750 mg/m² monthly × 6 doses

More toxicity than rituximab, less commonly used now

Plasma exchange (PLEX):

Indications:

Life-threatening disease (RPGN, mesenteric vasculitis)

Hyperviscosity (high cryocrit >10-15%)

Bridge to immunosuppression/DAA effect

Regimen: 3-5 liters per exchange, every other day, 5-10 exchanges

Replace with albumin ± FFP

Temporary measure (cryoglobulins reaccumulate quickly)

Hack: For severe cryoglobulinemic vasculitis requiring ICU admission (RPGN, mesenteric vasculitis):

Day 1-3: Methylprednisolone pulse + PLEX + Rituximab dose 1

Week 2: Rituximab dose 2

Start DAA therapy by week 1-2

Continue prednisone with rapid taper over 8-12 weeks

3. Non-HCV-associated cryoglobulinemic vasculitis:

Approach: Treat underlying condition + immunosuppression

Autoimmune disease-associated:

Treat underlying disease (Sjögren's, SLE, RA)

Immunosuppression as for HCV-associated (rituximab preferred)

Long-term maintenance therapy usually needed

Lymphoproliferative disorder-associated:

Treat underlying malignancy

May require chemotherapy regimens

Rituximab particularly appropriate (anti-CD20)

Idiopathic (no identifiable cause):

Immunosuppression with rituximab or other agents

Long-term therapy usually required

Higher relapse rates than HCV-associated (no curative treatment available)

For all patients, supportive measures:

Cold avoidance: Essential

Avoid cold exposure

Dress warmly, especially extremities

Heated environments

Wound care: For skin ulcerations

Pain management: For neuropathy (gabapentin, pregabalin, duloxetine)

Renal support: Dialysis if needed for RPGN

Management of complications: Treat infections aggressively (immunosuppressed patients)

Monitoring and Follow-up

During treatment:

Clinical symptoms (purpura, neuropathy, renal function)

Serum creatinine, urinalysis weekly (if renal involvement)

HCV RNA at weeks 4, 12 (during DAA), and 12 weeks post-treatment (SVR assessment)

Cryoglobulin levels, cryocrit, C4 every 4-8 weeks

Complement levels (C4, C3)

CBC (monitor for cytopenias with DAA or immunosuppression)

Post-treatment:

Cryoglobulins may remain detectable for months after SVR but should decrease

C4 normalizes in ~50% of patients achieving SVR

Persistent cryoglobulins without symptoms don't require treatment

Monitor for HCV recurrence (rare with DAAs but possible)

Monitor for B-cell lymphoma (annual CBC, physical exam for lymphadenopathy)

Long-term outcomes:

HCV eradication with DAAs: Vasculitis remission in 60-80%

Relapse rates low after SVR (<10%)

Persistent low-grade cryoglobulinemia common but usually asymptomatic

Renal function usually stabilizes or improves

Neuropathy may improve but often has residual deficits

Long-term lymphoma risk persists even after SVR (requires ongoing surveillance)

Oyster: Even after successful HCV eradication and vasculitis remission, patients retain a lifelong increased risk of B-cell lymphoma (5-10% over 10-15 years). Annual monitoring with CBC and physical examination is recommended indefinitely.

ICU Management Scenarios

Scenario 1: Rapidly progressive glomerulonephritis

58-year-old with known HCV presents with acute kidney injury (Cr 1.2 → 4.5 mg/dL over 1 week), purpura, hematuria

Management:

Urgent nephrology consultation

Renal biopsy (unless contraindicated)

Methylprednisolone 1000 mg IV daily × 3 days

Rituximab 1000 mg IV (repeat in 2 weeks)

Consider PLEX if dialysis-dependent

Initiate DAA therapy within 1-2 weeks

Renal replacement therapy as needed

Scenario 2: Acute mesenteric vasculitis

62-year-old with HCV develops severe abdominal pain, bloody diarrhea

Management:

CT angiography (bowel wall thickening, mesenteric vessel involvement)

Surgery consultation (assess for perforation, infarction)

NPO, bowel rest, TPN if needed

High-dose corticosteroids (methylprednisolone 1000 mg IV daily)

Rituximab

PLEX

Antibiotics (cover for translocation)

Surgical intervention if perforation/infarction

Scenario 3: Hyperviscosity syndrome (Type I cryoglobulinemia)

More common with Type I (monoclonal), but can occur with high cryocrit in mixed types

Symptoms: headache, blurred vision, altered mental status, bleeding, heart failure

Management:

Urgent PLEX (most effective therapy)

Keep patient warm (prevents further precipitation)

Treat underlying hematologic malignancy

Avoid blood transfusions if possible (worsen hyperviscosity)

Rituximab for B-cell disorders

Pearl: Distinguish true vasculitis (mixed cryoglobulinemia) from hyperviscosity (Type I). Treatment differs: vasculitis requires immunosuppression; hyperviscosity requires plasmapheresis + treatment of underlying disorder.

