alexa Complications and Mortality in Systemic Vasculitis – Vasculogenic Clinicopathologic Entities in Rheumatoid Arthritis and Progressive Systemic Sclerosis Autopsy Patients | Open Access Journals
ISSN: 2471-9544
Journal of Vasculitis
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

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

Miklós Bély1* and Ágnes Apáthy2

1Department of Pathology, Hospital of the Order of the Brothers of Saint John of God in Budapest, Hungary

2Department of Rheumatology, St. Margaret Clinic Budapest, Hungary

*Corresponding Author:
Miklós Bély
Department of Pathology, Hospital of the Order of the Brothers of Saint John of God in Budapest, Hungary
Tel: (36-1) 3686345
E-mail: [email protected]

Received date: April 05, 2017; Accepted date: April 21, 2017; Published date: May 05, 2017

Citation: Bély M, Apáthy Á (2017) Complications and Mortality in Systemic Vasculitis – Vasculogenic Clinicopathologic Entities in Rheumatoid Arthritis and Progressive Systemic Sclerosis Autopsy Patients. J Vasc 3:122. doi: 10.4172/2471-9544.1000122

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.

Visit for more related articles at Journal of Vasculitis

Abstract

Objective: The aim of this study was to determine: the complication(s) and mortality of systemic vasculitis or vascular changes of autoimmune origin (A-SV) in rheumatoid arthritis (RA) and progressive systemic sclerosis (SSc) patients, and to outline the consecutive complex pathological changes (clinicopathological entities) due to A-SV in various organs.

Patients and methods: One hundred sixty one (161) non- selected autopsy patients with RA were studied. This non-selected autopsy population of RA patients was compared with 11 autopsy patients suffering of SSc.

RA and SSc were confirmed clinically according to the criteria of the American College of Rheumatology (ARA).

The basic disease, the complication(s), and the lethal outcome caused by vasculitis were determined and analyzed retrospectively after reviewing the clinical and pathological reports, and confirmed by a study of extensive histological material.

The possible role of A-SV in RA or SSc, specifically in relation to complications and cause of death, furthermore to coexistent associated diseases was analyzed by Pearson’s chi-squared (χ2) test.

Results and conclusions: 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, and was present in further 14 (42.42%) of RA patients without a direct role in death. Twenty three of 33 patients died of cardiac, 6 of respiratory insufficiency, and 4 of cachexia, intestinal or renal necrosis. There was a significant and positive correlation between A-SV and multifocal myocardiocytolysis (χ2=40.7086, p<0.00001), or multifocal rheumatoid pneumonia (χ2=7.4069, p<0.006), which were outlined as new vaculogenic entities in RA.

SSc was the basic disease leading to death in each of 11 patients, and all of these were complicated by A-SV (with or without fibromuscular intimal proliferation–FIP). Five of 11 SSc patients died of circulatory failure caused by complex cardiomyopathy, with or without honeycomb lung. Complex nephropathy led to uremia in 6 of 11 cases. The significant and positive correlation between FIP and myocardiocytolysis (χ2=4.4818, p<0.034), or complex nephropathy (χ2=5.3047, p<0.021) indicate that these complications were directly related to A-SV in SSc patients. The abundant interstitial fibrosis in various organs may have been generated by immunological processes independent of vascular changes.

Keywords

Rheumatoid arthritis; Systemic sclerosis; Systemic Vasculitis; Complications; Cause of death

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 [4-7]. The cardiovascular complications–beside renal and pulmonary ones – are important in the mortality of SSc patients as well [8-10].

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 complex pathological changes (clinicopathological entities) due to A-SV in various organs.

Patients (autopsy population)

At the National Institute of Rheumatology 9475 patients died between 1969 and 1992; among them 161 with RA (females 116, average age: 64.95 years, range 87-16, onset of RA: 50.19, average disease duration: 14.79 years; males 45, average age: 66.29 years, range 88-19, onset of RA: 52.57, average disease duration: 13.46 years at death), and all of them were autopsied.

This non-selected autopsy population of RA patients was studied and compared with 11 autopsy patients with SSc (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).

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 (χ2) test (the correlations were calculated based on the total number of patients; in case of RA n=161, and SSc n=11) [13].

Results

RA and A-SV

A-SV complicated RA in 33 (20.49%) of 161 cases.

RA with A-SV: females 20, average age of 66.95 years, range 82-32, onset of RA: 58.5, disease duration: 10.89 years; males 13, average age of 67.46 years, range 83-53, onset of RA: 54.69, disease duration: 12.77 years at death.

