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Journal of Orthopedics & Bone Disorders Research Article 15 min read

Allied Disorders and Complications of Rheumatoid Arthritis - A Statistical Comorbidity Study of 234 Autopsy Patients

Bely M* and Apathy A*
* Corresponding author
ISSN: 2577-297X  10.23880/jobd-16000174  Received: March 08, 2019  Published: March 21, 2019
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Keywords
Rheumatoid Arthritis Allied Disorder RA Related Complications Statistical Analysis
Abstract

Objective: The incidence of co-morbidities is higher in rheumatoid arthritis (RA) than in the general population. Associated diseases accompanying RA may modify the clinical course and symptoms of RA and may influence the prevalence and mortality of complications related to the basic diseases and vica versa. The aim of this study was to determine statistically the possible effect of certain allied disorders: type 2 diabetes mellitus (DM), atherosclerosis (Ath), hypertension (HT), tuberculosis (Tb) with miliary dissemination (mTb), and malignant tumours (mTu) on the prevalence and mortality of RA related complications: systemic autoimmune vasculitis (AV), AA amyloidosis (AAa), lethal cardiac insufficiency (CI) caused by endo-, myo- or pancarditis, with or without interstitial pneumonitis, furthermore lethal septic infection (SI) combined with septic vasculitis (SV) or purulent arthritis (PA) Patients and Methods: Twohundred thirty four (234) non- selected autopsy patients with RA were studied. RA was confirmed clinically according to the criteria of the American College of Rheumatology (ACR). The presence of DM, Ath, HT, Tb, mTb, or mTu was determined and analyzed retrospectively, reviewing the clinical and pathological reports. The prevalence and mortality of AV, AAa, CI, SI, SV and PA was determined at autopsy and confirmed by a detailed review of extensive histological material. Demographics of different patient cohorts were compared with the Student (Welch) tprobe. The link between Ath, HT, DM, Tb, mTb, or mTu and AV, AAa, CI, SI, SV or PA was analyzed by Pearson's chisquared (χ2) test. Results: RA associated with DM in 41 (17.52%), with severe Ath in 107 (45.72%), with HT in 41 (17.52%), with with Tb in 28 (11.96%), including active disseminated mTb in 9 (3.85%), and with mTu in 27 (11.54%) of 234 patients. RA was complicated by AV in 43 (18.38 %), by AAa in 48 (20.51%), by CI in 15 (6.41%), and by lethal SI in 33 (14.10%) of 234 patients. SI was combined with PA in 15 (6.41% of 234; 45.45% of 33) or with SV in 7 (2.99% of 234; 21.21% of 33) patients; PA or SV did not occur without generalized SI. The relationship between Ath and AV, AV (lethal), AAa, AAa (lethal), CI, SI, PA or SV was consequently inverse and mostly significant. There was a positive and significant correlation between Tb or mTb and AV, furthermore between mTb and mortality of AV. Discussion and Conclusions: The consequently inverse and (in most cases) significant correlation between atherosclerosis and autoimmune vasculitis, amyloidosis or sepsis shows that the prevalence or mortality of AV, AAa and SI was not influenced by Ath. RA patients with Ath may represent a special group, characterized by lower incidence of SV, AAa, SI, CI, and carry a better prognosis. Ath is basically an age-dependent phenomenon, characteristically present in RA patients with advanced age, while AV, AAa (with or without lethal outcome) and SI are complications of RA, and characterize severe forms of disease, mostly in younger patients and with an earlier onset (without pronounced atherosclerosis). The positive and significant correlation between Tb or mTb and AV suggest a positive influence of Tb or mTb on the prevalence of vasculitis, e.g. the presence of Tb or endogenous exacerbation and miliary dissemination of Tb may promote the AV. The significant connection between mTb and mortality of AV indicates an increased risk of lethal outcome.

Introduction

The incidence of co-morbidities (including “hypertension, dyslipidemia, myocardial infarction or angina, stroke, osteoarthritis, lung cancer, colon cancer, pulmonary tuberculosis, asthma, diabetes, depression, thyroid disease and chronic kidney disease”) is higher in rheumatoid arthritis (RA) than in the general population [1]. According to van den Hoek, et al. (2017) the mortality in patients with rheumatoid arthritis is higher for cardiovascular, respiratory, musculoskeletal and digestive diseases than in the general population [2].

Associated diseases accompanying RA may modify the clinical course and symptoms of RA and may influence the prevalence and mortality of complications related to the basic diseases and vica versa [3].

The aim of this study was to determine statistically the possible effect of certain allied disorders: type 2 diabetes mellitus (DM), atherosclerosis (Ath), hypertension (HT), tuberculosis (Tb) with miliary dissemination (mTb), and malignant tumours (mTu) on the prevalence and mortality of RA related complications: systemic autoimmune vasculitis (AV), AA amyloidosis (AAa), lethal cardiac insufficiency (CI) caused by endo-, myo- or pancarditis, with or without interstitial pneumonitis, furthermore lethal septic infection (SI) combined with septic vasculitis (SV) or purulent arthritis (PA)

Patients and Methods

Twohundred thirty four (234) non- selected autopsy patients with RA were studied. RA was confirmed clinically according to the criteria of the American College of Rheumatology (ACR) [4].

The presence of DM, Ath, HT, Tb, mTb, or mTu was determined and analyzed retrospectively, reviewing the clinical and pathological reports. The prevalence and mortality of AV, AAa, CI, SI, SV and PA was determined at autopsy and confirmed by a detailed review of extensive histological material.

