Complications and Mortality in Systemic Vasculitis – Vasculogenic Clinicopathologic Entities in Rheumatoid Arthritis and Progressive Systemic Sclerosis Autopsy Patients

Copyright: © 2017 Bély M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Complications and Mortality in Systemic Vasculitis – Vasculogenic Clinicopathologic Entities in Rheumatoid Arthritis and Progressive Systemic Sclerosis Autopsy Patients


Introduction
In autoimmune diseases the vascular system is the most important target of immunological processes, manifesting as vasculitis or characteristic structural changes of blood vessels.
Systemic vasculitis of autoimmune origin (A-SV) may be regarded as one of the basic manifestations of rheumatoid arthritis (RA) as well. A-SV is one of the main, and the most likely lethal complication to be missed clinically with high probability of RA [1].
The vasculitis and vascular changes are so dominant in progressive systemic sclerosis (SSc) that the disease could be regarded as primary vascular disease. According to Gardner "Evidence of circulatory impairment in systemic sclerosis is so frequent that is natural to ask whether this is fundamentally not a vascular disorder" [2].
The knowledge of complications and associated diseases, furthermore the risk of mortality in various diseases is important in their prevention or earlier and more effective treatment [3]. Studies confirm the increased risk of cardiovascular diseases in RA [4][5][6][7]. The cardiovascular complications-beside renal and pulmonary ones -are important in the mortality of SSc patients as well [8][9][10].
The aim of this study was to determine: the complication(s) and mortality of A-SV in RA and SSc patients, and to outline the consecutive years; male 1, age of 65 years, onset of SSc and duration of disease not known).
RA and SSc were confirmed clinically according to the criteria of the American College of Rheumatology (ACR) [11,12].

Methods
The basic disease, the complication(s), and the lethal outcome caused by vasculitis were determined and analyzed retrospectively, reviewing the clinical and pathological reports, and confirmed by a detailed review of extensive histological material. From each patient 50-100 tissue blocks of 12 organs (heart, lung, liver, spleen, kidneys, pancreas, gastrointestinal tract, adrenal glands, skeletal muscle, peripheral nerve, skin and brain) were studied microscopically [1].
The possible role of A-SV on RA or SSc, specifically in relation to complications and cause of death, furthermore to coexistent associated diseases was analyzed by Pearson's chi-squared (χ 2 ) test (the correlations were calculated based on the total number of patients; in case of RA n=161, and SSc n=11) [13].

RA and A-SV
A-SV complicated RA in 33 (20.49%) of 161 cases.
A-SV led directly to death in 19 (57.57%) of 33 RA patients: in one case due to coronary arteritis with a large anteroseptal myocardial infarct (MI); in 11 cases coronary arteritis or arteriolitis caused multifocal microinfarcts of the myocardium (myocardiocytolysis-My); in 3 cases vasculitis of the pulmonary and bronchial arterioles and small arteries led to vasculogenic rheumatoid pneumonia with disseminated (multifocal) lobular-sublobular pneumonia (RhPn). In 2 cases cerebral vasculitis with multifocal brain necrosis led to death (in one case due to bronchopneumonia and in the second one due to femoral vein thrombosis, pulmonary embolism and septic infarction of the lung). In one patient thrombovasculitis of the main mesenteric artery caused hemorrhagic necrosis of the intestines; in another case thrombosis of the main renal artery led to renal insufficiency and incipient renal necrosis and was the cause of death.
A-SV was present in further 14 (42.42%) of 33 RA patients without direct role in death ( when it was the basic disease leading to death. Moderate changes like hyaline or sclerotic plaques -without causal role in death -were not mentioned as "atherosclerosis"; such changes are frequent in elderly RA patients.
The most important complications and causes of death or associated diseases in 161 RA patients with or without A-SV are listed bellow: My complicated RA in 11 (6.83%) of 161 patients, and all of these were accompanied with A-SV (Figures 1 and 2). Cardiac insufficiency (CI -sometimes mentioned as "heart failure", or circulatory failure" -partly related to RA, and partly related to Ath) was registered in 40 (24.84%) of RA 161 patients, and accompanied with A-SV in 9 of 40 patients.
Myocardial infarction (MI -partly related to RA, and partly related to Ath -was found in 11 (6.83%) of RA 161 patients, and accompanied with A-SV in 2 of 11 patients.
Adult type II diabetes mellitus (DM) associated to RA in 30 (18.6%) of 161 patients, and was accompanied with A-SV in 7 of 30 cases.
Post-primary (Fc -fibrocaseous, or F -fibrous) tuberculosis (Tb) was found in 21 (13.4%), complicated by active miliary dissemination   The basic disease, complication(s) and associated diseases of 33 RA patients with A-SV are summarized in Glossary to Table 1.
Basic disease: underlying disease related to death.
Complication: consequence of basic disease leading directly to death.
Cause of death (bold): fatal outcome of basic disease.
Associated (Accompanying) disease: Important disorder without direct causal role in death.
Severity of A-SV was determined histologically in one of our previous study [9]: Atherosclerosis (Ath) -was diagnosed in RA patients only in cases, when it was present macroscopically as a "severe" atherosclerotic process (characterized by occlusive thrombosis or sclerotic ulcers) or, The statistical link between A-SV and coexistent complications or associated diseases in 161 RA patients is summarized in Table 2.