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 (Table 1).

Basic disease Complication (1-2) Cause of death Associated Disease(s) Cl+ Cl- Severity of A-SV* Pr # /year
1 RA A-SV Coronary arteritis-arteriolitis Myocardiocytolysis, multiple   Cl- 0,227 20/70
2 RA A-SV Coronary arteriolitis Myocardiocytolysis, multiple Ath Cl- 0,238 81/70
3 RA A-SV Pulmonary arteritis Bronchial arteritis Rheumatoid pneumonia   Cl- 0,306 V/A
4 RA A-SV Coronary arteritis-arteriolitis Myocarditis Heart failure Ath-DM Cl- 0,375 114/71
5 RA A-SV Vasculogenic pancreatitis, multiple Circulatory failure TbF Cl- 0,630 174/72
6 RA A-SV   Cachexia Ath Cl- 0,313 288/73
7 RA A-SV Coronary arteritis-arteriolitis Nodular coronary arteritis Nodulavalvulitis, Nodular endocarditis Myocardial rheumatoid nodules Nodular epicarditis AA amyloidosis Myocardiocytolysis, multiple TbFc-mTb Cl+ 0,217 395/76
8 RA A-SV Coronary arteriolitis Microinfarction Circulatory failure Ath-Cirrhosis Cl+ 0,100 20/80
9 RA A-SV Coronary arteritis-arteriolitis Eosinophilicmycarditis Cortical necrosis of adrenals Myocardiocytolysis, multiple   Cl+ 1,500 110/80
10 RA A-SV   Purulent bronchiolitis   Cl- 0,271 175/82
11 RA A-SV Pulmonary arteritis Bronchial arteritis Rheumatoid pneumonia   Cl- 0,153 25/85
12 RA A-SV AA amyloidosis Uremia DM Cl- 0,111 43/85
13 RA A-SV AA amyloidosis Myocardial necrosis Ath-DM Cl- 0,069 90/85
14 RA A-SV Pulmonary arteritis Bronchial arteritis Rheumatoid pneumonia Ath Cl- 0,111 119/85
15 RA A-SV Aortitis Coronary arteritis-arteriolitis Pancarditis Nodulavalvulitis, Nodular endocarditis Myocarditis Myocardial rheumatoid nodules Epicarditis Vasculogenic pancreatitis, multiple Vasculitis of intestines Circulatory failure Ath-TbF Cl- 0,667 36/86
16 RA A-SV Cerebralvasculitis, multiple Brainnecrosis, multiple Deep vein thrombosis Pulmonary embolism Glomerulonephritis Interstitial nephritis Inflammed infarct of the lung   Cl- 0,042 123/86
17 RA A-SV Coronary arteritis-arteriolitis Nodular valvulitis AA amyloidosis Circulatory failure   Cl- 0,292 243/87
18 RA A-SV Coronary arteritis-arteriolitis Valvulitis Endocarditis Myocarditis Myocardiocytolysis, multiple   Cl+ 0,273 275/87
19 RA A-SV Cerebral vasculitis, multiple Secondary Sjögren’s disease Thyreoiditis Brain necrosis, multiple
Bronchopneumonia
DM-TbF-CAA Cl- 0,183 279/87
20 RA A-SV Coronary arteritis-arteriolitis Nodular valvulitis Endocarditis Myocarditis Myocardial rheumatoid nodules Myocardiocytolysis, multiple   Cl- 0,258 312/87
21 RA A-SV Thrombovasculitis renal artery Coronary arteriolitis Renal necrosis   Cl+ 0,455 194/88
22 RA A-SV Coronary arteriolitis Epicarditis Vasculitis of intestines AA amyloidosis Myocardiocytolysis, multiple TbF-mTb Cl- 0,652 240/88
23 RA A-SV Coronary arteritis-arteriolitis Pancarditis Nodulavalvulitis Nodular endocarditis Myocarditis Myocardial rheumatoid nodules Nodular epicarditis Myocardiocytolysis, multiple Ath Cl- 0,153 295/88
24 RA A-SV Valvular endocarditis Heart failure DM Cl- 0,042 40/89
25 RA A-SV Coronary arteriolitis Acute endocarditis Myocardial rheumatoid nodules Myocardiocytolysis, multiple TbFc-mTb Cl- 0,333 227/89
26 RA A-SV Coronary arteritis-arteriolitis Nodulavalvulitis, Myocardial rheumatoid nodules Nodular epicarditis Myocardiocytolysis, multiple   Cl- 0,153 285/89
27 RA A-SV Aortitis Coronary arteriolitis Pancarditis Nodulavalvulitis Nodular endocarditis Myocarditis Myocardial rheumatoid nodules Nodular epicarditis Myocardial microinfarctions Circulatory failure Ath-DM-TbFc Cl- 0,056 41/90
28 RA A-SV Coronary thrombovasculitis Coronary arteriolitis Myocardial necrosis Ath-TbFc-Ca Cl- 0,111 65/90
29 RA A-SV Coronary arteriolitis Nodular pancarditis Nodulavalvulitis, Myocardial rheumatoid nodules Nodular epicarditis Myositis Circulatory failure Ath-TbFc-mTb Cl- 0,083 87/90
30 RA A-SV Coronary arteriolitis Pancarditis Endocarditis Myocarditis Epicarditis Circulatory failure   Cl+ 0,045 146/91
31 RA A-SV Coronary arteriolitis Myocardiocytolysis, multiple   Cl- 0,167 221/91
32 RA A-SV Coronary arteritis Nodular pancarditis Nodular pancarditis Nodulavalvulitis, Myocardial rheumatoid nodules Nodular epicarditis Myositis Circulatory failure Bronchopneumonia Ath Cl- 0,750 14/92
33 RA SV Thrombovasculitis (Mesenteric artery) Intestinal necrosis DM Cl- 0,083 144/92
A-SV: – Systemic vasculitis of autoimmune origin (complication with lethal outcome in 19 of 33 patients (bold); complication without fatal outcome in 14 of 33 patients)
Cl+: – Clinically diagnosed systemic vasculitis in 6 (18.18%) of 33 patients (clinically recognized 4 of 19 lethal cases, and 2 of 14 not lethal cases).
Cl-: – Clinically not diagnosed systemic vasculitis in 27 (81.82%) of 33 patients (clinically not recognized 15 of 19 lethal cases, and 12 of 14 not lethal cases).
Myocardiocytolysis Multiple (multifocal) microinfarction of myocardium (My)
CAA – Cerebral amyloid angiopathy
Tb – Post-primary (Fc – fibrocaseous, or F – fibrous) tuberculosis
mTb – active miliary dissemination of Tb
DM – adult type II diabetes mellitus