Demographics of different patient cohorts were compared with the Student (Welch) t-probe [5]. The link between Ath, HT, DM, Tb, mTb, or mTu and AV, AAa, CI, SI, SV or PA was analyzed by Pearson's chi-squared (χ2) test [5].

Glossary of Definitions

  • Allied disorder: important comorbidity associated with RA with or without direct causal role in death
  • RA related complication: consequence of RA with or without direct causal role in death

Atherosclerosis 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” since such changes are frequent in elderly RA patients [3].

  • "Prevalence" of vasculitis: concerns the presence of inflammatory infiltration and structural changes in blood vessels of different calibers
  • Systemic vasculitis of autoimmune origin (AV): was defined as one of the basic manifestations of RA, excluding other causes of vasculitis, like hypertension, diabetes mellitus, tumors, septic infections etc. [3, 6].
  • Systemic vasculitis of septic origin (SV) was defined as an important complication of generalized lethal septic infection (SI). The clinically identified pathogenic agents and the strong, significant and positive correlation between SV and SI supported the infectious origin of SV [3, 7].
  • "Prevalence" of AAa: concerns the presence of amyloid A deposits in blood vessels of different calibers or in different tissue structures of various organs.
  • AAa was diagnosed histologically according to Romhányi by a modified (more sensitive) Congo red staining [8, 9]. Amyloid A deposits were identified in serial histologic sections by immunohistochemical and histo chemical methods [10].

Results

RA associated with DM in 41 (17.52%), with severe Ath in 107 (45.72%), with HT in 41 (17.52%), with with Tb in 28 (11.96%), including active disseminated mTb in 9 (3.85%), and with mTu in 27 (11.54%) of 234 patients.

Adult type 2 DM was clinically recognized and controlled in all cases and no patients died of it; the basic diseases leading to death were different in all RA patients associated with DM. Ath led directly to death in 61 (57.01% of 107 and 26.06% of 234), HT in 2 of 41, Tb with mTb in 3 of 28, and mTu in 12 of 27 patients. In lethal cases only the influence of Ath was analyzed as a RA related complication; the others, because of their limited numbers were not tested.

RA was complicated by AV in 43 (18.38%), by AAa in 48 (20.51%), by CI with lethal outcome (caused exclusively by endo-, myo- or pancarditis with or without interstitial pneumonitis) in 15 (6.41%), and by lethal SI in 33 (14.10%) of 234 patients. SI was combined with PA in 15 (6.41% of 234; 45.45% of 33) or with SV in 7 (2.99% of 234; 21.21% of 33) patients; PA or SV did not occur without generalized SI.

AV led to death in 24 (10.25%), AAa in 20 (8.54%) of 234 patients. The prevalence and mortality of CI, SI (with or without SV and PA) were identical, because only lethal cases were listed.

Demographics, onset and duration of RA associated with DM, Ath, HT, Tb, mTb and mTu or complicated by AV, AAa, CI and SI (including PA or SV) are summarized in Table 1.

| Sex | Number of autopsies | Mean age in years at death ± SD | Range (in years) | Mean age at onset of disease ± SD | Disease duration (in years) mean ± SD |
| :--- | :--- | :--- | :--- | :--- | :--- |
| RA patients (total) | 234 | 66.25±13.15 | 16–88 | 51.02±16.58 | 14.76±10.79 |
| Female | 170 | 66.31±12.82 | 16–88 | 50.46±15.92 | 15.42±11.12 |
| Male | 64 | 66.08±13.97 | 19–88 | 52.55±18.18 | 12.96±9.60 |
| With DM | 41 of 234 | 68.17±8.85 | 47–83 | 54.32±13.99 | 15.10±10.67 |
| Female | 30 | 66.77±8.04 | 47–82 | 53.00±14.52 | 15.13±11.74 |
| Male | 11 | 72.00±9.75 | 48–83 | 58.13±11.54 | 15.00±6.69 |
| With Ath | 107 of 234 | 71.90±10.76 | 47–88 | 56.85±14.23 | 14.43±11.56 |
| Female | 78 | 71.47±11.62 | 47–88 | 54.98±14.19 | 15.94±12.36 |
| Male | 29 | 73.03±7.69 | 56–88 | 61.70±13.12 | 10.50±7.90 |
| Ath (lethal) | 61 of 107 | 72.83±12.49 | 47–88 | 54.59±13.97 | 17.05±12.45 |
| Female | 49 | 72.15±13.44 | 47–88 | 53.67±13.79 | 17.61±13.01 |
| Male | 12 | 75.58±6.01 | 64–84 | 58.38±14.08 | 14.75±9.47 |

