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Association of Helicobacter pylori Infection with Systemic Lupus Erythematosus

Objective: Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology. However, a complex combination of host and environmental factors are believed to play a pivotal role. In the pathogenesis of SLE, several infectious agents have been held responsible such as Cytomegalovirus, Parvovirus B19, Epstein Barr virus and Retrovirus. There is a variable relationship between SLE and Helicobacter, which is different from that of lupus and other infections. The aim of this study was to investigate the association between Helicobacter pylori (H.pylori) infection and SLE development. Method: In this study, 82 serum samples and 65 stool samples were collected from the SLE patients as well as the control group, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to detect the presence of specific IgG/IgM antibodies against H.pylori in all serum samples. The presence of H.pylori antigen was examined in all stool samples by using stool antigen test. Suitable statistical analysis was applied. Results: Thirteen (15.9%) out of 82 SLE patients and 30 (36.6%) out of 82 control group were anti-H.pylori IgM seropositive. There was a significant difference between the level of IgM in SLE patients and control group (p<0.05). Anti-H.pylori IgG antibodies were present in 37 (45.1%) of SLE patients and in 41 (50%) of the control group without any significant difference. Regarding stool antigen examination, there were 24 (36.9%) and 26 (42/6%) positive samples among the SLE patients and control group, respectively. There was no significant difference between the patients and controls samples in the number of stool antigen test positive samples (p>0.05). Conclusions: Based on data obtained in this study, it is concluded that there was a significant difference between the number of IgM seropositive in SLE patients and control group, which shows that SLE disease may have an inhibitory role in H.pylori infection occurance.


Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can affect any organ of the body including the skin, mucous membranes, joints, kidneys, blood and brain [1][2][3][4][5][6][7]. SLE is the perfect model of autoimmune disorder, begin from innate immunity to adaptive immunity and leading to loss of self-tolerance [8,9]. The exact etiology of SLE is unknown, however, several genetic and environmental factors might have a role [3,10,11]. Epidemiologic studies showed variations in the prevalence and course of SLE between genders, different ages, races and geographic locations [7,12]. The incidence of SLE is estimated to be about 5 per 100,000 people per year with a prevalence of 40 to 80 per 100,000 [8]. Women are more frequently affected than men, with a sex ratio of approximately 9:1 between the ages of 15-45 years [1,3,12,13]. The disease is more common in Native American, African-American, Asian and Hispanic descent [2,14].
H.pylori is a gram-negative, spiral-shaped, flagellated and microaerophilic bacterium that colonizes the human gastric mucosa [19][20][21][22]. H.pylori infection is one of the most usual bacterial infections in humans. H.pylori infection is usually acquired in early childhood and continues life-long in the lack of medicine treatment [21][22][23]. H.pylori and humans have a lengthy period of coevolution, as long as human migration out of Africa about 60,000 years ago [24]. The prevalence of H.pylori infection differs broadly by geographic area, age, race, and socioeconomic status [19,22,25]. The overall prevalence of this bacterium is as high as 80% in many developing countries to 20-50% in industrialized countries [26]. H.pylori infection not only causes a several of gastrointestinal diseases including peptic ulcers, noncardia gastric adenocarcinoma and gastric mucosa associated lymphoid tissue (MALT) lymphoma, but also plays a role in the pathogenesis of various autoimmune disorders such as idiopathic thrombocytopenic purpura, rheumatoid arthritis (RA), autoimmune gastric atrophy, Sjogrenˊs syndrome and autoimmune thyroiditis [17,27]. This extended coexistence of H.pylori in humans may be in part beneficial to humans. Because, in some instances, there is some   There are several methods for the diagnosis of H.pylori, each with its own benefits, weaknesses and limitations [29]. Invasive techniques based on gastric specimens for histology, culture and a rapid urease test, and non-invasive techniques based on peripheral samples, such as blood, stools, urine, saliva or breath samples, for detection of bacterial antigens, antibodies or urease activity are used to diagnosis of H.pylori infection [22,30,31]. In this study, in order to investigate the possible association between H.pylori infection and the development of SLE, the prevalence of H.pylori Infection in SLE patients compared with the healthy individuals was evaluated.