Table 1: Mortality due to A-SV in RA – (A-SV n=33 of 161, Mortality of A-SV n=19 of 33).

Twenty three of 33 patients died of cardiac, 6 of respiratoric insufficiency, and 4 of cachexia, intestinal or renal necrosis.

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, 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).

vasculitis-Heart-multiple

Figure 1: Heart, multiple microinfarts (myocardiocytolysis) of myocardium in different stage of necrosis (Magnification: x4).

vasculitis-multiple-microinfarcts

Figure 2: Heart, multiple microinfarcts (myocardiocytolysis) of myocardium in different stages of necrosis
(a) HE, x50 (b) Sirius red F3BA, same as (a) x50.

RhPn complicated RA in 3 (1.86%) of 161 patients, and all of these were accompanied with A-SV (Figure 3).

vasculitis-small-bronchial

Figure 3: Lung, small bronchial artery, non-specific, acute vasculitis, with sublobular bronchopneumonia
(a) HE, x50 (b) same as (a) x125.

Bronchopneumonia (BrPn) – partly related to RA, and partly related to Ath – was noted in 22 (13.66%) of 161 patients, and was associated with A-SV in 2 of 22 cases.

AA amyloidosis (AAa) was observed in 34 (21.12%) of 161 RA patients, and accompanied with A-SV in 5 of 34 patients.

Atherosclerosis (Ath) accompanied RA in 74 (45.9%) of 161 cases, and was associated with A-SV in 12 of 74 cases.

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 (mTb) in 6 (3.73%) of 161 patients. Tb was associated with A-SV in 9, and active mTb in 4 of 21 cases.

The statistical link between A-SV and coexistent complications or associated diseases in 161 RA patients is summarized in Table 2.

