Pathogenetic Association of Digestive System Lesions with Systemic Lupus Erythematosus: Characteristics and Prevalence

Abstract

Introduction. The prevalence rate of the digestive system lesions in patients with systemic lupus erythematosus (SLE) ranges from 8.0 to 50.0%. The symptoms caused by systemic lupus erythematosus (immunocomplex inflammation, vasculitis, etc.) have not been clearly distinguished yet from those that are associated with co-occurring diseases or adverse effects of medications used to treat patients with SLE. 

Objective. To characterize and clarify the prevalence of the digestive system lesions that are pathogenetically associated with systemic lupus erythematosus.

Materials and methods. 370 patients (331 women and 39 men), stratified by age, duration, and activity of SLE, were included in the study and subjected to comprehensive examinations. The results were processed in Microsoft Excel using descriptive statistics, χ2 test, z-test for comparisons between two proportions; the relationship was considered to be statistically significant when p < 0.05.

Results. The digestive system lesions were detected in 225 (60.81%) patients with systemic lupus erythematosus. The prevalence of steatohepatitis, autoimmune hepatitis, and chronic pancreatitis rose with the progression of the underlying disease, so we concluded that they may be considered to be pathogenetically associated with systemic lupus erythematosus as syntropic comorbid lesions. Other digestive system lesions – chronic pharyngitis, cardiochalasia, gastroesophageal reflux disease, esophagitis, chronic gastritis, peptic ulcer, chronic duodenitis, duodenogastric reflux, duodenal ulcer, chronic viral hepatitis B, chronic viral hepatitis C, toxic hepatitis, liver cirrhosis, acalculous cholecystitis, chronic cholecystitis (asymptomatic gallstones, chronic calculous cholecystitis, gallbladder polyps), irritable bowel syndrome, chronic colitis, hemorrhoids, dolichosigma, peritoneal adhesions – are only comorbidities, ie. co-occurring digestive system lesions, since there was no relationship between their prevalence and the progression of the underlying disease. The mesenchymal inflammatory syndrome was detected in most patients with systemic lupus erythematosus and pathogenetically associated syntropic comorbid steatohepatitis. Hepatocellular dysfunction syndrome was detected in the three-fourths of patients with SLE and steatohepatitis. The mesenchymal inflammatory syndrome was also detected in all patients with SLE and pathogenetically associated syntropic comorbid autoimmune hepatitis. More than half of the patients with SLE and autoimmune hepatitis were also diagnosed with hepatocellular dysfunction and hepatic cytolysis syndromes. The asthenic-neurotic clinical syndrome occurred in the three-fourths of patients with SLE and pathogenetically associated syntropic comorbid chronic pancreatitis. Almost every second patient with SLE and chronic pancreatitis had a dyspeptic syndrome. Steatohepatitis was detected predominantly in patients aged 25 to 59 (young age subgroup II and middle age group). It was not detected in patients with the SLE duration of less than one year. Autoimmune hepatitis was detected predominantly in elderly patients and patients with the SLE duration of more than ten years. Chronic pancreatitis was significantly less prevalent in women and more prevalent in elderly patients – it occurred in almost half of them. It was absent in patients with the SLE duration of less than one year. Patients with the SLE duration of 6-10 years had the highest prevalence of chronic pancreatitis.

Background

Damage to the digestive system in patients with systemic lupus erythematosus (SLE) is not uncommon. According to various reports, its frequency varies from 8.0% to 50.0% [1-3] and includes lesions of almost every organ of the gastrointestinal tract. But there is still no clearly separation of symptoms caused directly by SLE (immunocomplex inflammation, vasculitis etc. [4-7]) from those that are the signs of comorbidities or side effects of drugs received by patients. In addition, the relationship between the sex of patients, their age, the duration of the underlying disease and the spectrum of digestive lesions pathogenetically associated with SLE has not been studied.

Aim

To describe and clarify the features of the spread of lesions of the digestive system, wich are pathogenetically associated with systemic lupus erythematosus.

Materials and Methods

After obtaining a written consent to conduct a comprehensive survey, in accordance with the principles of the Helsinki Declaration of Human Rights, the Council of Europe Convention on Human Rights and Biomedicine, relevant laws of Ukraine and international instruments, there were 370 patients included in the study: 331 women (89.46%) and 39 men (10.54%) aged 18 to 74 years, who were treated in the rheumatology department of the Municipal Non-Profit Enterprise of the Lviv Regional Council “Lviv Regional Clinical Hospital” in 2010–2018. This hospital is the clinical base of the Department of Internal Medicine No.1 and No.2 of Lviv National Medical University named after Danylo Halytsky. The patients were randomized with prior stratification for SLE (Order of the Ministry of Health of Ukraine № 676 dated 12.10.2006 On approval of medical care protocols in the specialty "Rheumatology", recommendations of the European League against Rheumatism (2010), the American Board of Rheumatologists (2010, 2012)).

