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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3774_Библиотеки_им_академика_М_И_Перельмана
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Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
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common and may mimic an acute abdomen. The abdominal pain is thought to be
due to immune complex deposition in the gut vessel walls leading to haemorrhage
and oedema within the bowel wall and mesentery. Gastrointestinal complications
such as perforation, intussusception and infarction may occur [28]. Joint involvement includes arthralgias or arthritis often affecting knees and ankles, which often
precede the development of palpable purpura. IgAV kidney involvement is frequent,
including haematuria, proteinuria, nephrotic or nephritic syndrome, with onset usually within a few months of the rash. Severe renal involvement occurs in 7% of
cases, most commonly adults, and may lead to end-stage renal disease [28].
Hypertension may develop at the onset or during recovery from IgAV; neurological
manifestations are rare [27].
HLA class I and class II HLA-DRB1 alleles appear to inuence predisposition to
this disease, and non-HLA gene candidates include those coding for cytokines, chemokines, adhesion molecules, T-cells, aberrant glycosylation of IgA1, nitric oxide
production, neoangiogenesis, the renin-angiotensin system, and lipid, pyrin and
homocysteine metabolism [28].
Upper respiratory tract infections precede the majority of cases, with many
pathogens implicated. Vascular deposition of IgA1-containing immune complexes
plays a pathogenic role, with complement activation, endothelial damage, perivascular leukocytic inltrates, chemokines and cytokines important factors in this process, thus suggesting an IgA-mediated dysregulated immune response to an
antigen [27].
Diagnosis is based on clinical criteria and non-mandatory tissue biopsy.
Histological features involving the skin are those of a leukocytoclastic vasculitis
primarily affecting the small supercial vessels. Vessel walls are inltrated by
ab
Fig. 16.3 IgA vasculitis. (a) Palpable purpura (b) skin biopsy showing leukocytoclastic vasculitis
(c) IgA deposition in vessel walls (d) glomerulonephritis with crescent (Periodic SchiffMethenamine (PASM) stain)
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M. Rischmueller et al.
c
Fig. 16.3 (continued)
d
neutrophil granulocytes, which partly degenerate and form nuclear dust (leukocytoclasia), located amongst extravasated erythrocytes (purpura) in the surrounding
dermis. The vessel walls are thickened and may be necrotic due to exudation of
neutrophils and variable amounts of brin. On direct immunouorescence, IgA
and, eventually, complement C3 can be seen deposited in the vessel walls. The
process is dynamic and not all of these features might be seen in a single biopsy
[27] (Fig.16.3).
Treatment is dictated by the severity of organ involvement. Treatment in patients
without renal involvement is supportive, including analgesia, rehydration, surgery
for intussusception, and wound care. Compression may be used for leg oedema.
Nephritis is treated with glucocorticoids and/or other immunosuppressive drugs,
including MMF, CYC, CyA, RTX or dapsone. IgAV has been associated with solid
tumours, mostly of the gastrointestinal tract, lungs or urinary tract in men over
60 years of age, and screening for cancer in this subgroup should be considered [27].
16.5.2.2 Cryoglobulinemic Vasculitis (CV)
CVis a small-vessel vasculitis involving mainly the skin, joints, peripheral nervous
system and kidneys, characterized by cryoprecipitable immune complexes which
may occur in the settings of chronic infection (mainly hepatitis C virus, HCV), or
without infection, particularly in the autoimmune rheumatic disease primary
Sjögren’s syndrome, and lymphoproliferative disorders [21] (Fig.16.4). These vasculitides result from the deposition of circulating immune complexes, activation of
the classic complement pathway and recruitment of neutrophils.
Symptoms from HCV-associated CV are mainly cutaneous, rheumatological and
renal. Serological and virological investigations support a pathophysiological role
for HCV infection in cryoglobulinaemia: positive anti-HCV testing (80–90% of the
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Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
ab
c
379
Fig. 16.4 Primary Sjögren’s syndrome-related cryoglobulinemic vasculitis. (a) Cutaneous palpa-
ble purpura (b) Raynaud’s phenomenon (c) vasculitis of the gall bladder wall
patients), circulating HCV-RNA, HCV in lesions and HCV-RNA in cryoprecipitate.