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Special Situations and Practical Considerations

Pregnancy and Vasculitis

General principles:

Pregnancy should be planned during disease remission

Some medications are teratogenic (cyclophosphamide, methotrexate, mycophenolate)

Preconception counseling essential

Medication safety:

Safe in pregnancy:

Prednisone (crosses placenta minimally)

Azathioprine

Hydroxychloroquine

Aspirin (low-dose)

Contraindicated:

Cyclophosphamide (teratogenic, causes infertility)

Methotrexate (teratogenic, abortifacient)

Mycophenolate mofetil (teratogenic)

Rituximab (avoid; use only if life-threatening disease)

ANCA vasculitis in pregnancy:

Increased risk of flares

Increased maternal and fetal morbidity

Continue azathioprine for maintenance if pregnant

Use prednisone for flares

Rituximab or cyclophosphamide only for life-threatening disease

GCA/TAK in pregnancy:

Generally compatible with successful pregnancy

Continue low-dose prednisone

Monitor for flares

Manage hypertension carefully (especially TAK)

Hack: For women of childbearing age with vasculitis requiring cyclophosphamide: refer for oncofertility consultation BEFORE starting treatment. Options include oocyte/embryo cryopreservation, ovarian tissue cryopreservation, or GnRH analog co-treatment (controversial efficacy).

Infection vs. Vasculitis Flare

The critical dilemma in critical care:

Fever, elevated inflammatory markers, and multiorgan dysfunction can represent either:

Infection in an immunosuppressed patient

Vasculitis flare

Both simultaneously

Clinical clues favoring infection:

Focal findings (pneumonia, UTI, cellulitis)

Positive cultures

Neutrophilia (vs. vasculitis which may have normal or low WBC)

No new vasculitis manifestations

Occurred shortly after immunosuppression dose reduction

Clinical clues favoring vasculitis flare:

New organ involvement (e.g., new hematuria, hemoptysis)

Rising ANCA titers (if ANCA vasculitis)

Purpura, skin lesions

Peripheral neuropathy

Lack of focal infection source

Practical approach:

Obtain cultures (blood, urine, sputum, others as indicated)

Imaging to identify infection source

Consider empiric broad-spectrum antibiotics

If strong suspicion for vasculitis flare AND patient is critically ill → treat both (antibiotics + immunosuppression)

De-escalate based on culture results and clinical response

Oyster: Infections can trigger vasculitis flares. It's not uncommon for patients to have both simultaneously. When in doubt in a critically ill patient, cover both possibilities rather than making a forced choice.

Vasculitis Mimics

Critical to recognize conditions that mimic systemic vasculitis:

1. Infective endocarditis:

Fever, embolic phenomena, glomerulonephritis

Can have positive ANCA (10-15% of cases)

Mimic of ANCA vasculitis

Blood cultures, echocardiography essential

2. Atrial myxoma:

Embolic phenomena, constitutional symptoms, elevated ESR

Echocardiography diagnostic

3. Cholesterol emboli syndrome:

After vascular procedure or anticoagulation

Livedo reticularis, "blue toe syndrome," eosinophilia, renal failure

Skin or kidney biopsy shows cholesterol clefts

4. Thrombotic microangiopathy (TTP/HUS):

Microangiopathic hemolytic anemia, thrombocytopenia, renal failure

ADAMTS13 activity, Shiga toxin

Requires different treatment (plasmapheresis for TTP, supportive for HUS)

5. Antiphospholipid syndrome:

Thrombosis, livedo reticularis, pregnancy morbidity

Antiphospholipid antibodies

Requires anticoagulation, not immunosuppression

6. Calciphylaxis:

ESRD patients with painful skin lesions

Elevated calcium-phosphate product

Skin biopsy: medial calcification

7. Malignancy:

Paraneoplastic vasculitis (rare)