Ath
(associated)		46 of 10770.67±7.8656 – 8859.84±14.0010.97±9.18
Female2970.34±7.6356 – 8457.26±14.5913.05±10.53
Male1771.24±8.2156 – 8863.92±11.937.67±4.92
With HT41 of 23469.37±8.6747 – 8649.05±14.0019.14±9.18
Female2968.93±7.6347 – 8646.44±15.0121.06±12.43
Male1270.42±6.9859 – 8256.88±13.6513.38±7.73
With Tb28 of 23468.93±10.1047 – 8454.96±15.6614.33±12.14
Female2169.76±10.7847 – 8455.00±16.8715.30±13.28
Male766.43±7.1156 – 7854.86±11.5411.57±7.40
With mTb9 of 2868.00±9.7550 – 8259.38±7.359.75±4.89
Female867.88±10.3450 – 8258.71±7.6310.43±4.87
Male169.00±0.0069 – 6964.00±0.005.00±0.00
With mTu27 of 23466.81±12.7234 – 8755.41±16.8611.64±8.04
Female1964.37±12.8434 – 8152.47±16.8111.41±8.23
Male872.63±10.3253 – 8764.40±12.6712.40±7.31
With AV43 of 23468.26±10.8032 – 8856.85±15.2412.08±10.82
Female2668.96±11.8432 – 8858.04±13.6812.71±9.58
Male1767.12±8.8453 – 8355.06±17.1611.13±12.39
AV (lethal)24 of 4363.96±10.8632 – 8252.83±16.3412.52±11.96
Female1565.00±12.6532 – 8254.29±13.6513.07±9.25
Male962.22±6.5653 – 7250.56±19.6011.67±15.20
With AAa48 of 23463.75±14.7619 – 8846.66±17.8217.18±9.85
Female3865.13±11.3632 – 8847.25±16.4817.75±10.55
Male1058.50±22.8119 – 8844.00±22.7214.63±5.02
AAa (lethal)20 of 4856.80±17.5519 – 8840.33±20.3117.28±9.44
Female1359.54±12.0932 – 7540.25±17.4918.67±10.74
Male751.71±23.8619 – 8840.50±25.0014.50±5.02
With CI15 of 23466.67±15.4520 – 8356.17±18.9911.17±9.95
Female969.56±10.1952 – 8261.14±17.5012.71±12.30
Male662.17±20.1820 – 8349.20±18.809.00±4.20
With SI33 of 23462.33±8.6341 – 8349.00±12.4113.45±9.04
Female2361.35±9.4241 – 8348.45±13.5013.20±9.65
Male1064.60±5.8752 – 7150.22±9.4314.00±7.48
With PA15 of 3359.47±7.0346 – 7144.08±10.4516.38±10.31
Female1058.20±6.6946 – 6842.88±10.8416.63±11.34
Male562.00±7.0152 – 7146.00±9.4916.00±8.39
With SV7 of 3361.57±7.7451 – 7051.14±12.0310.43±8.78
Female457.25±7.3651 – 6945.75±13.1211.50±11.15
Male367.33±3.0963 – 7058.33±4.199.00±3.27

Table 1: Sex, mean age with SD, range, onset and disease duration of RA patients associated with DM (n=41), Ath (n=107), HT (n=41

Table 1: Sex, mean age with SD, range, onset and disease duration of RA patients associated with DM (n=41), Ath (n=107), HT (n=41), Tb (n=28), mTb (n=9) and mTu (n=27) or complicated by AV (n=43), AAa (n=48), CI (n=15), SI (n=33) including PA (n=15) or SV (n=7). Glossary to Table 1: RA – Rheumatoid Arthritis Lethal – allied disorder or RA related complication with lethal outcome Associated – allied disorder (accompanying disease) without direct causal role in death DM – type 2 Diabetes Mellitus; Ath: Atherosclerosis; HT: HyperTension; Tb: Tuberculosis; mTb: miliary Tuberculosis; mTu: malignant Tumors; AV: systemic Autoimmune Vasculitis; AAa: systemic AA amyloidosis; CI: Cardiac Insufficiency with lethal outcome; SI: lethal Septic Infection; PA: Purulent Arthritis; SV: systemic Septic Vasculitis; SD: Standard deviation Comparing the mean age of female and male RA patients (n=234) associated with DM, Ath, HT, Tb, mTb and mTu or complicated by AV, AAa, CI and SI (including PA or SV) to the mean age of total population, there was no significant difference between patient cohorts except RA patients with Ath, lethal AAa, and SI including PA.

The mean age of RA patients associated with Ath (n=107) was significantly higher (71.90 years versus 66.25; p< 0.0000015), both of females (71.47 years versus 66.31; p< 0.00014) and males (73.03 years versus 66.08; p< 0.003).

Comparing the subgroups of Ath (lethal outcome n=61 of 107, and coexistent associated disease n=46 of 107) with the mean age of the total population (n=234), the tendency was the same only the levels of difference were disparate:

The mean age of RA patients with lethal outcome of Ath (n=61) was significantly higher (72.83 years versus 66.25; p< 0.0000043), for both females (72.15 years versus 66.31; p< 0.00036) and males (75.58 years versus 66.08; p< 0.001), and the mean age of RA patients with coexistent associated Ath (n=46) was significantly higher (70.67 years versus 66.25; p< 0.003), and it was the same in women (70.34 years versus 66.31; p< 0.022). The mean age of males was higher than the mean age of total population (71.24 years versus 66.08; p< 0.063 – NS), but this difference was not significant (Tables 1 & 2).

Comparing the onset of RA and duration of disease there was a collateral (parallel) tendency between RA patients (n=234) with mTb (n=9) or AV (n=43).

RA started later in patients with mTb (59.38 years versus 51.02; p< 0.033), who died earlier (9.75 years versus 14.36; p< 0.563; p< 0.020), and it was the same in women (58.71 years versus 50.46; p< 0.050, and 10.43 years versus 15.42; p< 0.040).

RA patients with complications of AV (n=43) showed a similar predisposition as patients with mTb. RA started later in patients with AV (56.85 years versus 51.02; p< 0.037), who died earlier (9.75 years versus 14.36; p< 0.167 – NS), but the latter was not significant. The tendency was similar both in women (onset of RA: 58.04 years versus 50.46; p< 0.022, and duration of disease: 10.43 years versus 15.42 p< 0.230 – NS) and men (onset of RA: 55.06 years versus 52.55; p< 0.630 – NS, and duration of disease: 11.13 years versus 12.96; p< 0.604 – NS), but partly without significant relationship.

