Vasculitides

"Vasculitides" are L2 conditions from Section 2.1.10 in the second edition of the CICM Syllabus for the Second Part Examination. The term may seem unusual, and one may be tempted to pronounce it like the name of a classical Athenian philosopher, but the reader is assured that this is correct proper grammar. The word is the mutant offspring of the Latin vasculum and the Greek itis, which pluralises into -itides. In fact the attentive reader will have noticed that the plural form of all such inflammatory conditions is an -itides of some kind (meningitides, bronchitides, arthritides, etc).

Jennette (2013) is a summary of the vasculitis nomenclature and is probably some kind of bare minimum (there is also a snippet of information for each disease, so it is not entirely nosological in content). Weyland et al (2018), a chapter from the Primer on the rheumatic diseases,  is 53 pages of rather extensive exploration of each vasculitis, which is much more than any CICM exam candidate needs; but for some of the questions that came up in the writing of this summary, it was instrumental. The entire assessment section was laboriously extracted from this text. And for the absolute devotee, who has pictures of Lotte Strauss and Jacob Churg on their wall, Systemic Vasculitides: Current Status and Perspectives (2016) is an essential read, as it is a densely packed 429-page compendium of every vasculitis you could ever want.  

Aetiology of vasculitides

Vasculitides are (these days) named and classified according to their pathophysiolgy and (perhaps somewhat unhelpfully) according to the size of the vessels they affect. At one stage, when we had no mechanisms to which we could attribute the clinical findings, it was more convenient to collect them as syndromes under the eponyms of famous physicians; but then some of these turned out to be Nazis, and besides that their underlying processes were uncovered and investigated, which means we can now refer to them by more informative names.

Assessment of a critically ill patient with suspected vasculitis

The urge to create a comprehensive resource often overtakes the pragmatic need to focus and abbreviate, and considering the extensiveness of the result, that urge could not be defeated. To the reader is left the exercise of bringing order to this disorganised list. 

History of an undifferentiated vasculitis:

• Age: Takayasu arteritis typically presents before age 50; giant cell arteritis after age 50.
• Systemic symptoms: Fever, malaise, weight loss, myalgia, all nonspecific, and not predictive of any particular condition, so not clear whether these are worth listing.
• End-artery vascular insufficiency symptoms: Limb claudication, headache, jaw claudication, visual disturbances (amaurosis fugax, diplopia) - all point to large vessel arteritis
• Associated conditions:
  • Polymyalgia rheumatica often coexists with GCA.
  • Hep B often coexists with polyarteritis nodosa
  • Hep C often coexists with cryoglobulinemic vasculitis
  • Chronic urticaria makes you think of hypocomplementemic urticarial vasculitis, but it is so freakishly rare, that you put those thoughts aside immediately.
• Abdominal pain/ postprandial mesenteric claudication (suggests large vessel arteritis, eg. GCA or Takayasu)
• URTI or a rhinitis - often precedes IgA vasculitis or EGPA
• Eye stuff, eg., conjunctivitis: Kawasaki disease in children, Cogan syndrome in adults; whereas uveitis is more a Behçet’s sort of thing
• Mucosal involvement: mucositis in Kawasaki disease in children, oral/genital ulcers in adults from Behçet’s
• Mononeuritis multiplex, peripheral neuropathy: polyarteritis nodosa
• Arthralgia: Cryglobulins and SLE are more likely
• Heavy smoker: Burger's disease (and it disappears completely if they stop)
• Organ patterns:
  • MPA: renal and lung (haematuria, haemoptysis).
  • GPA: upper airway, renal and lung (sinusitis, haemoptysis, haematuria).
  • EGPA: asthma, allergic rhinitis, neuropathy.
  • Anti-GBM: rapidly progressive renal failure and haemoptysis
  • A single organ, or just the skin, could be affected by a single-organ vasculitis
• >Drug exposure:
  • ANCA-associated vasculitides: hydralazine, propylthiouracil, methimazole, minocycline, allopurinol, penicillamine, levamisole-adulterated cocaine
  • Immune complex mediated cutaneous leukocytoclastic vasculitis: β-lactam antibiotics, sulfonamides, NSAIDs, thiazides, phenytoin, allopurinol, TNF inhibitors like infliximab

Examination of an undifferentiated vasculitis:

• Assymmetrical pulses, bruits over large arteries: large vessel vasculitis
• Tender or thickened temporal arteries: GCA, it for some weird reason prefers the carotid and its branches
• Visual impairment (GCA, or keratitis/uveitis of Cogans and Behçet’s)
• Erythema nodosum (sarcoid, a haematological malignancy, polyartertitis nodosa)
• Wheeze (EGPA)
• Microcirculatory occlusion: purpura, digital ischemia, Raynaud's (nonspecific but purpura is classically an IgA-mediated thing)
• Sinus stuff (sinus tenderness, nasal septal perforation) - GPA 
• Hepatosplenomegaly (hypocomplementemic urticarial vasculitis or , more commonly, malignancy)
• Superficial thrombophlebitis (Behçet’s, it also attacks veins)
• CNS features, decreased LOC, etc (SLE)

Investigations for an undifferentiated vasculitis:

• The words "vasculitic screen" are often uttered or written by exam candidates, and score no marks, as they are meaningless on their own. Some justification for the tests that are being ordered needs to be included in the answers.
• Urinalysis for haematuria protein and casts, looking for evidence of glomerular damage
• ANCA quickly distingushes between important categories:
  • >p-ANCA (PR3) positive in GPA
  • >c-ANCA (MPO) is positive in MPA, variable in EGPA
• ESR, CRP, WCC are expected to be elevated, but procalcitonin should not be elevated, and it is helpful to rule out sepsis, because the future is so full of steroids
• Normocytic anaemia is often present (chronic inflammation, innit)
• Eosinophilia  adds a maximum number of points into the EGPA diagnostic criteria
• Chest imaging: Cavitating nodules (GPA), alveolar hemorrhage (MPA), transient infiltrates (EGPA).
• Hep B and C serology, plus syphilis helps form associations with PAN and MPA
• Anti-GBM antibodies 
• Cryoglobulins
• Complement levels (low C4 in SLE, hypocomplementemic urticarial vasculitis)
• Anti-C1q antibodies (hypocomplementemic urticarial vasculitis).
• ANA, anti-dsDNA, rheumatoid factor, ACE level to screen for classically associated systemic diseases
• Biopsy of a lesion - some kind of gold standard
• Multiple blood, sputum and urine cultures - see below
• Bronchoscopy and lavage for culture and cell count, looking for eosinophilic infiltrate, but also mainly to exclude infection
• Imaging: MRI/MRA or CT angiography showing stenoses, aneurysms, wall thickening of aorta and major branches, aortic root dilatation, etc.

Regarding the vasculitis patient in your consult list, the following broad statements can be made:

• A vasculitis at the time of its referral to the ICU will often be:
  • Completely undifferentiated, with expensive tests still pending
  • Lifethreatening, almost by the definition of its referral, which means something therapeutic needs to be done quickly
  • Sufficiently indistinct from competing differentials to give pause to the idea of aggressive immunosuppressive treatment

The goal of early ICU assessment for vasculitis is therefore to first quickly exclude those competing differentials which would prevent or contraindicate emergency management for vasculitis, which is almost uniformly a cocktail of high-intensity immunosuppressants, preceded or followed by either plasma exchange, immunoglobulin, or both. The main differentials to exclude are therefore infectious ones.

Management of a vasculitic critical illness

The spectrum of management strategies might seem so limited, that one might question the attention and expense of making a precise diagnosis. What does it matter which vasculitis this is, if all we do is pulse steroids and plasma exchange? The cynical reader might conclude that the differentiation of specific aetiologies and subtypes is something done by rheumatologists preparing a case report or grand rounds presentation, while the intensivist does something very empirical and pragmatic. However, specific management strategies and caveats do exist for each vasculitis syndrome, and there are individualised approaches more suited to one over another.  Without trying to turn the CICM exam candidate into an expert on the management of rare autoimmune diseases, these can be listed fairly easily (there's not that many of them). Papiris et al (2007) and the now-dated Roane & Griger (1999) have some excellent tables that are still relevant, in the sense that the management strategies they list have not changed overmuch.

• Specific management for specific conditions:
  • Kawasaki disease: high dose aspirin, and IV immunoglobulin
  • Cryoglobulinemia - anti Hep C antivirals
  • Polyarteritis nodosa - anti Hep B antivirals
  • Targeted therapy for the underlying haematological malignancy, if that's what underlying the vasculitis
  • For proven ANCA-positive vasculitis, cyclophosphamide
  • Kronbichler et al (2024), discussing specific management of ANCA-positive vasculitides, also listed avacopan (a small molecule inhibiting the C5a complement receptor) as a steroid-sparing agent.  
• Nonspecific empirical management strategies:
  • High dose steroids to suppress autoantibody production
  • Plasma exchange to remove the autoantibodies
• And if those fail
  • Rituximab, to remove the B-cells that are producing the autoantibodies
  • Methotrexate to prevent any future development of the aforementioned B cells