SLE patients were stratified by age according to the World Health Organization classification, 2015 (at a young age (18 to 44 years)) (204 patients), middle-aged (45 to 59 years) (153 patients) and 13 elderly patients age (from 60 to 75 years)), as well as the duration of SLE (ill less than 1 year (21 patients), ill during 1-5 years (133 patients), ill during 6-10 years (78 patients) and those who are ill more than 10 years (138 patients).

Stratification by duration of the disease allowed us to divide all 370 patients with SLE involved in the study, into those who are ill for less than 1 year (21 patients), ill for 1-5 years (133 patients), ill for 6-10 years (78 patients) and those who have been ill for more than 10 years (138 patients).

Comprehensive clinical-laboratory and instrumental diagnostics of lesions of the digestive system was performed according to the Order of the Ministry of Health of Ukraine № 271 from 13.06.2005 "On approval of protocols for medical care in the specialty "Gastroenterology" ", assessing passport information, patient complaints, history of their illness and life, the results of a comprehensive objective examination, additional laboratory and instrumental examinations.

Diagnosis of alcohol (toxic) liver disease was performed on the basis of reports of daily alcohol consumption at a dose of at least 50.0 g in terms of pure ethanol for 2-5 years and screening for alcohol abuse (questionnaires CAGE-test, Alcohol Use Disorders Identification Test, Michigan Alcoholism Screening Test). Hepatitis B virus infection was identified by us by determining its serological markers (HBsAg, anti-HBcorAg, HBV DNA (qualitatively, quantitatively)), hepatitis C virus - its serological markers (anti-HCV, HCV DNA (qualitatively, quantitatively), genotyping), as well as information from the history of acute viral hepatitis. Autoimmune processes were evaluated by serological markers of autoimmune liver damage (ANA, SMA, anti-LKM1 or anti-LC1 in blood serum).

In the study we took into account if the patients have:

Clinical and laboratory syndromes of liver damage:

1. hepatocyte integrity disorder syndrome (cytolysis syndrome), which is clinically manifested by asthenia and fever; laboratory - by increasing the activity of enzymes: aspartate aminotransferase, alanine aminotransferase, total bilirubin and its fractions.
2. mesenchymal-inflammatory syndrome, the presence of which is clinically verified by the presence of hepatomegaly; laboratory - increase in the content of thymol sample, α2- or γ-globulins in the protein fraction, fibrinogen, seromucoid.
3. hepatocellular insufficiency syndrome (hepatodepressive syndrome), which is clinically manifested by increased biliousness, coagulation disorders (bruising, bleeding); laboratory - by reducing the content of cholinesterase, fibrinogen, prothrombin index, prothrombin, cholesterol, albumin.
4. cholestasis syndrome (excretory-biliary) is diagnosed when the patient has clinical - skin itch; laboratory: increase in the content of -glutamyltransferase, alkaline phosphatase, cholesterol.
5. Porto-caval shunt syndrome was detected when clinically found "vascular asterisks", varicose veins of the esophagus, splenomegaly, ascites; laboratory - increase in the content of ammonia, homocysteine.

Syndromes of pancreatic lesions:

1. pain syndrome;
2. dyspeptic syndrome, which is manifested by nausea, belching, heartburn, salivation, vomiting, which does not bring relief, flatulence, impaired defecation with a predominance of diarrhea, or alternating diarrhea and constipation;
3. pancreatic exocrine insufficiency syndrome includes weight loss, impaired absorption of vitamins, various variants of hypovitaminosis;
4. syndrome of intra-secretory insufficiency of the pancreas, which is manifested first by hyperinsulinism - a feeling of hunger, trembling throughout the body, weakness, sweating, and then the emergence of diabetes;
5. astheno-neurotic syndrome, which is manifested by general weakness, fatigue, adynamia, sleep disturbances;
6. inflammatory and enzymatic intoxication syndrome, which is manifested by fever, tachycardia, leukocytosis, accelerated erythrocyte sedimentation rate, general weakness, hypotension, loss of appetite;
7. surrounding compression syndrome, manifested by jaundice, duodenostasis with partial high intestinal obstruction, splenomegaly, varicose veins of the esophagus and pancreatic ascites (mainly in pseudo tumorous pancreatitis).

Among the instrumental methods of examination we used: ultrasound examination of the abdominal cavity with a diagnostic device "Acuson computed sonography 128 XP / 10 ART" (company "Acuson", USA) according to the standard protocol with multifrequency sensors (with frequencies C - 3.5 MHz ; L - 7–10 MHz and V - 4 MHz); esophagogastroduodenofibroscopy using a video endoscope "EG27-i10" (Pentax, Japan) and colonofibroscopy using a video colonoscope "EC34-i10L" (Pentax, Japan), in accordance with the requirements published in the endoscopy manual.

All patients with SLE were stratified into five groups based on the assessment of SLE activity (Systemic Lupus Erythematosus Disease activity index - SLEDAI): patients with inactive SLE (0 degree activity according to SLEDAI, 0 points) - seven patients with low activity SLE (activity of the I degree on SLEDAI, 1-5 points) - 61 patients, patients with activity of average degree (activity of the II degree on SLEDAI, 6-10 points) - 158 patients, patients with a high degree of activity of SLE (activity of the III degree on SLEDAI, 11-19 points) - 104 patients, patients with activity of very high degree (activity of IV degree on SLEDAI, more than 20 points) - 40 patients.

