Medium-sized vessel vasculitides
Small- and medium-sized vessel vasculitides are necrotizing vasculitides (except TPO),
dominated by neutrophil infiltration.
For medium-vessel vasculitis, think more of organ ischemia / digital gangrene / ulcers.
Polyarteritis Nodosa (PAN)
“PAN is a necrotizing vasculitis affecting predominantly medium-sized arteries, without
glomerulonephritis or vasculitis in arterioles, capillaries or venules and is not associated with
ANCA” (CHCC).
It is a rare disease but more common in areas endemic for HBV. 2-9 cases/106 per
year. Men are slightly more affected than women (1.5:1) and has a broad range of age, 40-
60yrs, but kids can be affected too, mostly in the form of DADA2. Distinguishing features:
arterial only, sparing of the lung, absence of granulomatous inflammation, lack of
association with autoantibodies, no GN, ANCA (-).
Causes
i) Idiopathic
ii) Secondary:
-Viral: HBV (mostly), CMV, HTLV, HIV, ParvoB19, EBV, HCV. HBV-PAN occurs in
people with chronic HBV, most of whom have active liver disease and within 4-6 months of
infection. Seroconversion of hepatitis B antibody status was associated with complete
remission and no relapse.
-Bacteria: Rickettsia, Borrelia, syphilis
-Autoimmune: RA (RV is mostly medium-sized), SLE, Sjögren, […].
-Autoinflammatory: DADA2, HA20, VEXAS, FMF
-Malignancy: hairy cell leukemia (in patients who have also undergone splenectomy,
cross-reactivity of antibodies between tumor cells and the endothelium, direct damage of
the endothelium by tumor cells and local production of pro-inflammatory cytokines,
triggering vessel wall damage, other hematologic malignancies), lymphoma, MDS.
-Medications: minocycline, ICIs, G-CSF, GVHD.
Clinical
Classic PAN is characterized by segmental necrotizing arterial lesions frequently with
microaneurysm formation and resulting in ischemia, infarction and hemorrhage. PAN can
present with nonspecific constitutional symptoms such as fever (60%), fatigue, malaise,
tachycardia without fever, myalgias and arthralgias (90%) in combination with single or
multiorgan manifestations resulting from ischemia or infarction. This phase of the illness can
last weeks or months. Often has cutaneous involvement and this differentiates it from LVV.
Unlike AAV, it is not associated with GN or pulmonary involvement. Microaneurysms
detectable by angiography are a hallmark of PAN.
-Kidney (70-80%): the most frequently involved organ in PAN. Nephropathy and not
GN (it doesn’t affect capillaries) can lead to multiple renal infarcts and renal failure. HTN (20-
50%) develops as a result of renal ischemia from renal artery or, less commonly, renal
parenchymal involvement; it is usually mild and is particularly associated with HBV.
-Gastrointestinal tract (50%): the small intestine is most commonly involved. Mostly
abdominal pain, nausea, vomiting, diarrhea, bleeding, mesenteric ischemia, bowel infarction
and perforation. The major cause of death in HBV-related PAN.
-Nerves:
, -peripheral (50-75%): mononeuritis multiplex, an asymmetric sensorimotor
neuropathy due to ischemia of peripheral nerves - might be the initial manifestation. Very
acute onset with pain and paresthesias radiating in the distribution of a peripheral nerve,
followed in hours by a motor deficit of the same peripheral nerve (ex. foot drop).
-CNS (10%): headache, seizures, cranial neuritis, cerebral hemorrhage,
stroke.
-Skin: livedo reticularis, ulcers, gangrene, nodules, bullous or vesicular eruptions.
More rarely, petechiae, purpura. Biopsy does not necessarily distinguish MPA from PAN.
-MSK: arthralgia (60%), arthritis (20%): asymmetric, episodic, non-deforming
polyarthritis of the larger joints of the lower extremity, early in the disease.
-Single-organ: testicle, gallbladder, appendix, ovary, breast, eye, pancreas or even
skin-limited. Testicular involvement, though characteristic, is less common, it is rarely the
first manifestation of the disease, is generally unilateral and is caused by ischemia of the
testicular artery.
-Heart: common pathologically but less often clinically. Can also cause coronary
arteritis and coronary artery ectasia, but MI is uncommon; mostly seen in autopsy.