The prevalence of complications or associated diseases The co-existent complications or associated diseases The statistical link (with association’s coefficient – Ac) between A-SV and complications or associated disease in 161 RA patients
in 161 RA patients in 33 RA patients with A-SV
with or without A-SV  
Myocardiocytolysis: Myocardiocytolysis: Ac: 1
n=11/161 n=11/33 χ2=40.7088, p<0.00001
Rheumtoid pneumonia: Rheumtoid pneumonia: Ac: 1
n =3/161 n =3/33 χ2=7.4069, p<0.006
Bronchopneumonia: Bronchopneumonia: Ac*: -0.4832
n=22/161 n=2/33 χ2=1.3044, p<0.253
AA amyloidosis: AA amyyloidosis: Ac*: -0.2425
n =34/161 n =5/33 χ2=0.8870, p<0.346
Atherosclerosis: Atherosclerosis: Ac*: -0.2435
n=74/161 n=12/33 χ2=1.5398, p<0.215
Cardiac insufficiency: Cardiaac insufficiency: Ac: 0.1736
n =40/161 n =9/33 χ2=0.6622, p<0.415
Myocardial necrosis: Myocardial necrosis: Ac*: -0.0793
n=11/161 n=2/33 χ2=0.036, p<0.849
Diabetes mellitus: Diabetes mellitus: Ac: 0.1027
n=30/161 n=7/33 χ2=0.1823, p<0.669
Tuberculosis: Tuberculosis: Ac: 0.5675
n=21/161 n=9/33 χ2=7.4096, p<0.006
mTb: mTb: Ac: 0.7935
n=6/161 n=4/33 χ2=5.4751, p<0.019
*Asterisk indicates negative value of association’s coefficient (invers relationship between A-SV and complications or associated disease in 161 RA patients). Bold indicates significant value

Table 2: The influence of A-SV on the prevalence of coexistent complications or associated diseases in 161 RA patients.

There was a significant and positive correlationbetween A-SV and prevalence of My2=40.7086, p<0.00001) between A-SV and prevalence of RhPn2=7.4069, p<0.006) between A-SV and prevalence of Tb2=7.4096, p<0.006), between A-SV and prevalence of mTb2=5.4751, p<0.019).

The correltion between A-SV and BrPn (χ2=1.3044, p<0.253), AA amyloidosis (χ2=0.8870, p<0.346), Ath (χ2=1.5398, p<0.215), CI (χ2=0.6622, p<0.415), MI (χ2=0.036, p<0.849), or DM χ2=0.1823, p<0.669) was not significant (even in case of BrPn, AAa, Ath, and MI – based on the negative association’s coefficients the relationships were inverse).

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.

vasculitis-scleroderma-epidermal

Figure 4: SSc, skin, scleroderma with epidermal atrophy accompanied by slight hyperkeratosisn, and discontinuous hyperpigmentation of the basal layer (a) HE, x50 (b) same as (a) x125.

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 endo-myocardial 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.

The lungs showed complex vascular changes – FIP (n=3), interstitial pneumonitis or fibrosis (n=11), and/or honeycomb-lungs (n=5) (Figure 5) in 11 of SSc 11 patients.

vasculitis-honeycomb-lung

Figure 5: SSc, honeycomb-lung characterized by excessive fibrous tissue, and cystic spaces
(a) HE, x50 (b) Sirius red F3BA, same as (a) x50.

Complex vascular changes FIP was accompanied by interstitial pneumonitis or fibrosis in 3 of 11, and honeycomb-lungs in 3 of 5 cases.

Complex nephropathy was characterised by complex vascular changes – FIP (n=9) (Figure 6), by interstitial nephritis and/or fibrosis (n=8), by mesangiopetroliferative or membranous glomerulonephritis (n=1), and by multifocal cortical necrosis (n=2) in 9 of SSc 11 patients.

vasculitis-small-artery

Figure 6: SSc, kidney, small artery, fibromuscular intimal proliferation–FIP and adventitial fibrosis
(a) HE, x125 (b) Sirius red F3BA, same as (a) x125.

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.

Basic disease Complications Cause of death Associated
disease(s)
Cl+Cl- Severity
Avg/Pt
Pr # /year
1 SSc A-SV
Complex nephropathy including
FIP
Glomerulonephritis and
Focal tubural necrosis (multiple)
Scleroderma
Multifocal pancreatitis
Gastrointestinal sclerosis
Interstitial pneumonitis
Interstitial fibrosis
Periductal biliary fibrosis
Uremia   Cl- 0,750 44/61
2 SSc A-SV
Complex nephropathy including
FIP and
Interstitialis nephritis
 