The 1b HCV genotype is most frequently associated with cryoglobulinaemia, while
genotypes 2–3 are associated with cryoglobulinaemia in coinfected HIV–HCV
patients. Reported prevalence of cryoglobulins was 45.7% in HCV patients and
prevalence of symptoms associated with cryoglobulins was 27%. Cryoglobulinaemia
can also be secondary to HBV infection [29]. Eradication of the hepatitis virus leads
to resolution of cryoglobulinaemia; short term glucocorticoids and immunosuppressants may be required for symptoms.
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16.5.2.3 Hypocomplementaemic Urticarial Vasculitis
(HUV, Anti-C1q Vasculitis)
HUV is an uncommon immune complex-mediated entity associated with anti-C1q
antibodies and characterized by leukocytoclastic vasculitis, severe angioedema,
pulmonary involvement, arthritis/arthralgia, glomerulonephritis, and uveitis.
Treatment is symptomatic for mild disease; severe disease is treated with CYC,
AZA or MMF in combination with glucocorticoids. CyA has been found useful in
patients with progressive airway obstruction. RTX and plasma exchange followed
by IVIg has been used in refractory cases [21].
16.5.2.4 Anti-Glomerular Basement Membrane (Anti-GBM) Disease
A vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, following GBM deposition of anti-GBM autoantibodies. Lung involvement causes pulmonary haemorrhage, and renal involvement causes glomerulonephritis with necrosis
and crescents [1].
M. Rischmueller et al.
16.6 Variable Vessel Vasculitis
16.6.1 Behcet’s Disease
Behcet’s disease (BD) is a systemic inammatory disorder characterized by multiorgan involvement including oral and genital ulcers, uveitis, skin lesions, central
nervous system and vascular manifestations [30, 31]. Supercial and deep venous
thrombosis are the most frequent vascular manifestations, affecting 15–40% of
patients. Thrombosis characteristically occurs in unusual sites, including the inferior and superior vena cava, suprahepatic veins with Budd-Chiari syndrome, portal
vein, cerebral sinuses and right ventricle. Arterial involvement, affecting 3–5% of
patients, typically presents with aneurysms affecting peripheral, visceral and pulmonary arteries, the rst sign of which may be massive haemorrhage. Vascular
events in BD are promoted by inammation of the vessel wall, with neutrophils
playing a key role in the pathogenesis of thrombotic events, and coagulation components such as brinogen, thrombin, factor Xa and factor VIIa amplifying the
inammatory cascade [30].
Pathophysiology of BD involves activation of both innate and adaptive immune
pathways triggered by several putative pathogens, with consequent interaction
between T lymphocytes (Th1 and Th17 phenotypes) and activated neutrophils.
The HLA class I allele HLA-B∗51 is the major genetic risk factor in many populations, especially along the ancient Silk Route which ranged from East Asia to the
Middle East and the Mediterranean area. The HLA-A∗26 allele is associated with
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BD independently of HLA-B∗51, and polymorphisms in genes encoding IL-10,
IL-23 receptor, IL-12 receptor, and STAT4 have been associated with BD in
Turkish, Japanese and Korean populations. Disease-associated non synonymous
variants in the familial Mediterranean fever gene MEFV, and TLR4, support the
involvement of innate immune responses and bacterial sensing mechanisms in
BD pathogenesis [31].