Lymphoma can mimic vasculitis

Always consider malignancy in elderly patients with new "vasculitis"

8. Drug-induced vasculitis:

Cocaine (midline destructive lesions mimicking GPA)

Levamisole-adulterated cocaine (ANCA-positive vasculitis)

Hydralazine, propylthiouracil (drug-induced ANCA vasculitis)

Minocycline, allopurinol, others

Pearl: Always obtain blood cultures in any patient with suspected vasculitis before initiating immunosuppression. Infective endocarditis is the most dangerous vasculitis mimic.

Vaccinations in Vasculitis Patients

General principles:

Vaccinate BEFORE immunosuppression if possible

Inactivated vaccines safe during immunosuppression (may have reduced efficacy)

Live vaccines contraindicated during immunosuppression

Recommended vaccinations:

Influenza (annually, inactivated)

Pneumococcal (PCV13 and PPSV23)

COVID-19 (per current guidelines)

Herpes zoster (recombinant Shingrix, safe during immunosuppression)

Hepatitis B (especially if HBV-negative before rituximab)

Contraindicated during immunosuppression:

Live attenuated influenza (FluMist)

MMR

Varicella

Yellow fever

Live zoster vaccine (Zostavax)—use Shingrix instead

Timing considerations:

Ideally vaccinate ≥2-4 weeks before starting immunosuppression

During rituximab: vaccines less effective (B-cell depletion)

Consider vaccinating ≥6 months after rituximab when B-cells recover

Or vaccinate ≥4 weeks before next rituximab dose

Close contacts should be vaccinated (especially influenza, COVID-19)

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Key Pearls and Clinical Hacks Summary

ANCA Vasculitis:

PR3-ANCA in appropriate clinical context has 95% specificity—treat before biopsy in sick patients

Reduced-dose steroid protocol (PEXIVAS) is now standard—fewer infections, same efficacy

Rituximab is first-line for relapsing disease and fertility preservation

Serial hemoglobin drops without hemoptysis can indicate DAH

B-cell depletion must be documented after rituximab—10-15% don't achieve it

Giant Cell Arteritis: 6. Jaw claudication has highest positive likelihood ratio for GCA 7. Normal ESR AND CRP together make GCA extremely unlikely (<1%) 8. Temporal artery biopsy stays positive 2-4 weeks after steroid initiation 9. Always add aspirin—reduces visual loss by ~70% 10. Tocilizumab is highly effective for relapsing/refractory GCA

Takayasu Arteritis: 11. Check bilateral arm AND leg blood pressures—differences are nearly universal 12. 30% of active disease has normal inflammatory markers 13. Defer elective surgery until remission (50% vs. 20% restenosis rate) 14. MRA with vessel wall imaging superior to conventional MRA for activity assessment 15. Tocilizumab is most promising biologic for TAK

Cryoglobulinemic Vasculitis: 16. Markedly low C4 with relatively preserved C3 is characteristic 17. False negative cryoglobulins common due to improper collection (must keep warm) 18. HCV DAAs cure vasculitis in 60-80%—now first-line for mild-moderate disease 19. Rituximab is first-line immunosuppression for severe HCV-associated cryoglobulinemia 20. Even after HCV cure, lifelong lymphoma surveillance needed

General: 21. Blood cultures before immunosuppression—endocarditis mimics vasculitis 22. Infections can trigger vasculitis flares—both can coexist 23. Never delay treatment for suspected GCA with visual symptoms—permanent blindness is irreversible 24. PLEX benefit questioned by PEXIVAS trial—individualize use for severe AAV 25. Oncofertility counseling before cyclophosphamide in reproductive-age patients

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Conclusion

Systemic vasculitides represent some of the most challenging conditions encountered in critical care medicine, requiring rapid diagnosis, aggressive treatment, and meticulous supportive care. The landscape of vasculitis management has evolved dramatically over the past decade, with rituximab emerging as a highly effective therapy for ANCA vasculitis and cryoglobulinemic vasculitis, tocilizumab revolutionizing treatment of large-vessel vasculitides, and direct-acting antivirals providing curative therapy for HCV-associated cryoglobulinemic vasculitis.

