Vasculitides

Background

• Necrotizing vasculitis of small and medium vessels characterized by granulomatous inflammation.
• Classically involves upper & lower respiratory tracts, kidneys.

Presentation

• Constitutional: weight loss, fevers, fatigue.
• ENT: sinusitis, rhinitis, saddle nose, otitis, nasal crusting & ulcers.
• Pulmonary: DAH, hemoptysis, nodules, dyspnea.
• Renal: RPGN.
• Ocular: (epi)scleritis, uveitis, corneal ulcers.
• Skin: palpable purpura, livedo reticularis.
• Neuro: mononeuritis multiplex.

Evaluation

• ANCA+ (90%, typically PR3-cANCA).
• ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV.
• UA with microscopy: hematuria, proteinuria, RBC casts, dysmorphic RBCs.
• CT sinus: sinusitis +/- bone erosions.
• CT chest: cavitations, nodules.
• Biopsy: necrotizing granulomatous vasculitis, pauci-immune glomerulonephritis.
• Clinical pearl: If you suspect renal disease (elevated Cr, hematuria), ask the renal or rheum fellow to help spin the urine to evaluate for RBC casting or dysmorphic cells (quick way to confirm active GN, since renal biopsy takes time to arrange).

Management

• Mild-moderate disease (upper airway): MTX + prednisone 0.5 mg/kg/day with taper.
• Severe disease (lung, kidney): RTX + IV methylpred 1mg/kg/day with taper.
• If failed response to RTX, CYC.
• RPGN, pulmonary hemorrhage, mononeuritis multiplex, or optic neuritis: IV
  methylprednisolone 7-15mg/kg/d (1000mg max) x3d for induction therapy.
• DVT ppx (high risk for DVT/PE.

Presentation

• Similar to GPA, but without granulomatous features (upper airway disease, pulmonary nodules).
• Classically only involves lungs and kidneys.

Evaluation

• ANCA+ (70%, typically MPO-pANCA).
• ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV.
• UA with microscopy: hematuria, proteinuria, RBC casts, dysmorphic RBCs.
• CT chest: cavitations, nodules.
• Biopsy: necrotizing vasculitis (no granulomas), pauci-immune glomerulonephritis.

Management

• Same as GPA - see above

Presentation

• Quite variable presentation but classically included adult-onset asthma followed by development of peripheral neurologic disease. May present with more vasculitis features similar to GPA/MPA but less common.
• ENT (more common than vasculitis): new-onset asthma, rhinosinusitis.
• Cardiac (accounts for 50% deaths from EGPA): coronary arteritis, myocarditis, HF, valvulopathy.

Evaluation

• ANCA+ (50%, typically MPO-pANCA)
• Peripheral eosinophilia
• IgE, ANA, RF, C3/C4
• Biopsy: necrotizing granulomatous vasculitis, fibrinoid necrosis, eosinophilic infiltrates, pauciimmune glomerulonephritis.
• TTE or cMRI in all patients.

Management

• Mild-moderate: prednisone 0.5-1 mg/kg/day for 6-12w with taper + mepolizumab.
• Severe: prednisone 0.5-1 mg/kg/day for 6-12w with taper + RTX or CYC.
• Life-threatening multiorgan involvement (cardiac, pulmonary, renal, neurologic): IV
  methylprednisolone 1000mg daily x3d for induction.
• DVT ppx (high risk for DVT/PE).

Background

• Cryoglobulins = circulating Igs that precipitate in cold temps & redissolving on warming.
• Type I: monoclonal immunoglobulin (IgM or G) – a/w plasma cell dyscrasias (Waldenström’s, MM, MGUS) — hyperviscosity, thrombosis.
• Type II: mixed (monoclonal IgM with +RF* + polyclonal IgG) – a/w infection (esp HCV) —immune complex deposition.
• Type III: mixed (polyclonal IgM + IgG with +RF) – a/w autoimmune disease — immune complex deposition.
• *RF activity = reactivity of an IgM component with the Fc portion of an IgG.

Presentation

• Type I: HA, TIA, visual disturbances, digital ischemia, livedo reticularis.
• Type II/III: fevers, Meltzer’s triad (purpura, arthralgias, weakness), mononeuritis multiplex, MPGN.