-Ocular (rare): visual impairment, retinal hemorrhage and optic ischemia. Retinal
vasculitis is relatively rare among the ocular manifestations. Anterior segment findings may
include episcleritis, scleritis, corneal or scleral ulcers and uncommonly iritis. Pseudotumor of
the orbit or extraocular muscle dysfunction may also be observed. Although the choroidal
arteries are most commonly affected, retinal vessel involvement may result in cotton-wool
spots, retinal edema, vitritis and hypertensive changes. Retinal venules may also be affected.
-Lungs: are usually spared, if pleural effusions or parenchymal infiltrates are seen
then they’re because of renal or cardiac involvement. The only lung arteries that can be
affected are the bronchial arteries.
FMF-PAN: much younger compared to classic PAN patients. Perirenal hematoma is a
distinctive feature in FMF-PAN since 50% develop this prior to or at diagnosis. Survival is
better in FMF-PAN than classic PAN.
Histology & Pathophysiology
Patchy (focal & segmental), transmural necrotizing inflammation in medium-sized muscular
arteries, sparing large arteries, capillaries and the venous system and fibrinoid necrosis but
no granulomatosis. Infiltrate is predominantly neutrophilic with variable numbers of
lymphocytes and eosinophils. Aneurysms can occur at the site of active lesions and this
morphologic appearance is what led to the term nodosa. Disruption of the elastic lamina of
the vessel wall can lead to aneurysmal dilatation at the site of the lesion. Vascular lesions in
PAN are typically segmental and occur in branching points.
If any clinical or laboratory features indicate involvement of small vessels, that
suggest an alternative form of vasculitis such as MPA.
After the inciting event, focal and segmental necrotizing inflammation of medium-
and small-sized arteries leads to intimal proliferation with subsequent thrombosis, resulting
in ischemia or infarction of the organ or tissue supplied by these arteries.
However, skin involvement and positive results of a skin biopsy do not always
indicate evidence of systemic involvement (ex. skin-limited PAN) and biopsy does not
necessarily distinguish MPA from PAN.
Lab
ESR, CRP, mild proteinuria or hematuria but no active sediment (no GN). ANCA, ANA, RF
should be negative; if they are positive they are non-diagnostic because of their poor
Small- and medium-sized vessel vasculitides are necrotizing vasculitides (except TPO),
dominated by neutrophil infiltration.
For medium-vessel vasculitis, think more of organ ischemia / digital gangrene / ulcers.
Polyarteritis Nodosa (PAN)
“PAN is a necrotizing vasculitis affecting predominantly medium-sized arteries, without
glomerulonephritis or vasculitis in arterioles, capillaries or venules and is not associated with
ANCA” (CHCC).
It is a rare disease but more common in areas endemic for HBV. 2-9 cases/106 per
year. Men are slightly more affected than women (1.5:1) and has a broad range of age, 40-
60yrs, but kids can be affected too, mostly in the form of DADA2. Distinguishing features:
arterial only, sparing of the lung, absence of granulomatous inflammation, lack of
association with autoantibodies, no GN, ANCA (-).
Causes
i) Idiopathic
ii) Secondary:
-Viral: HBV (mostly), CMV, HTLV, HIV, ParvoB19, EBV, HCV. HBV-PAN occurs in
people with chronic HBV, most of whom have active liver disease and within 4-6 months of
infection. Seroconversion of hepatitis B antibody status was associated with complete
remission and no relapse.
-Bacteria: Rickettsia, Borrelia, syphilis
-Autoimmune: RA (RV is mostly medium-sized), SLE, Sjögren, […].
-Autoinflammatory: DADA2, HA20, VEXAS, FMF
-Malignancy: hairy cell leukemia (in patients who have also undergone splenectomy,
cross-reactivity of antibodies between tumor cells and the endothelium, direct damage of
the endothelium by tumor cells and local production of pro-inflammatory cytokines,
triggering vessel wall damage, other hematologic malignancies), lymphoma, MDS.
-Medications: minocycline, ICIs, G-CSF, GVHD.
Clinical
Classic PAN is characterized by segmental necrotizing arterial lesions frequently with
microaneurysm formation and resulting in ischemia, infarction and hemorrhage. PAN can
present with nonspecific constitutional symptoms such as fever (60%), fatigue, malaise,
tachycardia without fever, myalgias and arthralgias (90%) in combination with single or
multiorgan manifestations resulting from ischemia or infarction. This phase of the illness can
last weeks or months. Often has cutaneous involvement and this differentiates it from LVV.
