Table 1.

Neoplastic, autoinflammatory, and primary immunodeficiency diseases and drugs causing large- and medium-vessel vasculitis in adults

Category	Disease	Epidemiology, patient characteristics	Mainly affected large and medium vessels or vessel beds (i)		Diagnostic pearls and pitfalls (ii)
			Large	Medium
Autoinflammatory diseases	Familial Mediterranean fever	FMF: onset childhood to early adulthood, AR inheritance (MEFV gene), prevalence Mediterranean region higher. “PAN-like” MVV: ~ 1% of FMF; m > f = 3.6:1; usually after onset of FMF. BS: associated with FMF in ~ 0.4%, f > m [6–8]	+ / − aorta (thoraco-abdominal); CCA, subclavian (“TAK-like”) [9, 10]	‡ “PAN-like” renal, cerebral, abdominal, cutaneous  + / − cardiac [6]	• Perirenal hematoma in ~ 50% (distinctive feature of “PAN-like” MVV) • “BS-FMF-overlap”: cutaneous, gastrointestinal and CNS involvement more frequent than in isolated BS [8] • “PAN-like” MVV: compared to classical PAN, FMF patients are younger, testicular/cardiac involvement less frequent; CNS involvement more frequent and GN is possible • Hepatitis B Infection is detected in up to ~ 7% of “PAN-like” FMF [6]
	Inflammatory bowel diseases	IBD onset usually adolescence to early adulthood (onset at any age possible). IBD (esp. CD) and TAK or “TAK-like” at younger age (~ 20 Y/A) than isolated TAK [11, 12]	‡ “TAK-like” or TAK: aorta, subclavian, vertebral [11, 12]	+ / − “TAK-like” or TAK: renal, mesenteric, cerebral, cutaneous, TA (only with associated GCA) [11, 12]	• IBD preceding vasculitis in most cases in ~ 70% • GCA with IBD rarely relapsing (in contrast to isolated GCA) • IBD usually not active at time of vasculitis onset • Due to limited data, differentiation of concomitant TAK or GCA and IBD vs. “TAK-like” and “GCA-like” disease with IBD not possible
	Chronic recurrent multifocal osteomyelitis	Onset usually in childhood, but possible in adults; f > m; globally. LVV very rare (onset 3 to ~ 50 Y/A) [13, 14]	‡ “TAK-like”: aorta (ascending, descending), CCA, subclavian [13, 14]	(iii)	• Further associations with pyoderma gangrenosum, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and IBD [13]
Primary immunodeficiency diseases	Common variable immunodeficiency	May manifest in childhood or in adulthood at any age; m = f; less common in developing nations; true prevalence of CVID unknown, estimated ~ 0.5–7/106; any form of vasculitis in ~ 2% of CVID [15••, 16, 17•]	‡ “TAK-like” or TAK: aorta, innominate, CCA, ICA, axillary, subclavian [18–20]	+ / − “TAK-like” or TAK: renal, mesenteric, celiac, coronary [18–20]	• Rule out other causes of hypogammaglobulinemia before diagnosing CVID • Detection of aortic aneurysm in CVID should trigger imaging for LVV • Consider deficiency of adenosin-deaminase-2 in CVID, esp. in patients with MVV • Screen for splenomegaly and lung disease in potential CVID • Limited significance of any serologic test if patient is receiving immunoglobulin replacement therapy
	Wiskott-Aldrich syndrome	Usually diagnosis in early childhood, exceptionally delayed to early adulthood in milder variants; X-linked recessive disorder; prevalence ~ 4/106; any form of vasculitis in ~ 1 – 29% [21, 22]	‡ aorta (frequent aortic aneurysms, often panaortic); + / − aortic arch arteries (“TAK-like”) [23, 24]	+ / − cerebral, kidney, cardiac, liver, bowel, stomach [25, 26]	• With longer survival of patients with Wiskott-Aldrich, aneurysms secondary to LVV may increasingly become recognized; screening beginning in childhood might be justified • Isolated presentation with thrombocytopenia is commonly called “X-linked thrombocytopenia”, a mild variant of Wiskott-Aldrich • Missing or reduced expression of the “WAS-protein” can be detected rapidly by lymphocyte flow cytometry in peripheral blood [21]
	Deficiency of adenosin-deaminase-2	Variable disease onset, can be delayed to adulthood; AR inheritance; m = f; globally (less common in Africa, East Asia); estimated prevalence ~ 4.5/10^6; any vasculitic feature ~ in > 75–90% [27•, 28, 29•]	(iii)	‡ “PAN-like” (including aneurysms): skin, muscle, mesenteric, celiac, hepatic, renal  + / − splenic, testicular, cerebral, coronary, pancreatic, TA [27•, 29•, 30]	• Screening with ADA2 activity testing (e.g., with dried plasma spots) • Biallelic mutations can be found in asymptomatic individuals (usually through screening of seemingly unaffected family members) • Sneddon syndrome is an important differential diagnosis (livedo racemosa and CNS lesions) • CNS involvement is much more common in DADA2 than in PAN • Skin biopsy can show leukocytoclastic SVV and necrotizing MVV
Malignancy—paraneoplasia Myeloid neoplasms	Myelodysplastic syndromes Myeloproliferative neoplasms	MDS/CMML: median onset ~ 70–75 Y/A (range 16–90 Y/A), m > f (MDS), m = f (CMML). MVV/LVV less frequent in polycythemia vera or essential thrombocythemia [31–33]	+ / − aorta, large veins (“BS-like” manifestation) [31, 34, 35]	‡ TA (“GCA-like”)  + / − “PAN-like” (renal, hepatic, mesenteric, TA (non-GCA), cerebral, cutaneous) [31, 36–35]	• Consider MDS/MPN in refractory MVV/LVV or with inflammatory dysimmune phenomena [36] • The finding of cytopenia in LVV or MVV should lead to consideration of MDS or MPN as underlying disease process • MDS with GCA has poorer outcome (relapses ↑, steroid dependency) [33]
	Acute and chronic myeloid leukemia	Any age possible, incidence increases with age. AML: often progression of MDS/MPN. MVV/LVV very rare	+ / − “TAK-like”: aorta, CCA/ICA, innominate, subclavian, axillary [37, 38]	+ / − “PAN-like”: lower leg, TA (“GCA-like”) [39–38]	• Basophilia and eosinophilia are common in chronic myeloid leukemia • A differential blood count with visual inspection is advised in the setting of vasculitis with leukocytosis
Lymphoid neoplasms	Hodgkin and non-Hodgkin lymphomas	Any age possible. Hodgkin and non-Hodgkin lymphoma occasionally with LVV/MVV, multiple myeloma only rarely [39]	+ / − aorta, iliac, femoral [37]	‡ cerebral; + / − “PAN-like”: renal, hepatic, mesenteric, infrabrachial, infrapopliteal, coronary; TA (“GCA-like”) [39, 37, 42–44]	• Lymphocyte flow cytometry of peripheral blood frequently shows monoclonality • Intravascular lymphoma is a potential mimic of MVV, especially in the CNS or skin [3]
	Hairy cell leukemia	Mean onset ~ 50 Y/A (any age possible); m > f; MVV very rare [44, 45]	(iii)	‡ “PAN-like”: cutaneous, hepatic, mesenteric, renal, cerebral, TA (occasionally TA aneurysm) [44–46]	• MVV is usually diagnosed in patients with known leukemia [44, 45] • “Hairy” cells can typically be identified in the peripheral blood smear
Other	VEXAS-syndrome	Usually manifests ~ 50–80 Y/A; male > 95%; associated MDS in > 30%; caused by somatic mutation in UBA1-gene; subset with polychondritis [47••, 48]	+ / − aorta [47••, 48]	‡ cutaneous (25%)  + / − TA [47••, 48]	• Consider VEXAS in refractory cases with inflammatory dysimmune phenomena • Elderly patient with autoinflammatory symptoms, cytopenias, and/or polychondritis: look for vacuoles in bone marrow [47••, 48]
Drug-induced vasculitis	Minocycline	Young patients (average 30 Y/A) with acne treatment (often long-term); f > m. [49, 50]	(iii)	‡ “PAN-like”: skin, nerves  + / − renal, mesenteric, gall bladder, liver, spleen, cervix [49, 50]	• Onset of MVV on average ~ 26 months after initiation of minocycline therapy [49, 50]
	Immune checkpoint inhibitors	Onset ~ 40–70 Y/A; f = m; vasculitis typically 1–3 months after initiation of treatment (ipilimumab, pembrolizumab, nivolumab) [51, 52]	+ / − aorta [51]	‡ TA (“GCA-like”), cerebral (similar to primary angiitis of the CNS), uterine and ovarian vessels; peripheral nerves [51]	• Vasculitis typically resolves after stopping immunotherapy (and/or a course of oral or intravenous glucocorticoids) • No fatalities related to vasculitis observed [51] • Overlap with other immunotherapy-related adverse events possible (pericarditis, myocarditis, endocrine, gastrointestinal, etc.) [52]
	Granulocyte colony–stimulating factor	Vasculitis occurs in ~ 0.3–0.5% of patients receiving G-CSF; mean ~ 60 Y/A; f > m [53, 54]	‡ aorta (abdominal < thoracic or panaortic); carotids; + / − iliac, femoral, innominate, subclavian [53, 54]	+ / − TA [53]	• No fatalities related to vasculitis were observed • In about 60%, vasculitis occurs within 10 days after G-CSF initiation (agents: pegfilgrastim; filgrastim; lipefilgrastim; lenograstim)
	Graft versus host disease	Vasculitis is a very rare manifestation	+ / − aorta, iliac, femoral, popliteal, subclavian[55]	+ / − cerebral [56]	• Cerebral vasculitis can manifest in long-term survivors [56]