Key principles for critical care physicians include:

Maintain high clinical suspicion in patients with multi-organ involvement and systemic inflammation

Recognize true emergencies (pulmonary-renal syndrome, visual symptoms in GCA, mesenteric vasculitis)

Initiate treatment promptly based on clinical suspicion without waiting for confirmatory tests

Balance aggressive immunosuppression with infection risk

Utilize modern treatment paradigms (reduced-dose steroids, rituximab, tocilizumab)

Provide comprehensive supportive care while addressing the underlying vasculitis

Early recognition and treatment remain the cornerstones of improving outcomes in these potentially devastating diseases. As critical care physicians, we must be vigilant diagnosticians, decisive in initiating treatment when indicated, and meticulous in managing the complex medical issues that arise in these critically ill patients.

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30.   Salvarani C, et al. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347(4):261-271.

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32.   Hayreh SS, et al. Visual loss and risk factors for it in giant cell (temporal) arteritis. Ophthalmology. 1998;105(8):1416-1423.

33.   Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA. 2002;287(1):92-101.

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35.   Karassa FB, et al. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med. 2005;142(5):359-369.

36.   Achkar AA, et al. How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann Intern Med. 1994;120(12):987-992.

37.   Dejaco C, et al. 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2015;74(10):1799-1807.

38.   Liu GT, et al. Visual morbidity in giant cell arteritis. Clinical characteristics and prognosis for vision. Ophthalmology. 1994;101(11):1779-1785.

39.   Proven A, et al. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum. 2003;49(5):703-708.

40.   Mazlumzadeh M, et al. Treatment of giant cell arteritis using induction therapy with high-dose corticosteroids: a double-blind, placebo-controlled, randomized prospective clinical trial. Arthritis Rheum. 2006;54(10):3310-3318.

41.   Nesher G, et al. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum. 2004;50(4):1332-1337.

42.   Alba MA, et al. Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore). 2014;93(5):194-201.

43.   Stone JH, et al. Trial of tocilizumab in giant-cell arteritis (GiACTA). N Engl J Med. 2017;377(4):317-328.

44.   Unizony S, et al. Clinical outcomes of treatment of giant cell arteritis with tocilizumab. Semin Arthritis Rheum. 2019;49(1):126-135.

45.   Mahr AD, et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum. 2007;56(8):2789-2797.

46.   Prieto-González S, et al. Large vessel involvement in biopsy-proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography. Ann Rheum Dis. 2012;71(7):1170-1176.

47.   Nuenninghoff DM, et al. Incidence and predictors of large-artery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum. 2003;48(12):3522-3531.

48.   Takayasu M. Case with unusual changes of the central vessels in the retina. Acta Soc Ophthalmol Jpn. 1908;12:554-555.

49.   Watts R, et al. Global epidemiology of vasculitis. Nat Rev Rheumatol. 2022;18(1):22-34.

50.   Kerr GS, et al. Takayasu arteritis. Ann Intern Med. 1994;120(11):919-929.

51.   Moriwaki R, et al. Clinical manifestations of Takayasu arteritis in India and Japan—new classification of angiographic findings. Angiology. 1997;48(5):369-379.

52.   Goel R, et al. Pulmonary artery involvement is common in Takayasu arteritis and is associated with pulmonary hypertension. J Rheumatol. 2018;45(9):1322-1328.

53.   Maksimowicz-McKinnon K, et al. Limitations of the role of serologic measurements in diagnosis and management of Takayasu arteritis. J Rheumatol. 2007;34(1):166-173.

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55.   Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33(8):1129-1134.

56.   Kerr GS, et al. Takayasu arteritis. Ann Intern Med. 1994;120(11):919-929.

57.   Hoffman GS, et al. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum. 1994;37(4):578-582.

58.   Li J, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of active Takayasu arteritis: a multi-center randomized controlled trial. Clin Rheumatol. 2020;39(4):1153-1162.

59.   Nakaoka Y, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis. 2018;77(3):348-354.

60.   Min PK, et al. Endovascular therapy combined with immunosuppressive treatment for occlusive arterial disease in patients with Takayasu's arteritis. J Endovasc Ther. 2005;12(1):28-34.

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64.   Ferri C, et al. HCV-related cryoglobulinemic vasculitis: an update on its etiopathogenesis and therapeutic strategies. Clin Exp Rheumatol. 2003;21(6 Suppl 32):S78-84.