Evaluation

• Cryoglobulins (fastidious collection, see above), C3/C4 (low), RF (positive in types II/III), ANA w/ reflex, HBV/HCV, SPEP, SFLC, serum viscosity, UA, +/- renal biopsy, skin biopsy (leukocytoclastic vasculitis).

Management

• Treat underlying etiology. Avoid cold (Type I).
• Moderate-severe disease/end-organ disease: prednisone + RTX or CYC.
• Hyperviscosity (Type I): PLEX.

Background

• Necrotizing vasculitis of medium-sized muscular arteries, leading to aneurysm formation, thrombosis, & downstream ischemia.
• Incidence: middle age/older adults (peaks in 50s).
• Most cases idiopathic; frequently associated with HBV, HCV, hairy cell leukemia.

Presentation

• Constitutional: fatigue, fevers, weight loss.
• Neuro: mononeuritis multiplex.
• Skin: livedo reticularis, palpable purpura, ulcers, tender erythematous nodules.
• Cardiac: coronary arteritis, ischemic CM.
• GI: abdominal pain, GI infarct.
• Renal: HTN.
• GU: gonadal pain, orchitis.

Evaluation

• Elevated ESR/CRP, CBC (normocytic anemia, leukocytosis), HBV, HCV, negative ANCA.
• Angiogram, CTA, MRA: microaneurysms or focal stenoses of renal/mesenteric arteries.
• Biopsy: transmural inflammation & fibrinoid necrosis of arterial wall.

Management

• Mild: prednisone 1mg/kg daily for 4w with taper +/- MTX or AZA.
• Moderate: prednisone 1mg/kg daily for 4w with taper + CYC.
• Severe (renal failure, proteinuria, GI/cardiac/neurologic): IV methylprednisolone 500-1000mg daily x3d, then prednisone 1mg/kg/d for 4w with taper + CYC.

Background

• Granulomatous inflammation of aorta & extracranial branches of carotids, particularly the temporal artery.
• Most common large-vessel vasculitis.
• Incidence: >60 years, F > M (3:1).
• Closely linked to PMR (~50% have PMR; ~15–30% of PMR patients develop GCA).
• T-cell dysregulation, IL-6-mediated inflammation, and macrophage-driven vascular remodeling cause intimal hyperplasia and vessel occlusion.

Presentation

• Constitutional: fatigue, fever, weight loss.
• Extracranial arteries: temporal unilateral headache, scalp tenderness, jaw claudication, visual disturbance (diplopia, blurred vision, amaurosis fugax, sudden irreversible loss).
• Temporal arteritis is a clinical presentation most commonly caused by GCA. Other vasculitides (GPA, Behcet’s) and infiltrative disorders (sarcoid, IgG4-RD, amyloid) can potentially mimic.
• Large-vessel arteries: arm claudication, bruits, aortic aneurysm/dissection. May present as FUO if only large vessel involvement.

Evaluation

• ESR/CRP (almost always elevated), CK, TSH.
• Evaluate for any temporal artery abnormalities (tenderness to palpation, presence of nodules).
• Ophthalmology evaluation if any concern for ocular involvement.
• Temporal artery biopsy by vascular surgery (typical in the US) or temporal artery ultrasound (halo sign). Only a biopsy can rule out mimics if the presentation is atypical.
• If high suspicion for GCA with negative biopsy or ultrasound, perform further imaging to evaluate for large vessel involvement (CT/CTA or MRI/MRA of aorta and/or branches).

Management

• Start steroids as soon as suspected. Do not delay awaiting biopsy!
• No vision sxs: prednisone 1mg/kg/d (max 60 mg) for 2-4 weeks with months-long taper.
• Vision sxs: IV methylprednisolone 500–1000 mg/day × 3 days → then prednisone 1 mg/kg/day (max 60 mg) with taper.
• Consider tocilizumab or upadacitinib as adjunctive in those with steroid-refractory disease or those at higher risk for glucocorticoid-related side effects (since most pts with GCA are elderly, this applies to most pts).
  • Bisphosphonates for osteoporosis prevention.