The mean age of RA patients with lethal AAa (n=20) was lower (56.80 years versus 66.25; p< 0.032), and RA started significantly earlier (40.33 years versus 51.02; p< 0.049), than in the general population (n=234).

The mean age of RA patients with SI (n=33) or PA (n=15) was significantly lower collate to the average of total population (62.33 or 59.47 years versus 66.25; p< 0.028 or p< 0.004). The mean age of females complicated by SI (n=23) or PA (n=10) was significantly lower as well (61.35 or 58.20 years versus 66.31 or 66.08; p< 0.031 or p< 0.005). The mean age of males complicated by SI (n=10) or PA (n=5) was lower also (64.60 or 62.00 years versus 66.08; p< 0.579 – NS or p< 0.337 – NS), but these differences were not significant.

The statistical links (“p” values of significance) between RA patients with DM, Ath, HT, Tb, mTb, mTu or complicated by AV, AAa, SI (including PA or SV) are summarized in Table 2.

RA patients n=234AgeOnset of diseaseDisease Duration
RA pts. n=234 versus pts. with DM n=41 of 234p< 0,240p< 0,251p< 0,873
Female n=170 of 164 versus n=30 of 41p< 0,797p< 0,459p< 0,915
Male n=64 of 164 versus n=11 of 41p< 0,113p< 0,294p< 0,493
RA pts. n=234 versus pts. with Ath n=107 of 234p< 0,00000p< 0,006p< 0,873
Female n=170 of 164 versus n=78 of 107p< 0,00014p< 0,065p< 0,793
Male n=64 of 164 versus n=29 of 107p< 0,003p< 0,287p< 0,026
RA pts. n=234 versus pts. Ath (lethal) n=61 of 107p< 0,00000p< 0,164p< 0,286
Female n=170 of 164 versus n=49 of 61p< 0,00036p< 0,258p< 0,386
Male n=64 of 164 versus n=12 of 61p< 0,001p< 0,348p< 0,652
RA pts. n=234 versus pts. Ath (associated) n=45 of 107p< 0,003p< 0,003p< 0,047
Female n=170 of 164 versus n=7 of 45p< 0,022p< 0,079p< 0,283
Male n=64 of 164 versus n=2 of 45p< 0,063p< 0,017p< 0,014
RA pts. n=234 versus pts. with HT n=41 of 234p< 0,055p< 0,517p< 0,062
  • Female n=170 of 164 versus n=29 of 41 p< 0,191 p< 0,249 p< 0,050
  • Male n=64 of 164 versus n=12 of 41 p< 0,125 p< 0,471 p< 0,900
  • RA pts. n=234 versus pts. with Tb n=28 of 234 p< 0,212 p< 0,242 p< 0,867
  • Female n=170 of 164 versus n=21 of 28 p< 0,193 p< 0,280 p< 0,970
  • Male n=64 of 164 versus n=7 of 28 p< 0,920 p< 0,678 p< 0,686
  • RA pts. n=234 versus pts. with mTb n=9 of 234 p< 0,634 p< 0,033 p< 0,020
  • Female n=170 of 164 versus n=8 of 9 p< 0,708 p< 0,050 p< 0,040
  • Male n=64 of 164 versus n=1 of 9
  • -
  • -
  • -
  • RA pts. n=234 versus pts. with mTu n=27 of 234 p< 0,832 p< 0,269 p< 0,116
  • Female n=170 of 164 versus n=19 of 27 p< 0,545 p< 0,654 p< 0,091
  • Male n=64 of 164 versus n=8 of 27 p< 0,157 p< 0,115 p< 0,892
  • RA pts. n=234 versus pts. with AV n=43 of 234 p< 0,285 p< 0,037 p< 0,165
  • Female n=170 of 164 versus n=26 of 43 p< 0,304 p< 0,022 p< 0,230
  • Male n=64 of 164 versus n=17 of 43 p< 0,715 p< 0,630 p< 0,604
  • RA pts. n=234 versus pts. with AV (lethal) n=24 of 234 p< 0,348 p< 0,629 p< 0,410
  • Female n=170 of 164 versus n=15 of 24 p< 0,713 p< 0,356 p< 0, 404
  • Male n=64 of 164 versus n=9 of 24 p< 0,201 p< 0,793 p< 0,821
  • RA pts. n=234 versus pts. with AAa n=48 of 234 p< 0,281 p< 0,149 p< 0,159
  • Female n=170 of 164 versus n=38 of 48 p< 0,572 p< 0,307 p< 0,256
  • Male n=64 of 164 versus n=10 of 48 p< 0,354 p< 0,368 p< 0,489
  • RA pts. n=234 versus pts. with AAa (lethal) n=20 of 234 p< 0,032 p< 0,049 p< 0,311
  • Female n=170 of 164 versus n=13 of 20 p< 0,082 p< 0,085 p< 0,354
  • Male n=64 of 164 versus n=7 of 20 p< 0,194 p< 0,338 p< 0,573
  • RA pts. n=234 versus pts. with CI n=15 of 234 p< 0,923 p< 0,397 p< 0,269
  • Female n=170 of 164 versus n=9 of 15 p< 0,405 p< 0,189 p< 0,614
  • Male n=64 of 164 versus n=6 of 15 p< 0,687 p< 0,746 p< 0,153
  • RA pts. n=234 versus pts. with SI n=33 of 234 p< 0,028 p< 0,449 p< 0,491
  • Female n=170 of 164 versus n=23 of 33 p< 0,031 p< 559 p< 0,366
  • Male n=64 of 164 versus n=10 of 33 p< 0,579 p< 0,589 p< 0,733
  • RA pts. n=234 versus pts. with PA n=15 of 234 p< 0,004 p< 0,049 p< 0,606
  • Female n=170 of 164 versus n=10 of 15 p< 0,005 p< 0,115 p< 0,791
  • Male n=64 of 164 versus n=5 of 15 p< 0,337 p< 0,267 p< 0,522
  • RA pts. n=234 versus pts. with SV n=7 of 234 p< 0,196 p< 0,982 p< 0,279
  • Female n=170 of 164 versus n=4 of 7 p< 0,121 p< 0,582 p< 0,588
  • Male n=64 of 164 versus n=3 of 7 p< 0,672 p< 0,193 p< 0,221