Patients and controls
Eighty-two SLE patients (76 females and 6 males) who fulfilled American college of rheumatology revised criteria for the classification of SLE were followed up at Rheumatology Clinic affiliated to Isfahan University of Medical Sciences [32]. The demographic data such as age; gender; education; age at the SLE onset; duration of disease; history of gastrointestinal disease and previous administration of anti-H.pylori medication were recorded. Disease activity was determined by the SLE disease activity index (SLEDAI-2k) [33]. In addition, eighty-two healthy subjects (77 females and 5 males) of matched gender were used as healthy control group. Sera of all patients and controls were obtained and stored at -20°C. Also, stool specimens at the same time with serum specimens were collected from 65 patients and controls in sterile containers and kept at -70°C.

Statistical analysis
All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 20). The prevalence of H.pylori infection among groups was compared by chi-square testing. Quantitative data were compared by student's t-test and described as mean ± SD. A p value of <0.05 was considered to be statistically significant for all data analyses.
Anti-H.pylori IgG antibodies were detected in 37 (45.1%) of SLE patients and in 41 (50%) of healthy controls. There was no significant difference between the patients and controls in the number of anti-H.pylori IgG seropositive samples (p=0.53). In addition, 13 (15.9%) of SLE patients and 30 (36.6%) of the control group were seropositive for anti-H.pylori IgM antibodies. Therefore, anti-H.pylori IgM seropositivity was found significantly higher in the control group than SLE patients (p=0.003). Regarding stool antigen test, there were 24 (36.9%) H.pylori positive samples among the 65 of SLE patients and 26 (42/6%) among the 61 of healthy controls which showed no statistically significant difference between two groups (p=0.58). In general, 3 (4.6%) of SLE patients and 10 (15.3%) of the control group were positive for anti-H.pylori IgM and IgG antibodies and stool antigen test. Results are shown in Table 1.
We investigated the possible associations of mean age of SLE onset, an average of disease duration, the frequency of lupus manifestations, history of gastrointestinal disease, used prescribed medications for H.pylori infection and used antibiotics between the SLE patients infected with H.pylori and H.pylori negative SLE patients. It was shown that there was no significant difference between both groups for all the above-mentioned factors (p>0.05). (Tables 2 and 3)

Discussion
Autoimmune diseases affect 5-10% of the general population and are a significant cause of morbidity and mortality worldwide [26]. The cause of these diseases such as SLE is unknown; although it might be resulted from the interaction between environmental and host factors [15]. The association between infection and autoimmune diseases over the last twenty years has been increasingly supposed [16,27]. Several infectious agents such as Cytomegalovirus, Parvovirus B19, Epstein Barr virus and Retrovirus, might play a major role in the pathogenesis of SLE [18,34]. However, there is a different relationship between SLE and Helicobacter, from that of other infections. Amongst bacteria, H.pylori seems to play a pathogenetic role in autoimmune diseases such as autoimmune gastritis, Sjögren's syndrome, atherosclerosis, immune thrombocytopenia purpura, inflammatory bowel diseases and autoimmune pancreatitis [15,17,27]. Also, H.pylori might have a protective role in allergic disorders [7,28], inflammatory bowel disease [35], asthma [36], immune thrombocytopenic purpura [37] and multiple sclerosis [38].
Fewer studies have conducted in order to understand a correlation between H.pylori infection and SLE. In an animal study, it was found that exposure to H.pylori urease can lead to production of anti-single stranded DNA antibodies [39]. Kalabay and colleagues studied the prevalence of anti-H.pylori antibodies in various autoimmune rheumatic diseases and they found the comparable prevalence of H.pylori in SLE patients and healthy controls [40]. Showji et al. showed that the titers of anti-H.pylori antibodies were lower in SLE than other autoimmune diseases [41]. In another study, Sawalha et [42]. The authors suggest that exposure to H.pylori may oer some protective benefit against developing SLE in this specific population. In the current study, our data showed no significant difference between the number of positive samples of anti-H.pylori IgG and stool antigen among SLE patients and healthy controls.
These studies have some limitations but nevertheless, all of them showed a negative relationship between SLE and H.pylori infection.
This difference might be resulted from the study population, diversity in the prevalence of H.pylori infection in the different part of the world and laboratory methods which applied to detective it.
In conclusion, our study shows that patients with SLE had a lower prevalence of acute H.pylori infection than healthy controls and there was a negative association between H.pylori infection and SLE. Based on obtained data, it could be concluded that SLE disease might have an inhibitory role in H.pylori infection occurrence. More studies are required to elucidate the possible association between the H.pylori infection and SLE.