BD typically runs a relapsing and remitting course, and the goal of treatment is
to promptly suppress inammatory exacerbations and recurrences to prevent irreversible organ damage. Ocular, vascular, neurological and gastrointestinal involvement are associated with a poor prognosis, however disease manifestations may
diminish over time [32]. Control of vascular thrombosis in BD is achieved with
immunosuppressant drugs rather than anticoagulants, in particular AZA or CyA in
conjunction with low-dose glucocorticoids for venous thrombosis, while treatment
with CYC or TNFi have been successfully used for arterial involvement [30]. TNFi
are also effective for control of mucocutaneous, ocular, neurological and refractory
venous thrombosis. IL-1βi may be useful for refractory disease, especially uveitis,
and IL6Ri for CNS disease [31]. The 2018 updated EULAR recommendations for
BD, based on low-level evidence [32], recommend that in addition to TNFi for
refractory venous thrombosis, anticoagulants may be added, provided the risk of
bleeding in general is low and pulmonary artery aneurysms have been ruled out. For
the management of pulmonary artery aneurysms, high dose glucocorticoids and
CYC are recommended, and IFX for refractory disease. Because of a high mortality
rate in surgically treated patients, intervention should be reserved for life- threatening
situations, with arterial embolization the preferred option. For both aortic and
peripheral artery aneurysms, medical management should be optimized when possible before surgical intervention, and medical management may be sufcient for
small, asymptomatic aneurysms. For both pulmonary and peripheral artery aneurysms, the choice of surgical intervention between graft insertion, ligation and
bypass surgery is dictated by the size and location of the aneurysm and the surgeon’s experience. Synthetic grafts are preferable since venous grafts have a higher
risk of thrombosis in patients with BD.The rst episode of cerebral venous thrombosis should be treated with high-dose glucocorticoids followed by tapering.
Anticoagulants may be added for a short duration, after screening for vascular disease at other sites [
32].
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16.6.2 Cogan’s Syndrome
Cogan’s syndrome is characterized by ocular inammatory lesions, including interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. Vasculitic manifestations may include
arteritis (affecting small, medium, or large arteries), aortitis, aortic aneurysms, and
aortic and mitral valvulitis [1].
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M. Rischmueller et al.
16.7 Vasculitis Associated withSystemic Disease
16.7.1 Autoimmune Rheumatic Diseases
Small vessel vasculitis may occur in the setting of known autoimmune rheumatic
diseases such as rheumatoid arthritis, systemic lupus erythematosus and primary
Sjögren’s syndrome. Biopsy is usually not required, and if performed will usually
show a non-specic leucocytoclastic vasculitis. Vasculitis usually occurs in patients
with active systemic disease, to which treatment is directed. In some cases more
aggressive treatment is required for the vasculitis itself. Cryoglobulinaemic vasculitis (discussed above) occurs in 4% of patients with primary Sjögren’s syndrome,
and is a predictor of the development of lymphoma and death [33].
16.7.2 IgG4-Related Disease (IgG4-RD)
IgG4-RD is a rare systemic sclerosing disorder, initially described in Japan and now
increasingly recognised throughout the world. Early recognition and treatment is
essential to minimise irreversible organ damage and unnecessary surgical intervention. IgG4-RD occurs most commonly in middle aged to elderly men, with a two to
four-fold male preponderance [34]. It is characterized by mass-like sclerosing lesions
which can involve almost any anatomic site, and many broinammatory and sclerosing disorders previously considered as distinct entities are now included within the
spectrum of IgG4-RD, including sclerosing cholangitis, idiopathic retroperitoneal
brosis and mesenteritis, some forms of aortitis and periaortitis, and sclerosing sialadenitis of salivary and lacrimal glands including Kuttner tumor and Mikulicz syndrome [34]. Four predominant clinical phenotypes of IgG4-RD have recently been
described [35]: (1) pancreato-hepatobiliary disease (31% of patients); (2) retroperitoneal brosis and/or aortitis (24%); (3) head and neck-limited disease (24%); (4) classic Mikulicz syndrome with systemic involvement (22%). Aortitis occurred in 10.3%
overall, and retroperitoneal brosis in 15.8%. In addition to sclerosing abdominal and
thoracic aortitis and periaortitis, IgG4-related vasculitis occurs with a predilection for
the rst and second aortic branches including carotid and coronary arteries.