Table 3: Statistical correlations (“p” values of significance) between female and male RA patients associated with DM, Ath,

Ath (n=107) accompanied AV in 12, AV (lethal) in 4, AAa in 12, AAa (lethal) in 4, CI in 5, SI in 9, PA in 3, SV in none of 107 patients. The relationship between Ath and Ath with lethal outcome (n=61) went together AV in 3 and AAa in none of 61 patients. The relationship between Ath (with lethal outcome) and AV or AAa was inverse and significant (Table 3). In other words Ath (lethal) was not associated with AV (lethal), AAa (lethal), CI, SI, PA or SV (since a patient may have only one cause of death; the links were inverse and usually significant (Table 3).

HT (n=41) occurred with AV in 4, AV (lethal) in 2, AAa in 8, AAa (lethal) in 3, CI in 2, SI in 3, PA in 1, SV in none of 41 patients.

Tb (n=28) coexisted with AV in 9, AV (lethal) in 5, AAa in 2, AAa (lethal) in none, CI in 3, SI in 5, PA in 1, SV in 1 of 28 patients.

mTb (n=9) accompanied AV in 4, AV (lethal) in 4, AAa in 2, AAa (lethal) in none, CI in 1, SI in 2, PA in none, SV in 1 of 9 patients. There was a positive and significant correlation between Tb and AV (χ²=4.0188, p<0.04) or mTb and AV (χ²=4.2406, p<0.03) (Table 3). There was a The statistical links (“p” values of significance) between allied disorders and prevalence or mortality of RA related complications are summarized in Table 3. *asterisk indicates a negative value of associations’ coefficient with inverse relationship.

very close connection between mTb and mortality of AVas well (χ²=11.88, p<0.0005).

mTu (n=27) was observed with AV in 1, AAa in 4, CI in 1, SI in 3, PA in 1, SV in none of 27 patients.

The links between allied disorders and the most important complications of RA, apart from the above mentioned positive and significant relationship of Tb and mTb, were in most cases not significant and mainly inverse.

AthAth
Allied disorders inHT 41 ofTb 28 ofmTb 9mTu 27
DM 41 of 234n=107 of(lethal)
RA234234of 28of 234
234n=61
Complications of RA
AV n=43 of 234²p²
p		²
p		²
p		²
p		²
p		²
p
AV lethal n=24 of 43²p²
p		²
p		²
p		²
p		²
p
		²
p
AAa n=48 of 234²p²
p		²
p		²
p		²
p		²
p		²
p
AAa lethal n =24 of
48		²p²
p		²
p		²
p		²
p		²
p		²
p
CI n=15 of 234²p²
p		²
p		²
p		²
p		²
p		²
p
SI n=33 of 234²p²
p		²
p		²
p		²
p		²
p		²
p
PA n=15 of 33²p²
p		²
p		²
p		²
p		²
p		²
p
SV n=7 of 33²p²
p		²
p		²
p		²
p		²
p		²
p

Table 4: The statistical links (“p” values of significance) between allied disorders and prevalence or mortality of RA related co

Table 3: The statistical links (“p” values of significance) between allied disorders and prevalence or mortality of RA related complications. Glossary to Table 3: RA: Rheumatoid Arthritis n=234 Ath: Atherosclerosis n=107 of 234, with lethal outcome n=61 of 107 HT: HyperTension n=41 of 234 DM: adult type 2 Diabetes Mellitus n=41 of 234 Tb: Tuberculosis n=28 of 234 mTb: Tuberculosis with miliary dissemination n=9 of 234 mTu: malignantTumour n=27 of 234 AV: systemic Autoimmune Vasculitis n=43 of 234, with lethal outcome n=24 of 43 AAa: AA amyloidosis n=48 of 234, with lethal outcome n=20 of 48

CI: Cardiac Iinsufficiency caused exclusively by endo-, myo- or pancarditis n=15 of 234 SI: Lethal Septic Infection n=33 of 234 SV: systemic Septic Vasculitis n=7 of 33 PA: Purulent Arthritis n=15 of 33 The most important RA related complications and comorbidities are demonstrated in Figures 1-10 including but not limited to all possibilities.