The study was conducted in three stages: the first stage diagnosed lesions of the digestive system in all patients with SLE (first step), establishing their nature and frequency, and (second step) eliminated those that are pathogenetically associated with SLE, i.e., are syntropic comorbid lesions. For this purpose, we studied the spread of each lesion of the digestive system depending on the degree of SLE activity and conducted a statistical analysis to find χ2 - a statistical criterion to test the null hypothesis that the observed random variable is subject to a certain theoretical distribution law. In the second stage, we described pathogenetically associated with SLE, i.e., syntropic comorbid lesions of the digestive system. In the third stage - found out the peculiarities of their prevalence depending on sex (first step), age (second step) and duration of the disease (third step).

Statistical processing of the obtained results was performed in the program "Excel" using descriptive statistics, χ2-criterion, z-criterion for comparison of two particles, statistically significant relationship was considered when p <0,05.

Results and Discussion

The first stage of the study

As predicted by the study design, the first stage consisted of two consecutive steps, where the first step – the determination of the frequency of all digestive lesions in patients with SLE, and the second step – the relationship between disease activity and frequency of lesions, thus distinguishing syntropic comorbid lesions pathogenetically associated with SLE.

The results of the first step of the study, which after a detailed study of complaints, history, clinical examination, laboratory and instrumental examinations in patients with SLE allowed us to diagnose a number of lesions of the digestive system. We diagnosed chronic pharyngitis in 21 patients (5.68%), cardiac insufficiency in seven patients (1.89%), esophagitis in five patients (1.36%), and gastroesophageal reflux disease in five patients (1.36%). Chronic gastritis occurred in 52 patients (14.09%), and gastric ulcer – in 32 patients (8.67%). We found duodenogastric reflux in 23 patients (6.23%), duodenitis – in 22 patients (5.96%), duodenal ulcer - in 21 patients (5.69%).

Toxic hepatitis was most often diagnosed among liver lesions; it was found in 69 patients (18.69%). Other liver lesions occurred with the following frequency: steatohepatitis – in 51 patients (13.78%), autoimmune hepatitis was detected in 31 patients with SLE (8.40%), liver cirrhosis – in two patients with SLE (0.54%), chronic viral hepatitis B - in one patient (0.61%), and chronic viral hepatitis C - in three patients (1.72%).

Among gallbladder lesions, noncalculous cholecystitis was diagnosed the most often (27 patients, 7.32%). Chronic calculous cholecystitis is present in 24 patients (6.50%), gallbladder polyps – in twelve patients (3.25%), chronic cholecystitis: latent stone disease - in three patients with SLE (0.81%).

Chronic pancreatitis was detected in 64 patients (17.34%).

We diagnosed Chronic Colitis in ten patients (2.71%), hemorrhoids - in eight (2.17%), dolichosigma - in three (0.81%), and irritable bowel syndrome - in two (0.54%), and peritoneal commissures - in nine patients with SLE (2.44%).

According to our results, lesions of the digestive system were diagnosed in 225 patients with SLE, which is 60.81% of all 370 examined patients with SLE, the most common of which are toxic hepatitis, chronic pancreatitis, chronic gastritis and steatohepatitis, and most rarely - chronic viral hepatitis B, liver cirrhosis, latent stone disease, dolichosigma, irritable bowel syndrome (equal to or less than 1.00%).

The results of the second step of this phase of the study, devoted to determination of the relationship between SLE activity and the frequency of lesions of the digestive system, are shown in Table 1.

Table 1. Frequency of lesions of the digestive system in patients with systemic lupus erythematosus depending on its degree of activity (n; %)