Recent work on the pathophysiology of IgG4-RD identied an essential role for
oligoclonally expanded CD4+ cytotoxic T lymphocyte populations (CD4+ CTLs),
which secrete pro-brotic cytokines including IL-1β, TGFβ and IFN-γ, and are
capable of perforin- and granzyme B-mediated cytolysis. They accumulate in tissue
lesions, representing the dominant T cell population in affected tissues [36]. Patients
with IgG4-RD also have elevations of oligoclonally expanded populations of somatically hypermutated plasmablasts, many of which are IgG4+, and because of the
profound clinical responses and decline in CD4+ CTLs observed following B-cell
depleting therapy, it is considered likely that activated B cells drive the activation of
CD4+ CTLs in affected tissues [37]. Upon relapse, distinct plasmablast clones
emerge, suggesting de novo recruitment of new plasmablast clones rather than neoplastic oligoclonal proliferations.
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T follicular helper (Tfh) and T regulatory (Treg) cells also likely play a critical
role in IgG4-RD, particularly with respect to class switching of B cells and induction of aberrant lymphoid follicle formation in tissues. Tfh cytokines IL-21 and IL-4
play a role in germinal center formation, B-cell differentiation, plasmablast induction, and production of IgG4. IL-10 and TGFβ production by Treg cells also likely
contributes to IgG4 class switching and brosis, respectively.
The role of plasmablasts and the IgG4 molecule in IgG4-RD remains uncertain.
They may act to perpetuate the immune response through reactivity to specic
antigens and antigen presentation to CD4+ CTLs. However, given that IgG4 has
been shown to be a relatively inactive immunoglobulin subclass, without the ability
to x complement or crosslink antibodies, it has been hypothesized that IgG4 production and the frequent IgG4+ plasma cells may be a secondary or reactive phenomenon to cytokine production, rather than being intrinsically pathogenic. It has
also been suggested that IgG4 has anti-inammatory properties and may be produced in an attempt to mitigate the inammatory response. It remains uncertain as
to which autoantigens might be responsible for the robust immune response in
IgG4-RD [34].
Elevation of serum IgG4 level is the most well-known laboratory feature used
to support a diagnosis of IgG4-RD, however up to half of patients with biopsy
proven and clinically active IgG4-RD have normal serum IgG4 concentrations
[34], and elevated serum IgG4 levels are neither sensitive nor specic for
IgG4-RD.Peripheral eosinophilia, polyclonal hypergammaglobulinemia, elevated
serum IgE levels, elevated CRP, and hypocomplementemia are relatively common.
Histopathology is required for a denitive diagnosis of IgG4-RD and should
include two or more characteristic features: (1) a dense lymphoplasmacytic inltrate, (2) brosis that is typically storiform in pattern (i.e. a matted, irregularly
whorled pattern), (3) obliterative phlebitis, (4) an increased number of IgG4+
plasma cells per high power eld, and (5) an IgG4+/IgG+ plasma cell ratio of
>40%. Obliterative phlebitis is the least often identied histologic feature of
IgG4-RD, although the most specic [
34].
Given the limitations of available biomarkers, a combination of imaging modalities, including CT, MR and ultrasound is the cornerstone for evaluating disease
burden and activity. 18F-FDG PET/CT has been validated for IgG4-RD assessment
and exclusion of concomitant malignancies, and provides anatomical and functional
information on the extent of organ involvement and disease activity [34].
Due to uncertainty about the molecular mechanisms sustaining IgG4-RD and
lack of controlled trial data, treatment is largely based on clinical experience and
expert opinion. Prompt intervention is strongly advised in cases affecting vital
organs (even sub-clinically) to prevent irreversible organ damage. Given the
relapsing- remitting nature of the condition, maintenance therapy should be considered. Immunosuppression is generally advised for cases with prominent lymphoplasmacytic inltrates on histological examination because they are more likely to
respond to pharmacological therapy. Conversely, surgical debulking should be considered for long-standing, end-stage brotic lesions since they typically respond
poorly to immunosuppression. Temporary stenting is frequently required for bile
duct or ureteric strictures.