Background

• Granulomatous inflammation of the aorta & major branches, often brachiocephalic & subclavian arteries.
• Vascular stenosis, occlusion, or aneurysm formation.
• Biphasic course: systemic inflammatory phase followed by vascular occlusive phase.
• Incidence: <40 years, F>M (8:1), most common in Asian descent.
• Etiology: T-cell and pro-inflammatory cytokines drive granulomatous inflammation of vessel wall.

Presentation

• Constitutional: fevers, fatigue, weight loss.
• Cardiovascular: angina, aortic aneurysm, AI, carotidynia (carotid tenderness), bruits.
• Neuro: vertigo, headache, syncope, strokes.
• Renovascular: HTN.
• Peripheral vascular: unequal pulses/BP in limbs, diminished or absent pulses (“pulseless disease”), claudication.

Evaluation

• ESR/CRP: elevated (75%)
• Arteriography: MRA or CTA of head/neck, chest, and abdomen/pelvis.

Management

• New arterial stenosis or aorta/carotid artery involvement: 1mg/kg prednisone daily (max 60-80mg) for 2-4 weeks followed by steroid taper.
• Organ threatening disease (coronary artery involvement, critical stenosis of carotid/vertebral arteries): 500-1000mg IV methylprednisolone daily for 1-3 days, then 1mg/kg prednisone daily for 2-4 weeks followed by steroid taper.
• No FDA approved steroid sparing therapy but many medications used off label.

Background

• Vasculitis affecting all vessel sizes (veins & arteries) associated with recurrent painful oral & genital ulcers.
• Incidence: 20-40 years, M=F (increased severity in M), more common in Middle East and Central Asia.
• Genetic association: HLA-B*51.
• Ddx: (consider a very broad ddx given many nonspecific features): Sweet syndrome, IBD, HSV, reactive arthritis, erythema multiforme, bullous disease.

Presentation

• ENT: painful oral apthous ulcers (usually >3x in 1st y of presentation).
• GU: scarring painful genital ulcers.
• Skin: erythema nodosum, pustules, pyoderma gangrenosum, pathergy reaction.
• Ocular: uveitis (often panuveitis), retinal vasculitis.
• MSK: non-erosive migratory oligoarthritis.
• GI: ileocecal ulceration, abdominal pain, GIB.
• Vascular: pulmonary artery aneurysm, DVT/PE, dural venous thrombosis, Budd-Chiari.
• CNS: brainstem or hemispheric lesions, aseptic meningitis, meningoencephalitise.

Evaluation

• Clinical diagnosis (requires A + [2 of the others]). Diagnosis = score 4+
• Criteria: A. recurrent oral ulcers (2), B. genital ulcers (2), C. ocular lesions (2), D. skin lesions (1), E. vascular lesions (1), F. positive pathergy test (1).

Management

• Mucocutaneous or arthritis: topical steroids, colchicine, apremilast, AZA, biologics (adalimumab, etanercept, etc.).
• Moderate/severe disease (uveitis, major organ involvement, vascular, CNS): prednisone 1mg/kg/d + steroid-sparing agent (TNFi, MTX, AZA).
• Thrombosis: anticoagulation (avoid if pulmonary artery aneurysms present due to risk of bleeding!)

Background

• PMR is a disorder of inflammatory pain and stiffness predominantly affecting shoulders and pelvic girdle (hips, sacrum, and coccyx).
• Incidence: typically >50 years, peak ages 70-80; more common in women (2:1).
• PMR is often seen in patients with GCA; occurs in up to 50% of GCA, while 15-30% of PMR patients develop GCA. Either condition may present initially, or may occur concomitantly.
• Etiology: poorly understood but likely genetic predisposition (HLA DR4 allele, Caucasian background) and environmental factors (including infections) contribute to IL-6-mediated inflammatory response.

Presentation

• Acute or subacute onset of:
  • bilateral, symmetric pain and stiffness of shoulders (in almost all cases), neck, and/or pelvic girdle that is worse in the morning and with inactivity.
  • +/- Difficulty with ADLs such as brushing their hair or teeth, lifting their arms to put clothing on, and rising from a seated position.
  • +/- Non-specific constitutional symptoms (fatigue, low-grade fever, weight loss).
• Physical exam: normal muscle strength. Objective muscle weakness should raise suspicion for another disease process.
• Screen for GCA red flag symptoms; headache, jaw claudication, visual changes, scalp tenderness).