No.	Lesions of the digestive system	Patients with SLE, activity 0 according to SLEDAI, n = 7		Patients with SLE, activity I on SLEDAI, n = 61		Patients with SLE, activity II on SLEDAI, n = 158		Patients with SLE, activity III on SLEDAI, n = 104		Patients with SLE, activity IV on SLEDAI, n = 40
		n	%	n	%	n	%	n	%	n	%
1	Chronic pharyngitis	0	0.00	7	11.48	7	4.43	7	6.73	0	0.00
2	Cardiac insufficiency	0	0.00	1	1.64	0	0.00	4	3.88	2	5.00
3	Esophagitis	0	0.00	0	0.00	2	1.27	3	2.91	0	0.00
4	Gastroesophageal reflux disease	0	0.00	0	0.00	0	0.00	3	2.91	2	5.00
5	Chronic gastritis	0	0.00	12	19.67	21	13.29	15	14.56	4	10.00
6	Gastric ulcer	0	0.00	8	13.11	15	9.49	6	5.83	3	7.50
7	Duodenogastric reflux	0	0.00	8	13.11	6	3.79	6	5.83	3	7.50
8	Chronic duodenitis	0	0.00	8	13.11	5	3.16	6	5.83	3	7.50
9	Duodenal ulcer	2	28.57	5	8.19	6	3.79	5	4.85	3	7.50
10	Autoimmune hepatitis	0	0.00	3	4.92	10	6.33	7	6.79	11	27.50
11	Toxic hepatitis	1	14.28	9	14.75	33	20.89	16	15.53	10	25.00
12	Chronic viral hepatitis B	n = 1	n = 17	n = 63	n = 56	n = 28
		0	0.00	1	5.88	0	0.00	0	0.00	0	0.00
13	Chronic viral hepatitis C	n = 6	n = 17	n = 65	n = 58	n = 28
		0	0.00	1	5.88	1	1.54	1	1.72	0	0.00
14	Steatohepatitis	1	14.29	2	3.28	16	10.13	17	16.51	15	37.50
15	Cirrhosis	0	0.00	1	1.64	1	0.63	0	0.00	0	0.00
16	Chronic pancreatitis	0	0.00	5	8.20	34	21.52	14	13.59	11	27.50
17	Chronic cholecystitis: latent calculi-bearing	0	0.00	0	0.00	3	1.89	0	0.00	0	0.00
18	Non-calculous cholecystitis	0	0.00	2	3.28	18	11.39	4	3.88	3	7.50
19	Chronic calculous cholecystitis	0	0.00	4	6.56	12	7.59	6	5.83	2	5.00
20	Gallbladder polyps	0	0.00	4	6.56	6	3.79	2	1.94	0	0.00
21	Chronic colitis	0	0.00	2	3.28	3	1.89	3	2.91	2	5.00
22	Hemorrhoid	0	0.00	3	4.92	5	3.16	0	0.00	0	0.00
23	Dolichosigma	0	0.00	0	0.00	2	1.27	0	0.00	1	2.50
24	Irritable bowel syndrome	0	0.00	0	0.00	0	0.00	2	1.94	0	0.00
25	Peritoneal commissures	0	0.00	0	0.00	7	4.43	0	0.00	2	5.00

Chronic pharyngitis was diagnosed in seven patients with SLE of I degree of activity (11.48%), in seven patients with SLE of II degree of activity (4.43%) and in seven patients with SLE of III degree of activity (6.73%). Patients with inactive SLE (SLEDAI activity 0) and SLE of IV degree of activity have no activity of chronic pharyngitis (0.00%). We did not establish a significant relationship between SLE activity and chronic pharyngitis (χ2 = 7.43, p = 0.12).

We did not detect any case of cardiac insufficiency in patients with inactive SLE and SLE of II degree of activity (0.00%). Cardiac insufficiency was diagnosed in one patient with SLE of I degree of activity (1.64%), in four patients with SLE of III degree of activity (3.88%) and two patients with SLE of IV degree of activity (5.00%). No association was found between cardiac insufficiency and SLE activity (χ2 = 7.47, p = 0.11).

Esophagitis was not diagnosed in patients with inactive SLE, SLE of I and IV degrees of activity (0.00%). Two cases of esophagitis were recorded in patients with SLE of II degree (1.27%) and three - in patients with SLE of III degree of activity (2.91%). No association was found between esophagitis and SLE activity (χ2 = 3.36, p = 0.49).

We diagnosed three cases of gastroesophageal reflux disease in patients with SLE of III activity (2.91%) and two - in patients with SLE of IV activity (5.00%), no other patient has this digestive lesion. In view of this, we did not find a significant relationship between SLE activity and gastroesophageal reflux disease (χ2 = 8.95, p = 0.06).

No cases of gastritis were detected in patients with inactive SLE (0.00%). Gastritis was diagnosed in twelve patients with SLE of I degree of activity (19.67%), in 21 patients with SLE of II degree of activity (13.29%), in 15 patients with SLE of III degree of activity (14.56%) and in four patients on SLE of I degree of activity (10.00%). The association between gastritis and SLE activity was not statistically confirmed (χ2 = 3.37, p = 0.49).

Gastric ulcer did not occur in patients with inactive SLE (0.00%). This disease was recorded in eight patients with SLE of I degree of activity (13.11%), in 15 patients with SLE of II degree of activity (9.49%), in six patients with SLE of III degree of activity (5.83%) and in three patients with SLE of IV degree of activity (7.50%). The association between gastric ulcer and SLE activity was not statistically confirmed (χ2 = 3.44, p = 0.49).

We did not detect any case of duodenogastric reflux in patients with inactive SLE (0.00%). We diagnosed such digestive lesions in eight patients with SLE of I degree of activity (13.11%), in six patients with SLE of II degree of activity (3.79%), in six patients with SLE of III degree of activity (5.83%) and in three patients with SLE of IV degree of activity (7.50%). There is also no association between duodenogastric reflux and SLE activity (χ2 = 7.15, p = 0.13).

There are no cases of duodenitis among patients with inactive SLE (0.00%). This lesion of the duodenum was diagnosed in eight patients with SLE of I degree (13.11%), in five patients with SLE of II degree of activity (3.16%), in six patients with SLE of III degree of activity (5.83%) and in three patients with SLE of IV degree of activity (7.50%). The presence of duodenitis is not associated with SLE activity (χ2 = 8.39, p = 0.08).