Honeycomb lung including
Interstitial pneumonitis and
FIP
Scleroderma
Chronic fibrous-fibrinoussynovialitis
Multifocal pancreatitis
Myocardial fibrosis
Uremia   Cl- 0,690 33/65
3 SSc A-SV
Honeycomb lung including
Interstitial fibrosis and
Peribronchialfibrinoid necrosis (focal)
 
Fibrous fascitis
Myositis
Scleroderma
Chronic fibrous-fibrinoussynovialitis
Complex nephropathy including
FIP and
Interstitialis nephritis
Gastrointestinal sclerosis
Endo-epicardial fibrosis
Periductal biliary fibrosis
Periductal fibrosis of pancreas
Strumitis-Focal interstitial fibrosis
Bronchopneumonia Circulatory failure   Cl- 0,833 4/83
4 SSc A-SV
Complex nephropathy including
FIP and
Interstitialis nephritis
Scleroderma
Chronic endocardial fibrosis
Peri-endoneural fibrosis
Gastrointestinal sclerosis
Chronic fibrous-fibrinoussynovialtis
Interstitial fibrosis
Peribronchial fibrosis
Uremia   Cl+ 1,063 35/83
5 SSc A-SV
Complex nephropathy including
FIP and
Interstitialis nephritis
Interstitial pneumonitis
Scleroderma
Gastrointestinal sclerosis
Multifocal pancreatitis
Chronic fibrous-fibrinoussynovialtis
Perineural fibrosis
Endocardial fibrosis
Fibrous fascitis
Periductal biliary fibrosis
Periductal fibrosis of salivary gland
Uremia Fibrocaseous tuberculosis Cl- 1,056 83/87
6 SSc A-SV
Complex cardiomyopathy including
FIP and
Endo-myocardial fibrosis-Valvulitis
Honeycomb lung including
Interstitial fibrosis and
FIP
Complex nephropathy including
FIP and
Interstitial nephritis
Scleroderma
Gastrointestinal sclerosis
Peri-endoneural fibrosis
Chronic fibrous-fibrinoussynovialtis
Periductal fibrosis of pancreas
Struma-Focal interstitial fibrosis
Sclerotisinglymphadenopathia
Circulatory failure Meningeom Cl+ 1,208 35/88
7 SSc A-SV
Complex nephropathy including
Chronic recurrent angiopathy - FIP
Interstitial nephritis and
Focal (multiple) tubular necrosis
Multifocal pancreatitis
Periductal fibrosis
Perineural fibrosis
Complex cardiomyopathy including
FIP
Microinfarcts (Myocardiocytolysis) and
Endo-myocardial fibrosis
Chronic fibrous-fibrinoussynovialtis
Gastrointestinal sclerosis
Duodenal ulcer
Scleroderma
Interstitial pneumonitis
Peritracheal and peribronchial fibrosis
Peri- and endoneural fibrosis
Myositis
Sjögren-syndrome
Struma-Focal interstitial fibrosis
Periductal biliary lymphoid infiltration
Periductal biliary fibrosis
Uremia   Cl- 1,750 96/88
8 SSc A-SV
Interstitialis nephritis
Gastrointestinal sclerosis
Interstitial pneumonitis
Peritracheal-peribronchial fibrosis
Chronic fibrous valvulitis (aorta)
Scleroderma
Fibrous fascitis
Chronic fibrous-fibrinoussynovialtis
Perineural fibrosis
Multifocal pancreatitis
Periductal fibrosis of pancreas
Uremia Actinomycosis
(Tonsilla)
Cl 0,924 V/89
9 SSc A-SV
Honeycomb lung including
Interstitial fibrosis
Complex cardiomyopathy including
FIP
Myocardiocytolysis,
Scarring microinfarcts,
Subacuteepicarditis
Fibrous endocarditis-valvulitis
Scleroderma
Sjögren-syndrome
Gastrointestinal sclerosis
Chronic fibrous-fibrinoussynovialtis
Peri-endoneural fibrosis
Complex nephropathy
FIP
Interstitial nephritis
Myositis (Interstitial fibrosis)
Circulatory failure   Cl- 1,050 147/97
10 SSc A-SV
Complex cardiomyopathy including
FIP of coronary artery
Myocardiocytolysis,
Endo-myocardial fibrosis and
Chronic fibrous valvulitis
Scleroderma
Multifocal pancreatitis
Periductal fibrosis of pancreas
Myositis
Fibrous fascitis
Peri-endoneural fibrosis
Gastrointestinal sclerosis
Interstitial fibrosis (focal)
Sclerosing lymphadenitis
Circulatory failure   Cl- 1,030 126/96
11 SSc A-SV
Complex cardiomyopathy including
FIP of coronary artery
Myocardial necrosis
Circumscriptendocardial fibrosis and
Interstitial myocardial fibrosis
Scleroderma
Gastrointestinal sclerosis
 