A-SV and SSc
A-SV and chronic structural changes of blood vessels were present in all of 11 SSc patients.
SSc with A-SV: females 10, average age: 53.6 years, range 62-37, onset of SSc: 43.3, disease duration: 10.0 years; male 1, age of 65 years, onset of SSc and duration of disease not known.
SSc was the basic disease leading to death in each of 11 patients (Figure 4), and all were complicated by A-SV. Blood vessels of all calibers (arterioles, small arteries and medium size arteries) were involved (capillaries were not evaluated. A-SV was characterized by a wide spectrum of vascular changes such as non-specific inflammatory infiltration, fibrinoid necrosis, fibromuscular intimal proliferation (FIP), and/or adventitial fibrosis (with or without thrombosis).
Vasculitis and vascular changes were accompanied by a wide spectrum of histological abnormalities in various organs.
In the heart complex vascular changes -FIP (n=5), multifocal myocardiocytolysis or myocardial necrosis (n=4), and/or endomyocardial fibrosis (n=10) was present in 10 of 11 SSc patients. Complex vascular changes -FIP was accompanied by myocardiocytolysis or myocardal necrosis in 4 of 5, and endo-myocardial fibrosis in 5 of 10 cases.
Complex vascular changes FIP was accompanied by interstitial pneumonitis or fibrosis in 3 of 11, and honeycomb-lungs in 3 of 5 cases.
FIP was associated to complex nephropathy in all of these 9 SSc patients.   FIP was accompanied by interstitial nephritis in 8 of 9, by glomerulonephritis in 1 of 1, by tubular necrosis in 2 of 2 cases.
Five of 11 SSc patients died of circulatory failure caused by histological changes of the heart and lungs. The renal changes led to uremia in 6 of 11 cases.
Associated diseases had, no causal role in death of SSc patient.
The basic disease, complication(s) and associated diseases of 11 SSc patients with A-SV and FIP are summarized in Table 3.
Cl-: -Clinically not diagnosed systemic vasculitis in 9 (81.82%) of 11 patients.     All of 11 SSc patients were complicated with A-SV; and FIP was present in 10 of 11 A-SV cases.
The statistical link between FIP and coexistent complications in 11 SSc patients is summarized in Table 4.

Discussion
Vasculitis or vascular changes of autoimmune origin are among the most important complications of RA or SSc, and are considered a direct consequence of the basic diseases.
The explicit extra-articular manifestation of A-SV, and extensive involvement of the cardiovascular, respiratory, urinary, and alimentary system in RA [14][15][16], or SSc [17][18][19] support and explain our data of mortality caused by A-SV of autoimmune origin.

Comments to A-SV in RA
In our study RA and A-SV, with or without other complications (AA amyloidosis) or associated diseases (atherosclerosis, etc,), led to death by cardiac insufficiency in 23 (multifocal microinfarction of myocardium -My n=11, large myocardial necrosis n=2, by heart failure or circulatory failure n=10), and due to respiratory insufficiency in 6 (rheumatoid pneumonia -RhPn n=3, bronchopneumonia n=2, infarct pneumonia n=1) of 33 cases. Four of 33 patients died of cachexia, intestinal or renal necrosis).
My or RhPn are regarded as direct consequences of A-SV, supported by the significant and very strong positive correlation between them, and may outline them as new vasculogenic entities in RA.

Summarized
formal pathogenesis of multifocal microinfarction of myocardium in RA Vasculitis distal to the involved vessels can cause local ischemia and regressive (necrobiotic) changes.  This process is more or less widespread and multifocal, depending on the number of involved vessels, i.e. on the severity of vasculitis.
The size of necrobiotic areas depends on the size of involved vessels. Vasculitis of the main coronary arteries with or without thrombosis may result in ischemia and may lead to a large myocardial infarct, macroscopically similar to myocardial necrosis due to coronary atherosclerosis and/or thrombosis. Vasculitis of the small arteries and arterioles causes small necrotic foci, 1-2 mm of diameter ( Figure 1).
The immunological processes in RA are recurrent events, and all types of autoimmune vasculitis are of a relapsing nature. Histologically different (acute -subacute-subchronic-chronic) stages of inflammation can be found simultaneously side by side in the same or in different vessels, reflecting the repeated process of vasculitis.
Repeated (recurring) ischemic attacks will be followed by small foci of myocardial necrosis in different stages of necrobiosis. Homogeneous necrotic areas alternating with small lytic foci of myocardium (myocardiocytolysis) and scars of a similar size are existing simultaneously side by side ( Figure 2).
Because of the recurrent nature of autoimmune vasculitis the regressive changes accumulate in the myocardium with time and may lead to unexpected sudden death [20].
It is difficult t o cl inically re cognize small accumulating f o ci of myocardial necrosis (myocardiocytolysis). The history of vasculitis, transient cardiac complaints, low voltage electrocardiogram (ECG) may help in the diagnosis [20].