Among patients with inactive SLE, two cases of duodenal ulcer were diagnosed (28.57%), among patients with SLE of I degree of activity - five cases (8.19%), among patients with SLE of II degree of activity - six cases (3.79%), among patients with SLE of II degree of activity - five cases (4.85%), and among patients with SLE of IV degree of activity - three cases (7.50%). There is no statistically confirmed association between the presence of duodenal ulcer and SLE activity (χ2 = 8.98, p = 0.06).

No autoimmune hepatitis was detected in patients with inactive SLE (0.00%). This lesion was diagnosed in three patients with SLE of I degree of activity (4.92%), in ten patients with SLE of II degree of activity (6.33%), in seven patients with SLE of III degree of activity (6.79%) and in eleven patients with SLE of IV degree of activity (27.50%). We found a significant association between the presence of autoimmune hepatitis and SLE activity (χ2 = 21.79 p = 0.00).

One patient with inactive SLE (activity 0 according to SLEDAI) was diagnosed with toxic hepatitis (14, 28%). This liver damage was also found in nine patients with SLE of I degree of activity (14.75%), 33 patients with SLE of II degree of activity (20.89%), 16 patients with SLE of III degree of activity (15.53%) and ten patients with SLE of IV degree of activity according to SLEDAI (25.00%). We did not find a significant relationship between SLE activity and toxic hepatitis (χ2 = 8.29, p = 0.08).

We diagnosed only one case of chronic viral hepatitis B in a patient with SLE of I degree of activity (5.88%), no other patient has this liver disease. Therefore, we did not find a significant association between SLE activity and the presence of chronic viral hepatitis B (χ2 = 8.76, p = 0.07).

Isolated cases of chronic viral hepatitis C among patients with SLE were also diagnosed, namely: one patient with SLE of I degree of activity (5.88%), one patient with SLE of II degree of activity (1.54%) and one patient with SLE of III degree of activity (1.72%). In other groups of patients there is no chronic viral hepatitis C (0.00%). No association was found between chronic viral hepatitis C and SLE activity (χ2 = 2.38, p = 0.67).

One patient with inactive SLE was diagnosed with steatohepatitis (14.29%). This liver damage was also found in two patients with SLE of I degree of activity (3.28%), in 16 patients with SLE of II degree of activity (10.13%), in 17 patients with SLE of III degree of activity (16.51%) and in 15 patients with SLE of IV degree of activity according to SLEDAI (37.50%). There is a statistically confirmed association between SLE activity and the presence of steatohepatitis (χ2 = 26.95, p = 0.00).

Cirrhosis of the liver is absent in patients with inactive SLE, SLE of III and IV degrees of activity (0.00%). One patient with SLE of I degree of activity (1.64%) and one patient with SLE of II degree of activity (0.63%) had cirrhosis of the liver. This distribution of patients does not allow to statistically confirm the relationship between the presence of liver cirrhosis and SLE (χ2 = 2.20, p = 0.69).

In our sample there are no patients with inactive SLE and chronic pancreatitis (0.00%), but found five patients with SLE of I degree of activity (8.20%), 34 patients with SLE of II degree (21.52%), 14 patients with SLE of III degree of activity (13.59%) and eleven with SLE of IV degree of activity (27.50%) with this lesion of the pancreas. This indicates a statistically significant association between SLE activity and the incidence of chronic pancreatitis (χ2 = 10.84, p = 0.03).

We diagnosed three cases of latent calculi-bearing disease in patients with SLE of III degree of activity (1.89%), no other patient has this lesion of the gallbladder. Therefore, we did not find a significant relationship between SLE activity and the presence of chronic cholecystitis: latent calculi-bearing (χ2 = 4.04, p = 0.40).

There are no cases of non-calculous cholecystitis among patients with inactive SLE (0.00%). This disease was diagnosed in two patients with SLE of I degree (3.28%), in 18 patients with SLE of II degree of activity (11.39%), in four patients with SLE of III degree of activity (3.88%) and in three patients on SLE of IV degree of activity (7.50%). Noncalculous cholecystitis is not associated with SLE activity (χ2 = 7.68, p = 0.10).

We identified four cases of chronic calculous cholecystitis in patients with SLE of I degree of activity (6.56%), 12 cases - in patients with SLE of II degree of activity (7.59%), six cases - in patients with SLE of III degree of activity (5.83%) and two cases - in patients with SLE of IV degree of activity (5.00%). In patients with inactive SLE, chronic calculous cholecystitis was not detected (0.00%). There is no association between the presence of chronic calculous cholecystitis and SLE activity (χ2 = 1.02, p = 0.91).

No patients with gallbladder polyps were found among patients with inactive SLE and SLE of IV degree of activity (0.00%). This disease was diagnosed in four patients with SLE of I degree of activity (6.56%), in six patients with SLE of II degree of activity (3.79%), in two patients with SLE of III degree of activity (1.94%). The relationship between the presence of gallbladder polyps and SLE activity was not statistically confirmed (χ2 = 4.41, p = 0.35).