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Glucocorticoid therapy leads to swift clinical responses in the majority of patients
with IgG4-RD regardless of the clinical presentation and organ involvement, thus
representing the rst line therapy for inducing remission. IgG4-RD relapses in up to
46% of cases during or after glucocorticoid tapering, and conventional steroid- sparing
agents such as AZA, MMF, MTX, and CYC have been used as maintenance therapy.
In a prospective open-label trial, 97% of patients responded to RTX at 6months even
in the absence of concomitant glucocorticoid treatment, and RTX is indicated as a
second-line treatment in IgG4-RD patients with recurrent or refractory disease [34].
M. Rischmueller et al.
16.8 Vasculitis Associated withProbable Aetiology
Apart from syphilitic and tuberculous aortitis, a causal relationship between infection and vasculitis has been proven in only few situations, such as HBV with PAN
and less commonly SVV and CV, and HCV with CV, discussed above. Relationships
between PAN and other infections, particularly streptococcal species, Klebsiella,
Pseudomonas, and Yersinia have been suggested, however causation has not been
strongly established [29].
16.8.1 Drug-Induced Vasculitis
Members of virtually every pharmacological class have been implicated in the
development of drug-induced vasculitis, and the mechanisms involved are mainly
related to immune complex deposits with antigen excess. Most frequently implicated are sulphonamides, penicillin, allopurinol, and thiazides. Penicillin causes
vasculitis by conjugating to serum proteins and mediating immune complex vasculitis. Drug induced AAV has also been reported, particularly with propylthiouracil,
hydralazine, allopurinol, penicillamine, and levamisole in cocaine [38], including a
fatal case of methimazole-associated MPO-AAV [39]. Several cross-sectional studies reported a prevalence of propylthiouracil-induced AAV between 20 and 64%. It
is essential to withdraw the inciting drug, which usually results in resolution, however immunosuppressant therapy may be required [40]. A high level of suspicion is
required, and a clue that AAV is drug-induced is the co-expression of more than one
autoantibody, typically MPO-ANCA, antiphospholipid antibodies, antinuclear antibodies (ANA), and sometimes PR3-ANCA.
16.8.2 Vasculitis Associated withCancer Immunotherapy
Immunotherapy has revolutionized the treatment of a number of types of metastatic
cancer. The family of therapeutic agents known as checkpoint inhibitors (CPIs),
which target “exhausted” tumour specic T lymphocytes to incite them to an active
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effector phenotype and thence destroy malignant cells, is associated with a new
group of immune-related adverse events (irAEs) in almost any organ system. Among
these irAEs, rheumatic complications are common and seem to have features that are
distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indenitely, after cessation of CPI
therapy [41]. Nearly every major category of rheumatic disease, including vasculitis,
is mirrored by a category of irAEs resulting from CPIs. GCA with or without polymyalgia rheumatica has been reported after treatment with both anti-cytotoxic
T-lymphocyte-associated protein 4 (CTLA4) and anti-PD-1 CPIs. Symptoms mirror
the traditional forms of disease, including hip and shoulder girdle stiffness, temporal
headache, jaw claudication and one incidence of amaurosis fugax. In TAB samples,
arteritis, disruption of the elastic lamina, and intimal proliferation have been detected.
Evidence exists that checkpoint dysfunction might contribute directly to GCA
pathogenesis and disease activity (discussed above), providing insights into how
CPIs might cause autoimmunity. For patients with pre-existing rheumatic diseases
who are treated with conventional or biologic DMARDs, as well as for patients with
incident rheumatic irAEs who require DMARDs or other immunosuppressive
drugs, it is not known whether concomitant immunosuppressive therapy will negate
the anti-tumour response of CPI therapy. Retrospective studies do not provide evidence of an adverse effect on tumour kinetics resulting from either glucocorticoids
or TNFi. For patients with the most severe irAEs, particularly those that are chronic,
the effect of long-term high-dose immunosuppression or other biologic therapies is
not known [41].