Figures 1-3 show different types and stages of autoimmune coronary vasculitis, Figures 4-5 early and late stages of amyloid a deposition in adrenal gland, Figures 6-7 fibrocaseous and exudative mTb, and Figures

Figure 1: RA, heart, main (medium size) coronary artery, non-specific subchronic vasculitis Sectorial accentuated lympho-plasmocellular infiltration and moderate fibromuscular intimal proliferation. More than 21 days old hemorrhage, with hematoidine crystals at the border of intima and media. (a) HE, x20 (b) same as (a) x50
Click to enlarge
Figure 1: RA, heart, main (medium size) coronary artery, non-specific subchronic vasculitis Sectorial accentuated lympho-plasmocellular infiltration and moderate fibromuscular intimal proliferation. More than 21 days old hemorrhage, with hematoidine crystals at the border of intima and media. (a) HE, x20 (b) same as (a) x50
Figure 2: RA, heart, main (medium size) coronary artery Subacute-subchronic vasculitis with incipient (early stage) rheumatoid nodule in media and adventicia, sectorial accentuated leuco-lympho-plasmocellular infiltration and moderate fibromuscular intimal proliferation. (a) HE, x20 (b) same as (a) x50
Click to enlarge
Figure 2: RA, heart, main (medium size) coronary artery Subacute-subchronic vasculitis with incipient (early stage) rheumatoid nodule in media and adventicia, sectorial accentuated leuco-lympho-plasmocellular infiltration and moderate fibromuscular intimal proliferation. (a) HE, x20 (b) same as (a) x50

8-10 the most frequent mTu (bronchoalveolar carcinoma) in RA.

Original magnifications correspond to the 24x36 mm transparency slide; the correct height: width ratio is 2:3. The printed size may be different; therefore it is necessary to indicate the original magnifications.

Figure 3: RA, heart, main (medium size) subepicardial coronary artery, subchronic nodular vasculitis Typical rheumatoid nodule in media and adventicia, sectorial accentuated granulomatous transformation of vessel wall and moderate fibromuscular intimal proliferation. (a) HE, x20 (b) same as (a) x50
Click to enlarge
Figure 3: RA, heart, main (medium size) subepicardial coronary artery, subchronic nodular vasculitis Typical rheumatoid nodule in media and adventicia, sectorial accentuated granulomatous transformation of vessel wall and moderate fibromuscular intimal proliferation. (a) HE, x20 (b) same as (a) x50

a b

Figure 4: RA, adrenal gland and periadrenal fat tissue, early stage of systemic secondary AA amyloidosis Amyloid A deposited within reticular zone of adrenal gland, in the wall of periadrenal blood vessels (arterioles) and along reticular and collagen fibers. (a) HE, x 50, (b) same as (a) Congo red staining, without alcoholic differentiation, covered with gum arabic. Viewed under polarized light x50
Click to enlarge
Figure 4: RA, adrenal gland and periadrenal fat tissue, early stage of systemic secondary AA amyloidosis Amyloid A deposited within reticular zone of adrenal gland, in the wall of periadrenal blood vessels (arterioles) and along reticular and collagen fibers. (a) HE, x 50, (b) same as (a) Congo red staining, without alcoholic differentiation, covered with gum arabic. Viewed under polarized light x50

a b

Figure 5: RA, adrenal gland and periadrenal fat tissue, late stage of systemic secondary AA amyloidosis Amyloid A deposited within the reticular, fascicular and glomerular zones of adrenal cortex, involving periadrenal blood vessels, reticular and collagen fibers (a) HE, x 50, (b) same as (a) x125, (c) same as Figure (a) Congo red staining viewed under polarized light, x50, (d) same as Figure (b and c) Congo red staining viewed under polarized light, x125
Click to enlarge
Figure 5: RA, adrenal gland and periadrenal fat tissue, late stage of systemic secondary AA amyloidosis Amyloid A deposited within the reticular, fascicular and glomerular zones of adrenal cortex, involving periadrenal blood vessels, reticular and collagen fibers (a) HE, x 50, (b) same as (a) x125, (c) same as Figure (a) Congo red staining viewed under polarized light, x50, (d) same as Figure (b and c) Congo red staining viewed under polarized light, x125
Figure 6: RA, miliary disseminated caseous tuberculosis in the lung (a) HE, x 50, (b) same as (a) x125
Click to enlarge
Figure 6: RA, miliary disseminated caseous tuberculosis in the lung (a) HE, x 50, (b) same as (a) x125

Figure 4: RA, adrenal gland and periadrenal fat tissue, early stage of systemic secondary AA amyloidosis Amyloid A deposited within reticular zone of adrenal gland, in the wall of periadrenal blood vessels (arterioles) and along reticular and collagen fibers. (a) HE, x 50, (b) same as (a) Congo red staining, without alcoholic differentiation, covered with gum arabic. Viewed under polarized light x50

Figure 7: RA, exudative miliary epithelioid granulomas in atrophic suprarenal gland (a) HE, x 50, (b) same as (a) x125
Click to enlarge
Figure 7: RA, exudative miliary epithelioid granulomas in atrophic suprarenal gland (a) HE, x 50, (b) same as (a) x125
Figure 8: RA, lung, undifferentiated bronchoalveolar carcinoma Irregular spaces separated by fibrotic septa, and enveloped by tall partly columnar epithelium (a) HE, x 40, (b) same as (a) x100, (c) Anti-human epithelial membrane antigen (mono/DAKO N1504), x 100 (d) same as (c) x200
Click to enlarge
Figure 8: RA, lung, undifferentiated bronchoalveolar carcinoma Irregular spaces separated by fibrotic septa, and enveloped by tall partly columnar epithelium (a) HE, x 40, (b) same as (a) x100, (c) Anti-human epithelial membrane antigen (mono/DAKO N1504), x 100 (d) same as (c) x200