No chronic colitis was detected among patients with inactive SLE. This intestinal lesion was diagnosed in two patients with SLE of I degree of activity (3.28%), in three - II degree of activity (1.89%), in three - III degree of activity (2.91%) and in two patients with SLE of IV degree of activity (5.00%). The coefficient χ2 calculated by us indicates no connection between the presence of lesions and SLE activity (χ2 = 1.48, p = 0.83).

Hemorrhoids are not diagnosed in patients with inactive SLE, SLE of III and IV degrees of activity (0.00%). Three cases of this disease were recorded in patients with SLE of I degree of activity (4.92%) and five - in patients with SLE of II degree of activity (3.16%). No association was found between hemorrhoids and SLE activity (χ2 = 6.24, p = 0.18).

The diagnosis of dolichosigma was established in two patients with SLE of II degree of activity (1.27%) and in one patient with SLE of IV degree of activity (2.50%). Among other groups of patients, such a lesion was not detected (0.00%), as well as no association between the presence of the disease and SLE activity (χ2 = 3.22, p = 0.52).

We have diagnosed only two cases of irritable bowel syndrome in patients with SLE of III degree of activity (1.94%), no other patient has this intestinal lesion. In view of this, we did not find a significant relationship between SLE activity and the presence of irritable bowel syndrome (χ2 = 5.19, p = 0.27).

There are no cases of peritoneal commissures among patients with inactive SLE, SLE of I and III degrees of activity (0.00%). This intestinal lesion was diagnosed in seven patients with SLE of II degree (4.43%), in two patients with SLE of IV degree of activity (5.00%). The presence of cutaneous disease is not associated with SLE activity (χ2 = 8.01, p = 0.09).

Based on our results, it can be argued that steatohepatitis, autoimmune hepatitis, chronic pancreatitis, which are closely related to SLE activity, are pathogenetically associated with SLE and can therefore be interpreted as syntropic comorbid lesions. And others (chronic pharyngitis, cardiac insufficiency, gastroesophageal reflux disease, esophagitis, chronic gastritis, gastric ulcer, chronic duodenitis, duodenogastric reflux, duodenal ulcer, chronic viral hepatitis B, chronic viral hepatitis C, toxic hepatitis, cirrhosis, non-calculous cholecystitis, chronic cholecystitis: latent calculi-bearing, chronic calculous cholecystitis, gallbladder polyp, irritable bowel syndrome, chronic colitis, hemorrhoids, dolichosigma, peritoneal commissures) belong to the comorbid diseases of the digestive system associated with SLE, because we have not recorded their connection with the increase in the activity of the underlying disease.

The results obtained by us at the first stage of the study show that lesions of the digestive system occur in 225 (60.81%) patients with SLE, in whom the incidence of steatohepatitis, autoimmune hepatitis and chronic pancreatitis increases with increasing SLE activity, and therefore, we believe they can be interpreted as pathogenetically associated with SLE, i.e., syntropic comorbid lesions.

This fact is the basis for the need for additional general characteristics of pathogenetically associated with SLE syntropic comorbid lesions of the digestive system, which is devoted to the second stage of the study, as well as to clarify their distribution depending on sex (first step), age (second step) and duration of SLE (third step), which is devoted to the third stage of the study.

The second stage of the study

We characterized pathogenetically associated syntropic comorbid autoimmune hepatitis and steatohepatitis by the presence of liver disease syndromes in patients, and chronic pancreatitis, respectively, by the presence of pancreatic syndrome. The obtained results are shown in tables 2, 3 and 4.

Table 2. Frequency of clinical and laboratory syndromes of liver damage in patients with systemic lupus erythematosus and pathogenetically associated syntropic comorbid steatohepatitis (n; %).

No.	Syndromes of liver damage	Patients, n=51
		n	%
1	Cytolysis syndrome	13	25.49
2	Mesenchymal-inflammatory syndrome	47	92.18
3	Hepatocellular insufficiency syndrome	36	70.59
4	Cholestasis syndrome	24	47.06
5	Portocaval shunt syndrome	0	0.00

In patients with SLE with pathogenetically associated syntropic comorbid steatohepatitis mesenchymal-inflammatory syndrome (47 patients, 92.18%) was found the most often, in almost three-quarters - hepatocellular insufficiency syndrome (36 patients, 70.59%), in almost half - cholestasis syndrome (24 patients, 47.06%) and in one quarter of patients - cytolysis syndrome (13 patients, 25.46%). No portal hypertension syndrome was detected (0.00%).

Table 3. Frequency of clinical and laboratory syndromes of liver damage in patients with systemic lupus erythematosus and pathogenetically associated syntropic comorbid autoimmune hepatitis (n; %)

No.	Syndromes of liver damage	Patients, n=31
		n	%
1	Cytolysis syndrome	16	51.61
2	Mesenchymal-inflammatory syndrome	31	100.00
3	Hepatocellular insufficiency syndrome	17	54.84
4	Cholestasis syndrome	12	38.71
5	Portocaval shunt syndrome	0	0.00

We found mesenchymal-inflammatory syndrome in all patients (100.00%) with SLE with pathogenetically associated syntropic comorbid autoimmune hepatitis, in more than half - hepatocellular insufficiency syndrome (17 patients, 54.84%) and cytolysis syndrome (16 patients, 51.61%). Slightly more than a third of such patients had cholestasis syndrome (12 patients, 38.71%). No patient had portal hypertension syndrome (0.00%).

