Toxoplasmosis is a cosmopolitan infection caused by an intracellular obligatory protozoan, Toxoplasma gondii. Infection to this parasite in immunocompetent patients is usually asymptomatic, but today it is believed that the infection can be a risk factor for a variety of diseases, including rheumatoid arthritis (RA). RA is an autoimmune disease and the most common type of inflammatory arthritis that is a major cause of disability. The aim of this systematic review and meta-analysis was to address the association between RA and toxoplasmosis in light of the available research. Based on the keywords, a systematic search of eight databases was conducted to retrieve the relevant English-language articles. Then, the studies were screened based on the inclusion and exclusion criteria. The random effect model was used to calculate the odds ratio (OR) using forest plot with 95% confidence interval (CI). Overall, 4168 Individual, extracted from 9 articles were included for systematic review evaluation, with 1369 RA patients (46% positive toxoplasmosis) and 2799 individuals as controls (21% positive toxoplasmosis). Then, eight articles (10 datasets) were used for meta-analysis (1244 rheumatoid arthritis patients and 2799 controls). By random effect model, the combined OR was 3. 30 (95% CI: 2. 05 to 5. 30) with P < 0. 0001. Although toxoplasmosis could be considered as a potential risk factor for rheumatoid arthritis, more and better quality studies are needed to determine the effect of T. gondii infection on induction or exacerbation of RA. Our study was registered at the International Prospective Register of Systematic Reviews (PROSPERO; code: CRD42017069384).
Toxoplasmosis is a parasitic disease with worldwide distribution caused by obligate intracellular coccidian protozoan Toxoplasma gondii (T. gondii) [1]. It is estimated that one-third of the world’s population are infected with this parasite in both developed and developing countries [2,3]. Humans can be infected with the parasite through different routes, including consumption of raw or undercooked meat containing tissue cysts of the parasite, ingestion of sporulated oocysts from contaminated water and food, and vertical transmission during pregnancy through the placenta to the fetus [4]. T. gondii remains in the infected host tissues perpetually [5]. Most immunocompetent individuals, if infected with this parasite, are asymptomatic or show minor symptoms [6]. The most common symptom of toxoplasmosis in humans is lymphadenopathy that may be associated with fever, sore throat, muscle pain, fatigue, and headache [4]. In congenitally infected and immunocompromised patients, this disease is more likely to bring about severe complications [7]. Myocarditis and polymyositis have been reported in immunocompetent individuals with acute toxoplasmosis [8]. Furthermore, toxoplasmosis may cause polyarthritis in the hand and knee joints [9]. Polytenosynovitis (inflammation of a tendon sheath) caused by T. gondii has also been reported [10]. Rheumatoid arthritis (RA) is a common autoimmune disease, which is a major cause of inflammation of the joints and the principal cause of disability that affects 0. 5–1% of the population [11,12]. The disease presents with swollen joints, production of autoantibodies (rheumatoid factor), and systemic effects [13]. In recent years, the role of infectious agents, especially bacteria and viruses, has been identified in the pathogenesis of autoimmune diseases, while the role of parasitic infections due to their vague effects on host immunity has not been well-investigated. Experimental evidence may support the protective effect of specific parasitic infections in the susceptibility to autoimmunity [14]. Some geoepidemiological studies showed that host genetic susceptibility interacts with lifestyle and environmental factors, such as socioeconomic status, dietary habits, environmental pollutants, and ultraviolet radiation exposure; further, infections increase the risk of developing autoimmunity [15]. On the other hand, infectious diseases may contribute to the development of autoimmune diseases through molecular mimicry and epitope spreading [16]. Therefore, the aim of this systematic review and meta-analysis was to provide an updated review of data about the relationship between toxoplasmosis and RA.
This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and its checklist [17]. Individuals with RA, along with a control group, were surveyed. To begin, we searched scientific databases for all the articles on the association between toxoplasmosis and RA published up to the first of January 2018. These keywords were used alone or in combination: “Toxoplasma gondii”, “toxoplasmosis”, “seroprevalence”, “prevalence”, “rheumatoid arthritis”, “rheumatoid factor”, “meta-analysis”, and “systematic review”. A literature review was carried out using English databases including “PubMed”, “Google Scholar”, “Science Direct”, “Scopus”, “Web of Science”, “EMBASE”, “CINAHL”, and “ProQuest”. The systematic search of articles was conducted from March 4 to December 31,2017 by two researchers independently. Also, for completing the checklist, we investigated all the references lists of the selected articles manually. In this study, only English-language articles were analyzed; furthermore, unpublished studies were not evaluated. After completing the search, the selected articles were reviewed by the two researchers independently. All the duplicate and irrelevant studies were excluded after reviewing the title, abstract, and full text of the articles. Moreover, to prevent reprint bias, the results of the articles were carefully investigated and duplicates were omitted. In order to assess the quality of reporting of the studies, standard Strengthening the Reporting of Observational Studies in Epidemiology checklist (STROBE) was used [18]. S1 Checklist represents the quality score of different eligible studies. This checklist included items assessing the study methodology, study type, study population, sample size, sample collection methods, statistical tests, and presentations. In our study, articles were evaluated based on STROBE assessment (low quality: less than 16. 5, moderate quality: 16. 6–25. 5, and high quality: 25. 6–34). The articles we entered in our meta-analysis had acceptable quality. Abstracts and full texts were assessed independently by the two researchers using a piloted form. The final decisions about the eligibility or exclusion of studies were made separately. Disagreements were resolved with provision for arbitration from a third reviewer. Following the removal of duplicate entries, articles were evaluated according to the following criteria: (1) cohort or case-control studies about the relationship between toxoplasmosis as an exposure and rheumatoid arthritis as a disease, (2) the studies conducted only on humans, (3) the presence of case and control groups, (4) the studies where toxoplasmosis was diagnosed by detecting IgG and/or IgM antibodies against T. gondii in individuals with definitive diagnosis of RA, and (5) the studies providing details on the seroprevalence rate of toxoplasmosis and RA. The exclusion criteria comprised: (1) studies that were only descriptive, (2) studies that only presented the final result and did not provide the raw data, (3) articles that were not available in English language, and (4) the studies conducted on animals. Articles were carefully studied and the following data were extracted: first author, year of publication, the number of patients and controls, the number and percentage of the positive and negative cases of serum IgG and IgM in patients and controls, as well as information about age and gender and laboratory results. In studies where two different populations were studied, data were extracted separately. The meta-analysis was executed with the Stats Direct statistical software (http: //statsdirect. com). For displaying the heterogeneity between studies, χ2-based Cochrane test (Q) and I2 index were applied [19]. Due to significant heterogeneity between the studies, a random effect model was used to combine the results of the studies. Forest plot was used to indicate the prevalence of toxoplasmosis in each study and to determine pooled estimate prevalence in the studies. Odds ratios (ORs) and 95% confidence intervals (CI) were used for estimating the risk of T. gondii infection (the significance of P<0. 05). OR > 1 indicates the positive effect of Toxoplasma on RA and an OR < 1 shows that toxoplasmosis has a protective effect against RA. Publication bias was examined by funnel plots and the statistical significance was assessed by the Egger test [20]. Also, it was performed a sensitivity analysis to identify probably effect of each article on the overall results by excluding them using Stata version 14 (Stata Corp, College Station, TX, USA). The study protocol (CRD42017069384) was registered on the website of the International Prospective Register of Systematic Reviews (PROSPERO) [21].
Our preliminary search of eight databases yielded 8234 papers. After a primary screening of the titles of the articles based on keywords, 124 studies were extracted. Sixty-five articles were also excluded from the study due to duplication. In the next step, by screening the abstracts of the articles and based on the inclusion/exclusion criteria, 43 other articles were excluded. After reading the full text of the articles, 10 other papers were omitted, and three studies were added to the collection after reviewing the references. After the final review of the articles, nine eligible studies [14,16,22–28] were identified for systematic review. Another study was excluded due to the absence of a healthy control group [16]. Finally, eight of these nine articles [14,22–28] were entered into the meta-analysis with respect to the inclusion/exclusion criteria (Fig 1). The studied articles were published between 2007 and 2017. We identified 11 datasets from the nine articles that met the inclusion criteria, eight of which were case-control, two cross-sectional, and one were cohort studies (Table 1). The surveys were conducted in Latin America [14], Europe [14,16], Egypt [24,25], Iraq [22,23,27], Czech and Slovak [26], and China [28]. Our meta-analysis was performed among 4168 people including 1369 RA patients and 2799 controls. In all the studies, blood samples were collected from patients and controls. To identify anti-Toxoplasma antibodies (IgG and IgM) in those studies, ELISA [22–24,26–28], CFT [26], EIA [25], chemiluminescence [16], and BioPlex 2200 system [14] were used (Table 1). Except for Fischer et al. [16], who only evaluated IgG, other authors surveyed both IgG and IgM antibodies. However, only three studies had reported a titer of antibodies [23–25], and others had described the percentage of positive antibodies in patients and controls. Finally, all the studies analyzed the relationship between toxoplasmosis and RA with respect to the percentage of seropositive and seronegative individuals (patients and controls). As shown in Fig 2, the prevalence of toxoplasmosis in RA patients in these studies varied from 25% to 77% with an overall seroprevalence of 46% (95% CI [37; 56]). However, the total prevalence of this disease in the control subjects entered in these studies was 21% (95% CI [14; 28]), which varied from 0% to 48% in various studies (Fig 3). According to Fig 4, the odds of toxoplasmosis in RA patients are 3. 30 times compared to that of controls with 95% CI: 2. 05 to 5. 30 and P < 0. 0001. Nonetheless, the heterogeneity analysis of the effect size of arthritis (Q = 32. 77, P = 0. 0001, I2 = 72. 5%) showed a relatively high heterogeneity in our meta-analysis. Begg and Egger tests were used to evaluate publication bias. Negligible publication bias was observed using both Begg test (P = 0. 0286) and Egger test (P = 0. 0446) in the included studies. The results of sensitivity analysis showed that the impact of each study on meta-analysis was not significant on overall estimates (Fig 5).
One of the most important achievements of our study is that although T. gondii infection affects about one-third of the world’s population and possibly causes and exacerbates the symptoms of RA, only few studies have addressed this subject. These studies were conducted only in Latin America, Europe, and few regions of Asia and Africa. Accordingly, further studies are needed to achieve accurate results from other parts of the world. Also, further studies will be necessary to clarify the pathogenesis of T. gondii in humans to understand whether T. gondii is a cofactor in the development of autoimmune diseases.
Toxoplasma gondii is an intracellular obligatory protozoan, which causes toxoplasmosis. T. gondii infection in immunocompetent individuals is mostly asymptomatic, but it may be reactivated as a result of immune disorders inducing serious complications. Rheumatoid arthritis (RA), as a complex autoimmune disease, is a major cause of significant and progressive disability, articular complications, and premature death. Studies confirmed an interaction between infections and environmental factors as the potential risk or protective factors determining the development of autoimmune diseases. In this study, we investigated the association between toxoplasmosis and RA.
rheumatology
medicine and health sciences
enzyme-linked immunoassays
toxoplasma gondii
immunology
parasitic diseases
parasitic protozoans
rheumatoid arthritis
clinical medicine
protozoans
mathematics
toxoplasma
statistics (mathematics)
immunologic techniques
research and analysis methods
mathematical and statistical techniques
arthritis
immunoassays
protozoan infections
research assessment
toxoplasmosis
eukaryota
clinical immunology
meta-analysis
systematic reviews
autoimmune diseases
biology and life sciences
physical sciences
statistical methods
organisms
Toxoplasmosis seroprevalence in rheumatoid arthritis patients: A systematic review and meta-analysis