Evaluation

• Diagnosis: clinical diagnosis; can use ACR/EULAR 2012 classification criteria for patients ≥50 with new shoulder pain and elevated ESR/CRP (≥4 if not using ultrasound; ≥5 if using ultrasound): morning stiffness lasting >45 min (2 points), hip pain or limited range of motion (1 point), negative RF and CCP titers (2 points), presence of pain in other joints (1 point), shoulder/hip ultrasound findings of inflammation (1 point)
• Labs: elevated ESR and CRP (almost always); consider TSH, CK, RF, anti-CCP to rule out mimics
• Imaging: MSK ultrasound may demonstrate bursitis, tenosynovitis, or non-PMR etiologies; similarly, MRI may confirm inflammation or demonstrate structural pathology

Management

• 1st line: steroids, initially 12.5-25mg prednisone daily à assess response with expected improvement within 2-4 weeks. Lack of improvement strongly suggests an alternative diagnosis unless the patient has GCA.
• Taper: decrease slowly to the minimum effective dose (often 5mg/day for up to 1-2 years). CRP/ESR can help provide additional insight into disease remission/ guide taper.
• Refractory disease or high risk of steroid side effect: consider sarilumab to reduce steroid use.

Adult-Onset Still’s Disease (AOSD)

Meridith Balbach

Background

• Rare autoinflammatory syndrome characterized by systemic inflammation, spiking fevers, arthralgia/arthritis, and a salmon-colored rash.
• Autoinflammatory diseases involve dysregulation of innate immune system (rather than dysregulation of the adaptive immune system, as in autoimmune disease).
  • Includes both inherited (e.g. monogenic syndromes like Familial Mediterranean Fever (FMF), cryopyrin-associated periodic syndromes (CAPS), and TNF receptor–associated periodic syndrome (TRAPS)) and acquired syndromes (e.g. AOSD and VEXAS).
• Incidence: generally sporadic (no clear genetic predisposition) at 16-35y but can occur at any age. Slight female predominance (51-60%). Rare (~0.16–0.4 cases per 100,000 persons annually).
  • AOSD is the adult counterpart to systemic juvenile idiopathic arthritis.

Presentation

• Classic triad: quotidian fevers (often late afternoon/evening), arthralgias/arthritis (often polyarticular and migratory), evanescent salmon-colored rash (maculopapular, often nonpruritic) RHEUMATOLOGY 602.
• Additional features: sore throat, lymphadenopathy, hepatosplenomegaly, serositis, elevated LFTs, hyperferritinemia.

Evaluation

• Diagnosis of exclusion: must rule out infection, malignancy, other inflammatory etiologies.
• Serologic workup: elevated ESR/CRP, very high ferritin, CBC (mild leukocytosis, thrombocytosis, anemia), elevated LFTs, ANA and RF (should be negative).
• Imaging workup: consider to identify serositis or lymphadenopathy (nonspecific).
• 2023 ACR/EULAR classification criteria may help with diagnosis (requires ≥5 points total, including ≥2 clinical criteria; sensitivity: ~85% and specificity: ~99%).
• Clinical criteria: fever ≥39°C for ≥3 days (2), arthralgia or arthritis (2), evanescent rash (2), pharyngitis (1), lymphadenopathy and/or hepatosplenomegaly (1), serositis (pleuritis or pericarditis) (1).
• Laboratory criteria: neutrophils ≥80% (1), ferritin >1000 ng/mL (1), negative ANA and RF (1).

Management

• Treatment is based on severity:
  • Mild/moderate: NSAIDs and/or steroids.
  • Moderate/severe or steroid-refractory: steroids (prednisone 0.5–1 mg/kg/day) + IL-1 or IL-6 inhibitor.
  • Severe systemic or refractory: steroids + IL-1 or IL-6 inhibitor.
• Monitor for progression to secondary macrophage activation syndrome (progressive cytopenias, hyperferritinemia, coagulopathy, liver dysfunction, multiorgan failure).