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Suggested Further Reading

Comprehensive Reviews:

69.   Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.

70.   Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020;6(1):71.

ANCA-Associated Vasculitis:

71.   Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75(9):1583-1594.

72.   Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622-631.

Giant Cell Arteritis:

73.   Dejaco C, Duftner C, Buttgereit F, et al. The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease. Rheumatology (Oxford). 2017;56(4):506-515.

74.   Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19-30.

Takayasu Arteritis:

75.   Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum. 2007;56(3):1000-1009.

76.   Mason JC. Takayasu arteritis—advances in diagnosis and management. Nat Rev Rheumatol. 2010;6(7):406-415.

Cryoglobulinemic Vasculitis:

77.   Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012;379(9813):348-360.

78.   Cacoub P, Comarmond C, Domont F, et al. Cryoglobulinemia vasculitis. Am J Med. 2015;128(9):950-955.

Treatment Guidelines:

79.   Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014;53(12):2306-2309.

80.   Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68(3):310-317.

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Abbreviations

AAV - ANCA-associated vasculitis

ACR - American College of Rheumatology

ANCA - Anti-neutrophil cytoplasmic antibody

AION - Anterior ischemic optic neuropathy

APD - Afferent pupillary defect

AR - Aortic regurgitation

BAL - Bronchoalveolar lavage

BVAS - Birmingham Vasculitis Activity Score

CABG - Coronary artery bypass grafting

CHCC - Chapel Hill Consensus Conference

CNS - Central nervous system

CRAO - Central retinal artery occlusion

CRP - C-reactive protein

CTA - CT angiography

DAA - Direct-acting antiviral

DAH - Diffuse alveolar hemorrhage

EGPA - Eosinophilic granulomatosis with polyangiitis

ELISA - Enzyme-linked immunosorbent assay

EMG - Electromyography

ENT - Ear, nose, and throat

ESR - Erythrocyte sedimentation rate

ESRD - End-stage renal disease

FDG-PET - Fluorodeoxyglucose positron emission tomography

FFP - Fresh frozen plasma

FFS - Five Factors Score

GBM - Glomerular basement membrane

GCA - Giant cell arteritis

GI - Gastrointestinal

GnRH - Gonadotropin-releasing hormone

GPA - Granulomatosis with polyangiitis

HBV - Hepatitis B virus

HCV - Hepatitis C virus

HFNC - High-flow nasal cannula

ICU - Intensive care unit

IF - Immunofluorescence

IL-6 - Interleukin-6

IV - Intravenous

LFT - Liver function test

MPA - Microscopic polyangiitis

MPGN - Membranoproliferative glomerulonephritis

MPO - Myeloperoxidase

MRA - Magnetic resonance angiography

MRI - Magnetic resonance imaging

NCS - Nerve conduction study

NIH - National Institutes of Health

PCI - Percutaneous coronary intervention

PEEP - Positive end-expiratory pressure

PET-CT - Positron emission tomography-computed tomography

PLEX - Plasma exchange

PMR - Polymyalgia rheumatica

PR3 - Proteinase 3

PTA - Percutaneous transluminal angioplasty

RA - Rheumatoid arthritis

RBC - Red blood cell

RF - Rheumatoid factor

RPGN - Rapidly progressive glomerulonephritis

SLE - Systemic lupus erythematosus

SPEP - Serum protein electrophoresis

SVR - Sustained virological response

TAK - Takayasu arteritis

TIA - Transient ischemic attack

TNF - Tumor necrosis factor

TPN - Total parenteral nutrition

TPMT - Thiopurine methyltransferase

TTP - Thrombotic thrombocytopenic purpura

WBC - White blood cell

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Acknowledgments

The author acknowledges the contributions of the numerous investigators whose groundbreaking clinical trials and observational studies have advanced our understanding and treatment of systemic vasculitides over the past decades, transforming these once-uniformly fatal conditions into treatable diseases with significantly improved outcomes.

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Correspondence:

Questions regarding this review or clinical cases may be directed to appropriate rheumatology, nephrology, or critical care consultants at your institution.

Conflicts of Interest:

None declared.

Funding:

No external funding was received for the preparation of this manuscript.

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This review article is intended for educational purposes for postgraduate trainees and practicing clinicians in critical care medicine. Clinical decisions should be individualized based on patient-specific factors, local resources, and current evidence-based guidelines.

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