(i) Main vessels or vessel beds identified by our literature searches (i.e., arteries or vessel beds not listed, could still be affected). If not specified otherwise, the vessel names indicate arteries. The vessel sizes are defined as follows: “Large” (the aorta and distributing vessels of the extremities and neck, originating proximal to the elbow, knee, and dura mater), “small” (arterioles, capillaries, venules, and small intraparenchymal arteries and veins), “medium” (remaining vessels, including visceral arteries). (ii) Pearls mostly reflect the personal experience of the authors and are only partially referenced. (iii) Not identified by our literature search. Special characters: ‡, typically affected vessels or vessel beds; + / − , occasionally to rarely affected vessels or vessel beds; ~ , approximately

AR autosomal recessive; BS Behçet’s syndrome, CCA common carotid artery, CD Crohn’s disease, CNS central nervous system, CMML chronic myelomonocytic leukemia, CVID common variable immunodeficiency, DADA2 deficiency of adenosine-deaminase-2, ESR erythrocyte sedimentation rate, FMF familial Mediterranean fever, GCA giant cell arteritis, G-CSF granulocyte colony–stimulating factor, IBD inflammatory bowel disease, ICA internal carotid artery, LVV large-vessel vasculitis, MDS myelodysplastic syndrome, MPN myeloproliferative neoplasm, MVV medium-vessel vasculitis, PAN polyarteritis nodosa, TA temporal artery, TAK Takayasu arteritis, UC ulcerative colitis, VEXAS vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic, Y/A years of age