Figure 5: RA, adrenal gland and periadrenal fat tissue, late stage of systemic secondary AA amyloidosis Amyloid A deposited within the reticular, fascicular and glomerular zones of adrenal cortex, involving periadrenal blood vessels, reticular and collagen fibers (a) HE, x 50, (b) same as (a) x125, (c) same as Figure (a) Congo red staining viewed under polarized light, x50, (d) same as Figure (b and c) Congo red staining viewed under polarized light, x125

Figure 9: RA, lung, undifferentiated bronchoalveolar carcinoma Irregular spaces separated by fibrotic septa, and enveloped by tall columnar epithelium. (a) HE, x 40, (b) same as (a) x100, (c) Anti-human epithelial membrane antigen (mono/DAKO N1504), x 100, (d) Anti- human carcinoembrionic antigen 1:100 (mono/DAKO N1503) x100
Click to enlarge
Figure 9: RA, lung, undifferentiated bronchoalveolar carcinoma Irregular spaces separated by fibrotic septa, and enveloped by tall columnar epithelium. (a) HE, x 40, (b) same as (a) x100, (c) Anti-human epithelial membrane antigen (mono/DAKO N1504), x 100, (d) Anti- human carcinoembrionic antigen 1:100 (mono/DAKO N1503) x100

a b

Figure 10: RA, DM, pancreas, severe atherosclerosis involving small arteries (a) HE, x 50, (b) same as (a) x125
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Figure 10: RA, DM, pancreas, severe atherosclerosis involving small arteries (a) HE, x 50, (b) same as (a) x125

a b

Figure 11
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Figure 11

a b

Figure 12
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Figure 12

c d

Figure 13
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Figure 13
Figure 14
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Figure 14

a b Figure 6: RA, miliary disseminated caseous tuberculosis in the lung (a) HE, x 50, (b) same as (a) x125

Figure 15
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Figure 15
Figure 16
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Figure 16

a b Figure 7: RA, exudative miliary epithelioid granulomas in atrophic suprarenal gland (a) HE, x 50, (b) same as (a) x125

Figure 17
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Figure 17
Figure 18
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Figure 18
Figure 19
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Figure 19
Figure 20
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Figure 20

a b c d Figure 8: RA, lung, undifferentiated bronchoalveolar carcinoma Irregular spaces separated by fibrotic septa, and enveloped by tall partly columnar epithelium (a) HE, x 40, (b) same as (a) x100, (c) Anti-human epithelial membrane antigen (mono/DAKO N1504), x 100 (d) same as (c) x200

Figure 21
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Figure 21
Figure 22
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Figure 22
Figure 23
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Figure 23
Figure 24
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Figure 24

a b

Figure 25
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Figure 25

c d

Figure 26
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Figure 26

a b Figure 10: RA, DM, pancreas, severe atherosclerosis involving small arteries (a) HE, x 50, (b) same as (a) x125

Discussion

Severe atherosclerosis was present nearly in half, in 107 (45.72%) of 234 RA patients, and led to death in more than half 61 (57.01%) of them. Ath was the most important allied disorder leading to death in RA.

The mean age of atherosclerotic female and male RA patients was higher than the mean age of the others or of the total population, and RA started consequently later in these patients. RA associated with Ath may represent a special subgroup of RA patients with a better prognosis, which may correspond to the clinically benign elderly- onset or late-onset RA [11]. The negative correlations between allied disorders and RA related complications represent an inverse relationship between them. The high prevalence of allied disorder suggests a rarer (less common) occurrence of RA related complication. Ath with lethal outcome surmises an especially lower risk for RA related complications (AV, AV lethal, AAa, AAa lethal, CI, SI or PA), based on the strong and significant but negative correlations between them. With other words, the most important complications of RA are presumably less frequent in atherosclerotic RA patients.

The negative correlation between Ath and CI shows that cardiac insufficiency in our patients’ group was caused by endo-, myo-, epi- or pancarditis, and polyserositis with or without interstitial pneumonitis, which complicated RA earlier and in younger patients (without prominent atherosclerosis).

The lower mean age of RA patients complicated by lethal AAa (56.80 years versus 66.25; p< 0.032) and the early onset of disease (40.33 years versus 51.02; p< 0.049) in these patients indicate also, that the most dangerous complications of RA involve mainly the younger generation, which was also supported by the strong negative and significant correlations to Ath (χ=5.83*, p<0.01) or to Ath with lethal outcome (χ²=6.30*, p<0.01).

Septic complication including PA led to early death of the patients (SI: 62.33 and PA: 59.47 years versus 66.25; p< 0.028 and p< 0.004), which also showed a distinct difference in women (SI: 61.35 and PA: 58.20 years versus 66.31; p< 0.031 and p< 0.005). The strong negative and significant relationship between Ath and SI(χ=5.27*, p<0.02) or PA (χ²=3.23*, p<0.07 – NS), and between Ath with lethal outcome and SI (χ=12.05*, p<0.0005) or PA(χ=4.29*, p<0.03) referred again to the explicit involvement of younger people.

Diabetes and hypertension are the basic risk factors of atherosclerosis and its complications. DM and HT raise the prevalence of Ath, cardiovascular diseases, limited renal function, progressive endothelial dysfunction, higher intraocular pressure, decreased erectile function etc. independently from each other, and the risk of these increases in case of coexistence [12, 13, 14].

According to our data mTu did not influence the prevalence and mortality of RA related complications. The prevalence and mortality of malignant tumors in pertinent literature and our RA autopsy population is summarized in Table 4.