Honeycomb lung (focal) including
Interstitial pneumonitis
FIP and
Circuscript pleural fibrosis
Complex nephropathy including
Chronic renal angiopathie -FIP and
Interstitial nephritis
Peri-endoneural fibrosis
Chronic fibrous fascitis
Myositis
Sclerotising lymphadenitis
Systemic AA amyloidosis
Heart failure   Cl- 2,063 196/97

Table 3: Mortality due to A-SV in SSc–(A-SV n=11 of 11, complicated by FIP n=10 of 11).

A-SV: Systemic vasculitis of autoimmune origin (complication with lethal outcome in 11 of 11 patients; accompanied with fibromuscular intimal proliferation – FIP in 10 of 11 patients)

Severity of A-SV was determined histologically in one of our previous study: [9]

Cl+: Clinically recognized “vasculitis” (Ad litteram – “explicit verbis”) in 2 (18.18%) of 11 patients.

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.

The prevalence of histological changes Co-existence of FIP The statistical link (with association’s coefficient – Ac) between FIP and histological changes in 11 SSc patients
in various organs in various organs
of 11 SSc patients of 11 SSc patients
Endomyocardial fibrosis: n=10/11 accompanied by FIP: Ac: 0.9166
n=5/10 χ2=0.0091, p<0.9237
Myocardiocytolysis or myocardial necrosis: accompanied by FIP: Ac: 1
n=4/11 n=4/4 χ2=4.4818, p<0.034
Interstitial pneumonitis and/or fibrosis: accompanied by FIP: Ac: 1
n =11/11 n =3/11 χ2=0.3636, p<0.546
Honeycomb-lung: accompanied by FIP: Ac: 1
n=5/11 n=3/5 χ2=2.3871, p<0.122
Complex nephropathy: accompanied by FIP: Ac: 1
n=9/11 n =9/9 χ2=5.3047, p<0.021
Interstitial nephritis: accompanied by FIP: Ac: 0.7777
n=9/11 n=8/9 χ2=0.0763, p<0.7825
Tubular necrosis: accompanied by FIP: Ac: 1
n=2/11 n=2/2 χ2=0.0763, p<0.7825
Glomerulonephritis: accompanied by FIP: Ac: 1
n=1/11 n=1/1 χ2=0.7486, p<0.386
Ac: association’s coefficient
Bold indicates significant value

Table 4: The influence of FIP on the prevalence of coexistent complications in 11 SSc patients.

Ac: association’s coefficient

Bold indicates significant value

There was a significant and positive correlationbetween FIP and prevalence of My or myocardial necrosis (χ2=4.4818, p<0.034) between FIP and prevalence of complex nephropathy2=5.3047, p<0.021). In our patients the correltion between FIP and interstitial pneumoniitis and/or interstitial fibrosis (χ2=0.3636, p<0.546), honeycomb-lung (χ2=2.3871, p<0.122), interstitial nephritis (χ2=0.0763, p<0.7825), tubular necrosis (χ2=0.0763, p<0.7825), or glomerulonephritis (χ2=0.7486, p<0.386) was not significant.

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 [14-16], or SSc [17-19] 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 to clinically recognize small accumulating foci 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 inflammation does not have a hemorrhagic 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 borders 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 foci in the lungs. The history of vasculitis, transient 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 lack of significant (even inverse) correlation between A-SV and bronchopneumonia, AA amyloidosis, atherosclerosis, cardiac insufficiency, myocardial necrosis, or adult type II diabetes mellitus show, that these complications or associated diseases are more or less independent of A-SV.

The significant and positive correlation between A-SV and tuberculosis or miliary tuberculosis means a positive influence of 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 between 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 [24-26].

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.

References

Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Article Usage

  • Total views: 152
  • [From(publication date):
    June-2017 - Nov 20, 2017]
  • Breakdown by view type
  • HTML page views : 123
  • PDF downloads : 29
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri & Aquaculture Journals

Dr. Krish

[email protected]

1-702-714-7001Extn: 9040

Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001Extn: 9040

Clinical Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

Food & Nutrition Journals

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

General Science

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics & Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Materials Science Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Nursing & Health Care Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

Ann Jose

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001Extn: 9042

 
© 2008- 2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords