{'fraction_non_alphanumeric': 0.03980152027027027, 'fraction_numerical': 0.023331925675675675, 'mean_word_length': 4.710066305003014, 'pattern_counts': {'":': 0, '<': 4, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Association between Helicobacter pylori infection and Sjögren syndrome

Supplemental Digital Content is available in the text


Introduction
Helicobacter pylori is a widely prevalent bacterium, and its infection rate in population ranges from 28.3% to 98.6% in different areas over the world, which is especially higher in less developed countries. [1] Helicobacter pylori has been proved to be a risk factor of many diseases, including not only some gastrointestinal-related diseases like chronic atrophic gastritis, [2] gastric mucosa-associated lymphoid tissue (MALT) lymphoma, [3] peptic ulcer disease, [4] but also other systemic diseases like immune thrombocytopenic purpura, [5] and diabetes mellitus. [6] As a systemic autoimmune disease, Sjögren syndrome (SS) was reported to have a link with H. pylori infection by some researchers, [7][8][9][10] which characterized by lymphocytic infiltration and destruction of exocrine glands. [11] This phenomenon may result from bacterial induced autoimmune response, and H. pylori is one of commonly known infectious factors that trigger the autoimmune reactions. However, some studies found there were no significant differences of H. pylori infection rate between SS and control group. [12][13][14][15][16] Therefore, whether H. pylori infection is a risk factor of SS remains controversial.
We performed this meta-analysis to have a better understanding of whether the relation between H. pylori and SS existed. The association between the 2 diseases may be of great value for patients with SS with gastrointestinal diseases to receive more reasonable treatment.   European criteria, [34] 2002 + Ram et al [12] 2013 Latin America ELISA (H. pylori IgG) Serum 66/82 113/140 European criteria, [34] 2002 À ELISA = enzyme-linked immunosorbent assay, H. pylori = Helicobacter pylori, pSS = primary Sjögren syndrome, SS = Sjögren syndrome, sSS = secondary Sjögren syndrome.

Data extraction
Data extraction was conducted by the 2 authors (CQQ and XYZ) independently. We reviewed and collected the information including the 1st author(s), year of publication, country or area of study, study design type, way of diagnosis, amount of study subjects, population of H. pylori infection in SS and control group from the selected studies. We only included 1 study if the same raw data were published in different studies. The raw data of ELISA would be collected if the study contained more than 1 detection method.

Statistical analysis
We used Chi-squared test and I 2 test to measure the heterogeneity among studies. There was no significant heterogeneity in this study when P > .1 and I 2 < 50%. The Mantel-Haenszel fixedeffects model was applied to evaluate odds ratio (OR) and 95% confidence interval (CI) in this meta-analysis if heterogeneity was no significant, or a random-effect model was applied. [17] Publication bias was assessed by using funnel plots as a qualitative analysis, Egger linear regression test (Egger test) and Begg rank correlation test (Begg test) as quantitative analysis. [18,19] P-values <.05 of all tests in this article were statistically significant. We conducted statistical analysis with the STATA 12.0 (2000; STATA Corp, College Station, TX). No approval of ethics was needed because all studies included in this meta-analysis were published previously.

Characteristics of the studies
We totally included 9 studies which met the criteria in this metaanalysis.

Subgroup analysis
We found a small but significantly higher H. pylori infection rate in patients with SS than that in controls from the forest plot ( Fig. 1) of overall meta-analysis (OR 1.19, 95% CI 1.01-1.41, P = .033 < .05). Though the heterogeneity was low (I 2 = 0), subgroup analysis was made since there are 2 different types of SS (pSS and secondary SS). We excluded 2 literatures where the type of SS was unclear. The association still existed in patients with pSS according to the forest plot, in which OR was 1.24, 95% CI 1.03-1.50, P = .026 < .05 (Fig. 2). The patients with pSS had a more likely higher H. pylori infection rate than controls. However, no significant difference was found when comparing secondary SS (sSS) with controls after analysis of 3 literatures with mentioned sSS population (OR 1.24, 95% CI 0.87-1.76, P = .238) (Fig. 3) We also conducted a subgroup analysis according to the different detection ways of H. pylori infection.
The patients with SS had a higher H. pylori infection rate than controls by using ELISA to confirm infection (OR 1.22, 95% CI 1.03-1.44, P = .024) (Fig. 4). The other 2 studies did not show significantly difference between SS and controls with tissues biopsy conformation.