Table 4. Frequency of clinical syndromes in patients with systemic lupus erythematosus and pathogenetically associated syntropic comorbid chronic pancreatitis (n; %).

No.	Clinical syndromes	Patients, n=64
		n	%
1	Pain syndrome	17	26.56
2	Dyspeptic syndrome	31	48.44
3	Syndrome of exocrine insufficiency	23	35.94
4	Internal secretion insufficiency syndrome	0	0.00
5	Astheno-neurotic syndrome	48	75.00
6	Inflammatory and enzymatic intoxication syndrome	0	0.00
7	Syndrome of compression of surrounding organs	0	0.00

We diagnosed astheno-neurotic syndrome (48 patients, 75.00%) the most often among patients with SLE with pathogenetically associated syntropic comorbid chronic pancreatitis. Almost half had signs of dyspepsia (31 patients, 48.44%), and a third had exocrine insufficiency syndrome (23 patients, 35.94%) and pain syndrome (17 patients, 26.56%). Syndrome of internal secretion insufficiency, inflammatory and enzymatic intoxication and compression of surrounding organs was not detected (0.00%).

Thus, the vast majority of the patients with SLE and pathogenetically associated syntropic comorbid steatohepatitis have clinical and laboratory mesenchymal-inflammatory syndrome and almost three quarters - the syndrome of hepatocellular insufficiency. All patients with SLE and pathogenetically associated syntropic comorbid autoimmune hepatitis have clinical and laboratory mesenchymal-inflammatory syndrome, and more than half of patients have syndromes of hepatocellular insufficiency and cytolysis. Three-quarters of patients with SLE and pathogenetically associated syntropic comorbid chronic pancreatitis have astheno-neurotic clinical syndrome and almost every second have dyspepsia.

The third stage of the study

The results of the first step of this phase of the study, which is devoted to elucidating the prevalence of syntropic comorbid lesions of the digestive system pathogenetically associated with SLE depending on sex, are shown in Table 5.

Table 5. Features of the spread of syntropic comorbid lesions of the digestive system depending on the sex of patients with systemic lupus erythematosus (n; %; p). Note * - statistically confirmed difference with the number of cases in women (p <0,05).

No.	Lesions of the digestive system	Patients with SLE
		Women, n = 331		Men, n = 39
		n	%	n	%
1	Steatohepatitis	45	13.60	6	15.39
2	Autoimmune hepatitis	30	9.09	1	2.56
3	Chronic pancreatitis	52	15.76	12	30.77*

The frequency of steatohepatitis is almost the same in both women and men (13.60% of women vs. 15.39% of men). Although autoimmune hepatitis was diagnosed more often in women than in men (9.09% vs. 2.56%, respectively), there was no statistically significant difference between the prevalence. Only chronic pancreatitis was significantly less common in women than in men (15.76% in women versus 30.77% in men).

The results obtained by us indicate that in patients with SLE syntropic comorbid chronic pancreatitis associated with it pathogenetically is less common in women than in men. And such associated syntropic comorbid lesions of the digestive system as autoimmune hepatitis and steatohepatitis do not depend on the sex of the patient.

The results of the second step of this phase of the study, which is devoted to determining the frequency of pathogenetically associated with SLE syntropic comorbid lesions of the digestive system depending on the age of the patient, are shown in table 6.

Table 6. Features of the prevalence of syntropic comorbid lesions of the digestive system depending on the age of patients with systemic lupus erythematosus (n; %; p). Notes: * - statistically confirmed difference with the number of cases of lesions in patients at a young age I (p <0,05); # - statistically confirmed difference with the number of cases of lesions in patients at a young age II (p <0,05); ^ - statistically confirmed difference with the number of cases in middle-aged patients (p <0,05).

No.	Lesions of the digestive system	Patients with SLE
		At a young age, n = 204				Middle-aged, n = 153		Elderly, n = 13
		At a young age І, n = 42		At a young age ІІ, n = 162
		n	%	n	%	n	%	n	%
1	Steatohepatitis	1	2.38	25*	15.29	25*	16.34	0	0.00
2	Autoimmune hepatitis	6	14.29	10*	6.17	10*	6.58	5*#^	38.46
3	Chronic pancreatitis	0	0.00	16	9.88	42	27.63	6#	46.15

According to the information presented in Table 6, steatohepatitis was more common among young patients II and middle-aged patients (25 cases (15.29%) and 25 cases (16.34%), respectively). This is significantly more than among young patients I (one case, 2.38%). No case (0.00%) of steatohepatitis was detected in elderly patients.

Autoimmune hepatitis is significantly more common in the elderly - in 38.46% of patients in this age group. The lowest number of cases of autoimmune hepatitis was diagnosed in young and middle-aged patients (ten cases each (6.17% and 6.58%, respectively)). Six cases of this liver lesion were found in young patients I (14.29% of patients in this age group), which is significantly more than among young patients II and middle-aged, and significantly less than among elderly patients.