According to the literature, DM is often associated with HT, and it is also mentioned in several studies as an evidence statement [15, 16, 17, 18]. According to our data DM, HT or Ath did not influece the prevalence and mortality of RA related complications, and the clinically well controlled DM or HT does not diminish the chances of survival.

Tuberculosis is one of the most important associated diseases accompanying RA [3]. The positive and significant correlation between Tb and AV (χ²=4.02, p< 0.04) or mTb and AV (χ²=4.24, p< 0.03) suggest a positive role of tuberculosis on the prevalence and mortality of autoimmune vasculitis in RA. The presence of Tb (especially of its fibrocaseous form) or endogenous exacerbation and miliary dissemination of tuberculosis (mTb) increases, promotes, and facilitates the risk of AV and modifies the histological type of vasculitis [19, 20]. The significant connection between mTb and mortality of AV (χ²=11.88, p< 0.0005) means an increased risk of lethal outcome. This statement was also supported by the late and collateral (parallel) onset of RA in patients with mTb (59.38 years versus 51.02; p< 0.033) and AV (56.85 years versus 51.02; p< 0.037) compared these to the total population. The tendency was the same and especially pronounced in females with mTb (58.71 years versus 50.46; p< 0.033) and with AV (58.04 years versus 50.46; p< 0.022).

Published data indicate that the overall risk of malignancy (especially prevalence of lymphomas and lung cancer) is higher in RA, compared with the general population [21, 22]. According to Buchbinder, et al. the incidence of malignancy was low in an Australian RA patients’ cohort and anti-tumour necrosis factor treatment did not increase the risk of malignancy. Only the incidence of melanoma increased in comparison with the general population [23].

Tumor
AuthorsYear of Publication-[References]No of AutopsyPrevalenceMortality
N - %N - % of Total
Bayles1943 [24]23ND2 of 23– 8.7%
Baggenstoss and Rosenberg1943 [25]30ND1 of 30– 3.3%
Young and Schwedel1944 [26]33ND2 of 33– 6.1%
Bywaters1950 [27]27ND4 of 27– 14.8%
Gedda1955 [28]45ND1 of 45 – 2.2%

Table 5: Literature on the morbidity and mortality of malignant tumors in autopsied RA patients. Glossary to Table 4 ND: no data

Goehrs, et al.1960 [29]36ND4 of 36– 11.1%
Lebowitz1963 [30]62ND6of 62– 9.7%
Gardner1972 [31]14224 – 16.9%ND
Vroninks, et al.1973 [32]62ND7 of 62– 11.3%
Rainer, et al.1978 [33]79ND2 of 79 – 2.53%
Lindahl1984 [34]82ND3 of 82 – 3.7%
Suzuki, et al.1994 [35]81ND5 of 81 – 6.2%
Bély and Apáthy1998 [36]16113 – 8.1%7 of 13 – 4.4%
Bély and Apáthy2003 [37]161*15 – 9.3%7 of 15 – 4.4%
Bély and Apáthy2005 [38]234*27 – 11.5%12 of 27 – 6.4%

Table 6: Literature on the morbidity and mortality of malignant tumors in autopsied RA patients. Glossary to Table 4 ND: no data

Conclusion

The consequently inverse and (in most cases) significant correlation between atherosclerosis and autoimmune vasculitis, amyloidosis or sepsis shows that the prevalence or mortality of AV, AAa and SI was not influenced by Ath. RA patients with Ath may represent a special group, characterized by lower incidence of SV, AAa, SI, CI, and carry a better prognosis. Ath is basically an age- dependent phenomenon, characteristically present in RA patients with advanced age, while AV, AAa (with or without lethal outcome) and SI are complications of RA, and characterize severe forms of disease, mostly in younger patients and with an earlier onset (without pronounced atherosclerosis).

The positive and significant correlation between Tb and AV (χ²=4.02, p < 0.04) or mTb and AV (χ²=4.24, p < 0.03) suggest a positive influence of Tb or mTb on the prevalence of vasculitis, e.g. the presence of Tb or endogenous exacerbation and miliary dissemination of Tb may promote the AV; and modify the histological type of vasculitis [19, 20]. The significant connection between mTb and mortality of AV (χ²=11.88, p< 0.0005) indicates an increased risk of lethal outcome.

Finalizing the results of interaction between coexistent allied disorders and complications of RA it may be concluded that there is a more or less close link between them. The knowledge of these complications and the likelihood of their occurrence should be considered when management, particularly therapeutic decisions are made: “one sees what one knows”.

References

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@article{bely2019,
  title   = {Allied Disorders and Complications of Rheumatoid Arthritis - A Statistical Comorbidity Study of 234 Autopsy Patients},
  author  = {Bely M* and Apathy A},
  journal = {Journal of Orthopedics & Bone Disorders},
  year    = {2019},
  volume  = {3},
  number  = {1},
  doi     = {10.23880/jobd-16000174}
}
Bely M* and Apathy A (2019). Allied Disorders and Complications of Rheumatoid Arthritis - A Statistical Comorbidity Study of 234 Autopsy Patients. Journal of Orthopedics & Bone Disorders, 3(1). https://doi.org/10.23880/jobd-16000174
TY  - JOUR
TI  - Allied Disorders and Complications of Rheumatoid Arthritis - A Statistical Comorbidity Study of 234 Autopsy Patients
AU  - Bely M* and Apathy A
JO  - Journal of Orthopedics & Bone Disorders
PY  - 2019
VL  - 3
IS  - 1
DO  - 10.23880/jobd-16000174
ER  -