Evaluation of publication bias
From the funnel plot, we found no publication bias (Fig. 5) Fig. 7]).

Discussion
We found a small but significant higher H. pylori infection in SS than controls from this meta-analysis. As we know, it was the 1st meta-analysis about the association between H. pylori and SS. Some assumptions were proposed to explain this association. Firstly, H. pylori infection has been proved to play an important role in the pathogenesis of many autoimmunity diseases, and similar mechanisms may also exist in SS. As antigens, H. pylori or other microbes induce immune response in human body. Some investigators found a heat shock protein of 60 kDa (HSP60) produced by H. pylori induced the activation of human lymphocytes by molecular mimicry as a component of H. pylori antigens, which could damage the immunologic tolerance of human body because of the protein's homology between human and microbes. [10,20] The significant higher prevalence rate of anti-HSP60 in patients with SS reported by Aragona et al [10] might demonstrate the role of HSP60 in the pathogenesis of SS. The correlation between H. pylori and SS may provide a new explanation of many interesting phenomena occurring in patients with SS clinically and histologically. It was reported that patients     with SS have more possibilities of chronic gastritis, [21] which H. pylori infection has been widely considered as a main causative factor. [2] Moreover, the histologic manifestation of lymphocytic infiltration in gastric mucosa is similar to salivary glands in patients with SS. [22] Researchers tried most to explain the fact that patients with SS had a higher risk of development to lymphoma, and most of lymphoma following SS are MALT lymphoma. [23] As is well known, gastric MALT lymphoma is strongly correlated with H. pylori infection, [24] and eradication therapy will induce regression of the lymphoma. [25] Although the MALT lymphoma along with SS was mainly found in silvery glands [26] as a result of routine salivary glands biopsy for diagnosis according to the SS classification criteria, [27] regression of lymphoma was actually found after these patients with SS with gastric H. pylori infection received eradication therapy in some case reports. [28,29] Based on the results of our above study, it is likely that H. pylori infection would be a risk factor of SS-associated MALT lymphoma. H. pylori eradication might be effective as a prevention of lymphoma in patients with SS. More studies are needed to be conducted in this area.

Type of SS
In this meta-analysis, we found a significant higher H. pylori infection rate in patients with pSS than controls but nonsignificant in patients with sSS. Due to the lack of data or obfuscation of SS type, only three selected studies with 104 patients were included in sSS group analysis, while seven studies with 423 patients in pSS group. The unneglected gap of population may affect the meta-analysis results of sSS between pSS and sSS. Also, the components difference of primary diseases per se was possible to contribute to the different results though the association between these primary diseases (mainly other autoimmune diseases) and H. pylori are inconclusive. [20] 4.2. Ways of H. pylori testing There were significant differences between SS group and controls by serologic test but such difference did not exist by tissue biopsy in our subgroup analysis. As only 2 studies were included, it was reasonable to believe that the difference was a result of small number of samples. Although serologic test was considered highly accurate and specific in the recent guidelines, [30] the 13 C-UBT was regarded as the best recommended noninvasive way to diagnose H. pylori infection in recent guidelines. [30] However, none of the studies included in this meta-analysis used 13 C-UBT to confirm H. pylori infection. Therefore, it is necessary to conduct studies by 13 C-UBT to compare results among different methods of detection.

Limitations of the study
Firstly, the number of selected studies or participants was relatively small. Secondly, the diagnostic criteria of SS varied in details because of unavoidable limitation of areas and times. [31][32][33][34] Thirdly, the control groups were selected differently across studies included. Fourthly, geographical and socioeconomic difference in H. pylori infection may have an impact on the results. Lastly, exclusion of non-English in the meta-analysis could lead to statistically bias.

Conclusion
This meta-analysis was the 1st meta-analysis about the association between H. pylori and SS. And the pooled data suggested a significantly higher H. pylori infection rate in patients with SS. More prospective or multicenter retrospective researches could be conducted in the future.