Almost half of elderly patients were diagnosed with chronic pancreatitis (six cases, 46.15%). This is significantly more than in young patients II (16 cases, 9.88%) and slightly more than in middle-aged patients (42 cases, 27.63%). In patients of young age I (from 18 to 29 years) we did not find any case of chronic pancreatitis (0.00%).

According to our information, it can be stated that steatohepatitis is more common in young patients II (25-44 years) and middle-aged (45-59 years), and autoimmune hepatitis and chronic pancreatitis - in elderly patients (60-74 years).

The results of the third step of this stage of the study, which is devoted to elucidation of the frequency of pathogenetically associated with SLE syntropic comorbid lesions of the digestive system depending on the duration of the underlying disease, are shown in table 7

Table 7. Features of the spread of syntropic comorbid lesions of the digestive system depending on the duration of systemic lupus erythematosus (n; %; p). Notes: * - statistically confirmed difference with the number of cases in patients with systemic lupus erythematosus lasting less than 1 year (p <0.05); # - statistically confirmed difference with the number of cases in patients with systemic lupus erythematosus lasting 1-5 years (p <0.05); ^ - statistically confirmed difference with the number of cases in patients with systemic lupus erythematosus lasting 6-10 years (p <0,05).

No.	Lesions of the digestive system	Duration of SLE
		Less than 1 year, n = 21		1-5 years, n = 133		6-10 years, n = 78		More than 10 years, n = 138
		n	%	n	%	n	%	n	%
1	Steatohepatitis	0	0,00	19*	14.29	11*	14.10	21*	15.22
2	Autoimmune hepatitis	2	9.52	5	3.76	2	2.56	22#^ ?	15.94
3	Chronic pancreatitis	0	0.00	26*	19.55	20*	25.64	18*^	13.04

According to the information in table 7, steatohepatitis occurs with almost the same frequency in patients whose SLE lasts 1-5 years (19 cases, 14.29%), 6-10 years (eleven cases, 14.10%) and more than 10 years (21 cases, 15.22%). No cases of steatohepatitis have been reported in patients with SLE lasting less than a year.

Autoimmune hepatitis is the most common in patients with SLE lasting more than 10 years (22 cases, 15.94%), which is significantly more common than in patients with SLE lasting less than one year (two cases, 9.52%), 1-5 years (five cases, 3.76%) and 6-10 years (two cases, 2.56%).

Chronic pancreatitis was the most often diagnosed in patients whose SLE lasted 6-10 years (20 cases, 25.64%). Slightly fewer cases of pancreatic lesions were found in patients with SLE who were ill for 1-5 years (26 cases, 19.55%) and more than 10 years (18 cases, 13.04%). Among patients with a duration of SLE less than a year, chronic pancreatitis is not diagnosed.

Thus, autoimmune hepatitis is the most common in patients with the longest duration of SLE (more than 10 years), and steatohepatitis and chronic pancreatitis do not occur in patients with a disease duration of less than a year.

The results obtained by us indicate certain features of the prevalence of pathogenetically associated with SLE syntropic comorbid lesions of the digestive system depending on sex, age and duration of the disease, namely - steatohepatitis is mainly in patients aged 25 to 59 years (young II and middle-aged) and it’s not diagnosed in patients with SLE with a disease duration of up to one year. Autoimmune hepatitis - mainly in the elderly and in those patients with SLE lasting more than ten years. Chronic pancreatitis - significantly less often in women, most often in almost half of elderly patients. It is absent in patients whose SLE lasts up to a year, and is most often diagnosed in patients with a disease duration of 6-10 years.

Conclusion

Lesions of the digestive system occur in 60.81% of patients with systemic lupus erythematosus, and the most common among them are toxic hepatitis (18.69%), chronic pancreatitis (17.34%), chronic gastritis (14.09 %) and steatohepatitis (in 13.78%). The frequency of steatohepatitis, autoimmune hepatitis and chronic pancreatitis, which occur in 13.78%, 8.40% and 17.34%, respectively, increases with increasing activity of systemic lupus erythematosus, which gives grounds to treat them as pathogenetically associated with it, and therefore as syntropic comorbid lesions;

in all patients with systemic lupus erythematosus with syntropic comorbid steatohepatitis the mesenchymal-inflammatory syndrome occurs in the vast majority and almost three quarters of the syndrome of hepatocellular insufficiency; with autoimmune hepatitis - clinical and laboratory mesenchymal-inflammatory syndrome, and more than half of patients - syndromes of hepatocellular insufficiency and cytolysis; three-quarters of patients with syntropic comorbid chronic pancreatitis have astheno-neurotic clinical syndrome and almost one in two has dyspepsia;

autoimmune hepatitis is more common in the elderly and in patients with systemic lupus erythematosus lasting more than ten years, steatohepatitis - mainly in patients aged 25 to 59 years (young II and middle-aged) and is not diagnosed in patients with SLE with the disease lasts up to one year, and chronic pancreatitis is significantly less common in women, most often in almost half of elderly patients. It is absent in patients whose disease lasts up to a year, and is most often diagnosed in patients with a duration of six to ten years.