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16.9 Vasculitis Mimics
16.9.1 Raynaud’s Phenomenon
Raynaud’s phenomenon (RP)is a common disorder manifest by triphasic colour
change of the ngers and toes from white to blue to red, occurring in 5% of the
population [42]. RP may be bilateral, may be incited by cold or emotion, and usually presents with normal pulses. It is more prevalent in women than in men, and
there may be a genetic predisposition. RP can be divided into primary (PRP) and
secondary (SRP), the latter associated with rheumatologic as well as noninammatory conditions. PRP compared with SRP tends to occur at a younger age, is painless, and is rarely associated with tissue breakdown. The most common disorders
associated with SRP are systemic sclerosis (scleroderma), systemic lupus erythematosus, primary Sjögren’s syndrome, and anti-synthetase syndrome- systemic autoimmune diseases associated with signicant morbidity and increased mortality.
Immediate referral for further evaluation and diagnosis is therefore recommended
for patients suspected of having SRP, which may be the rst manifestation of one of
these conditions. Transition from PRP to SRP may rarely occur, but is unlikely
when the original symptoms are minimal, antinuclear antibodies are absent, and
nailfold capillaroscopy is normal [42].
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Vasomotor tone in the digital circulation results from interaction between endothelium, smooth muscle, autonomic and sensory nerves, thus RP can result from
alterations in various pathways. There are physiological differences between PRP
and SRP: nutritional capillary blood ow is normally protected from cold-induced
sympathetic vasoconstriction; this protection is mildly impaired in patients with
PRP, and severely interrupted in systemic sclerosis. This difference probably reects
the presence of endothelial dysfunction in patients with systemic sclerosis; dysfunctional endothelial cells have reduced reactivity to vasodilators, nitric oxide, and
prostacyclin and can express increased thrombotic and inammatory activity,
including the increased release of the vasoconstrictor endothelin-1.The maintenance of nutritional capillary blood ow is normally ensured by the conduction of
vasodilatation to upstream vessels that results from ow-mediated activation of the
endothelium. Impairment of this protective mechanism, combined with structural
limitations of the vascular supply in patients with systemic sclerosis, probably contributes to compromised nutritional blood ow in patients with this disease, leading
to tissue injury and ulceration [42].
The diagnosis of RP is usually made by history or by witnessing an episode or
photograph (Fig.16.4). Avoidance of cold remains the most effective therapy for
RP; systemic and local warming are highly effective at increasing blood ow in the
skin. A variety of factors can potentially aggravate the disorder and should be
avoided, including smoking and the use of sympathomimetic drugs.
Drug therapy is initiated when nonpharmacologic approaches are ineffective in
reducing the severity of vasospastic attacks which are impacting quality of life.
Although there is paucity of clinical trials, current evidence supports the use of
calcium channel blockers, phosphodiesterase type 5 (PDE-5) inhibitors and topical
nitrates, alone or in combination. There is also some evidence to support the use of
selective serotonin reuptake inhibitors such as uoxetine, and angiotensin II–receptor blockers. Prostacyclin inhibits vasoconstriction, thrombosis, inammation, and
pathologic vascular remodelling, and stimulates the release of endothelium-derived
nitric oxide. A systematic review supported the use of intravenous prostacyclin analogues in patients with severe SRP, with reduced severity of vasospastic attacks,
increased healing and prevention of digital ulcers. Endothelin-1 receptor antagonists failed to reduce the frequency of vasospastic attacks, but decreased the development of new digital ulcers in scleroderma [
42].
M. Rischmueller et al.
16.9.2 Thromboangitis Obliterans (TAO, Buerger’s Disease)
TAO is a segmental inammatory condition affecting small and medium-sized
arteries, veins and nerves. It typically affects people under the age of 50years who
use tobacco, usually in the form of cigarettes. Atherosclerotic risk factors other than
smoking are usually absent. Incidence varies by geographic location, with the highest prevalence of greater than 10 per 100,000 observed in the Middle East, Asia,
Mediterranean, and Eastern Europe. Clinical manifestations of TAO include pain in
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