Unlike AAV, it is not associated with GN or pulmonary involvement. Microaneurysms
detectable by angiography are a hallmark of PAN.
-Kidney (70-80%): the most frequently involved organ in PAN. Nephropathy and not
GN (it doesn’t affect capillaries) can lead to multiple renal infarcts and renal failure. HTN (20-
50%) develops as a result of renal ischemia from renal artery or, less commonly, renal
parenchymal involvement; it is usually mild and is particularly associated with HBV.
-Gastrointestinal tract (50%): the small intestine is most commonly involved. Mostly
abdominal pain, nausea, vomiting, diarrhea, bleeding, mesenteric ischemia, bowel infarction
and perforation. The major cause of death in HBV-related PAN.
-Nerves:
, -peripheral (50-75%): mononeuritis multiplex, an asymmetric sensorimotor
neuropathy due to ischemia of peripheral nerves - might be the initial manifestation. Very
acute onset with pain and paresthesias radiating in the distribution of a peripheral nerve,
followed in hours by a motor deficit of the same peripheral nerve (ex. foot drop).
-CNS (10%): headache, seizures, cranial neuritis, cerebral hemorrhage,
stroke.
-Skin: livedo reticularis, ulcers, gangrene, nodules, bullous or vesicular eruptions.
More rarely, petechiae, purpura. Biopsy does not necessarily distinguish MPA from PAN.
-MSK: arthralgia (60%), arthritis (20%): asymmetric, episodic, non-deforming
polyarthritis of the larger joints of the lower extremity, early in the disease.
-Single-organ: testicle, gallbladder, appendix, ovary, breast, eye, pancreas or even
skin-limited. Testicular involvement, though characteristic, is less common, it is rarely the
first manifestation of the disease, is generally unilateral and is caused by ischemia of the
testicular artery.
-Heart: common pathologically but less often clinically. Can also cause coronary
arteritis and coronary artery ectasia, but MI is uncommon; mostly seen in autopsy.
-Ocular (rare): visual impairment, retinal hemorrhage and optic ischemia. Retinal
vasculitis is relatively rare among the ocular manifestations. Anterior segment findings may
include episcleritis, scleritis, corneal or scleral ulcers and uncommonly iritis. Pseudotumor of
the orbit or extraocular muscle dysfunction may also be observed. Although the choroidal
arteries are most commonly affected, retinal vessel involvement may result in cotton-wool
spots, retinal edema, vitritis and hypertensive changes. Retinal venules may also be affected.
-Lungs: are usually spared, if pleural effusions or parenchymal infiltrates are seen
then they’re because of renal or cardiac involvement. The only lung arteries that can be
affected are the bronchial arteries.
FMF-PAN: much younger compared to classic PAN patients. Perirenal hematoma is a
distinctive feature in FMF-PAN since 50% develop this prior to or at diagnosis. Survival is
better in FMF-PAN than classic PAN.
Histology & Pathophysiology
Patchy (focal & segmental), transmural necrotizing inflammation in medium-sized muscular
arteries, sparing large arteries, capillaries and the venous system and fibrinoid necrosis but
no granulomatosis. Infiltrate is predominantly neutrophilic with variable numbers of
lymphocytes and eosinophils. Aneurysms can occur at the site of active lesions and this
morphologic appearance is what led to the term nodosa. Disruption of the elastic lamina of
the vessel wall can lead to aneurysmal dilatation at the site of the lesion. Vascular lesions in
PAN are typically segmental and occur in branching points.
If any clinical or laboratory features indicate involvement of small vessels, that
suggest an alternative form of vasculitis such as MPA.
After the inciting event, focal and segmental necrotizing inflammation of medium-
and small-sized arteries leads to intimal proliferation with subsequent thrombosis, resulting
in ischemia or infarction of the organ or tissue supplied by these arteries.
However, skin involvement and positive results of a skin biopsy do not always
indicate evidence of systemic involvement (ex. skin-limited PAN) and biopsy does not
necessarily distinguish MPA from PAN.
Lab
ESR, CRP, mild proteinuria or hematuria but no active sediment (no GN). ANCA, ANA, RF
should be negative; if they are positive they are non-diagnostic because of their poor