Summarized formal pathogenesis of rheumatoid pneumonia (vasculogenic disseminated (multifocal) lobular-sublobular pneumonia) in RA
Severe necrotizing vasculitis, with or without thrombosis plays a major role in the pathogenesis of vasculogenic or so-called rheumatoid pneumonia (RhPn). Diminished blood supply due to vasculitis distal to the involved vessels may result in ischemia and vulnerable territories (loci minoris resistentiae) for a secondary infection (via bronchogenic or hematogenic route) ( Figure 3). According to the size of involved vessels lobular or sublobular pneumonia may develop (usually less than 10-20 millimeters in diameter), more or less respecting the anatomic borders of pulmonary units. The i nflammation does no t ha ve a he morrhagic character, in contrast to infarct-pneumonia due to thrombovasculitis with simultaneous venous congestion. Vasculogenic RhPn differs from bronchopneumonia as well, which is bronchocentric, has no sharply demarcated borders and is independent of the fine anatomic b orders of the lung.
Any forms of autoimmune vasculitis are of a relapsing (recurrent) nature, leading to the silent accumulation of inflammatory foci side by side in different stages of inflammation. The number of inflammatory foci (severity RhPn) depends on the number of involved vessels and on the frequency of repeated exacerbation of vasculitis [21].
Clinically it is difficult to recognize the small (silently accumulating) inflammatory f oci i n t he l ungs. Th e hi story of va sculitis, tr ansient pulmonary complaints with or without fever may help in the diagnosis. In case of multifocal, transient (migratory) pneumonia which is refractory to antibiotics, RhPn should be considered [21].
The l ack o f s ignificant (e ven in verse) co rrelation be tween A-SV and bronchopneumonia, AA amyloidosis, atherosclerosis, cardiac insufficiency, my ocardial ne crosis, or adult ty pe II diabetes me llitus show, that these complications or associated diseases are more or less independent of A-SV.
The significant a n d p o sitive correlation b e tween A -SV a n d tuberculosis or miliary tuberculosis means a positive influence o f A-SV (or its therapy with immunosuppressive drugs, or anti-TNF alpha treatment) on prevalence of tuberculosis with or without active miliary dissemination in RA. The presence of A-SV increases the risk of tuberculosis, and endogenous exacerbation and miliary dissemination of tuberculosis [1].

Comments to A-SV in SSc
In SSc patients A-SV with or without FIP led to death by uremia in 6, by cardiac insufficiency in 4, and by respiratory insufficiency in 1 (honeycomb-lung and bronchopneumonia) of 11 cases.
There was a strong positive (significant) correlation be tween FIP and complex nephropathy (χ²=5.3047, p<0.021), or myocardiocytolysis and/or myocardial necrosis (χ²=4.4818, p<0.034). Our data support the thesis that SSc could be regarded as a primary vascular disease [2,22].
We did not find significant correlation between FIP and interstitial inflammation or fibrosis. The lack of significant correlation between FIP and endo-myocardial fibrosis, pneumonitis-pulmonary fibrosis, interstitial nephritis, glomerulonephritis, tubular necrosis may be explained by the small number of cases.
The pathogenic role of capillaries and capillary changes (could) should not be ruled out in these interstitial histological changes of the heart, lungs or kidneys (capillaries with very characteristic electronmicroscopic changes were not evaluated in this study).
"There is intense interest in the possibility that dermal fibroblasts may synthesize excess and/or abnormal collagen and proteoglycan, partly for genetic reasons, but partly in response to local abnormalities of the circulation" [23].
The progressive sclerosis in various organs of SSc patients may be the result of direct qualitative changes in the interstitial collagen fibres, generated by extravascular immunological processes independent of vascular changes. Previous studies support this possibility as well [24][25][26].

Conclusion
Interactions of coexisting complications in RA or SSc modify the basic disease as well as the typical clinical manifestations of the complications. These changes may lead to misdiagnosis or late recognition of the complications.
The coexisting associated diseases may mask the characteristic clinical symptoms of RA or SSc and may lead to an incorrect diagnosis or late recognition of basic diseases or on the contrary even the recognition of associated diseases may be delayed.
Knowledge of formal pathogenesis of new clinical pathological entities is important from the viewpoint of prevention and effective treatment of these.
Detailed histological evaluation -based on a large autopsy population of RA and SSc patients in one institution may support or statistically confirm theories (for example Gardner's concept [23]) regarding the determination of excessive interstitial fibrosis in SSc patients.
Our recommendation is to look for minor symptoms of modified complications and associated diseases; knowing of these possibilities ("we see what we know") may help in treatment or prevention.