Infections Cause Reactive Arthritis

Identification of endogenously presented peptides from Chlamydia trachomatis with high homology to human proteins and to a natural self-ligand of HLA-B27.JJ Cragnolini, JA de Castro. Mol Cell Proteomics 2008 Jan;7(1):170-180. "Mass spectrometry-based comparative analysis of HLA-B27-bound peptide pools led to identification of three HLA-B27 ligands differentially presented in the transfectant cells. Sequencing of these peptides confirmed that they were derived from the bacterial DNA primase. One of them, spanning residues 211-221, showed 55% sequence identity with a known self-ligand of HLA-B27 derived from its own molecule. The other two bacterial ligands, P-(112-121) and P-(112-122), were derived from the same region and differed in length by one residue at the C terminus. Both peptides showed >50% identity with multiple human protein sequences that possessed the optimal peptide motifs for HLA-B27 binding."

Cragnolini / Mol Cell Proteomics 2008 full article

Short- and long-term effects of bacterial gastrointestinal infections. A Ternhag, A Törner, A Svensson, K Ekdahl, J Giesecke. Emerg Infect Dis 2008 Jan;14(1):143-148. "Within 1 year, we found an increased risk for reactive arthritis among patients with Yersinia enteritis (n = 5,133; SIR 47.0, 95% CI 21.5-89.2), Salmonella infection (SIR 18.2, 95% CI 12.0-26.5), and Campylobacter infection (SIR 6.3, 95% CI 3.5-10.4)."

Ternhag - Emerg Infect Dis 2008 full article / PubMed Central
Ternhag / Emerg Infect Dis 2008 full article

A comparison of self-reported joint symptoms following infection with different enteric pathogens: effect of HLA-B27. P Schiellerup, KA Krogfelt, H Locht. J Rheumatol 2008 Mar;35(3):480-487. 2105 patients with positive fecal culture. "[Reactive joint pain] was reported by 294 subjects: Campylobacter, 131 (13.1%); Salmonella, 104 (16.8%); Yersinia, 21 (23.1%); Shigella, 10 (9.8%); and E. coli, 28 (9.7%). There was a significant association between severity of gastroenteritis and development of arthralgia (p = 0.001). The odds ratio (OR) for JPrea in an HLA-B27-positive individual was 2.62 (95% CI 1.67-3.93) for the entire group. A significant association between JPrea and HLA-B27 was found for Salmonella, Shigella, and Yersinia; not, however, for Campylobacter and E. coli. HLA-B27-positive patients had a significantly increased risk for severe joint symptoms."

Schiellerup - J Rheumatol 2008 abstract / PubMed

Symptomatic acute reactive arthritis after an outbreak of salmonella. S Rohekar, FW Tsui, HW Tsui, N Xi, R Riarh, R Bilotta, RD Inman. J Rheumatol 2008 Aug;35(8):1599-1602. 592 acute gastroenteritis patients. "62.5% of respondents reported extraintestinal symptoms that were consistent with ReA. The most commonly reported features were joint pain, swelling or stiffness (46.2%), stiffness > 30 min (35.6%), ocular symptoms (24.0%), and visibly swollen joints (19.2%). Subjects with Salmonella infection had a similar incidence of HLA-B27, regardless of whether they developed symptoms consistent with ReA or not. Notably, HLA-B27 was present more frequently in those who developed Salmonella infection than in healthy controls (OR 3.0)."

Rohekar - J Rheumatol 2008 abstract / PubMed

Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study.JM Townes, AA Deodhar, ES Laine, K Smith, HE Krug, A Barkhuizen, ME Thompson, PR Cieslak, J Sobel. Ann Rheum Dis 2008 Dec;67(12):1689-1696. " A total of 6379 culture-confirmed infections were reported; 70% completed screening interviews. Of these, 575 (13%) developed possible ReA; incidence was highest following Campylobacter (2.1/100,000) and Salmonella (1.4/100,000) infections. Risk was greater for females (relative risk (RR) 1.5, 95% CI, 1.3 to 1.7), adults (RR 2.5, 95% CI, 2.0 to 3.1) and subjects with severe acute illness (eg, fever, chills, headache, persistent diarrhoea). Risk was not associated with antibiotic use or human leukocyte antigen (HLA)-B27. A total of 54 (66%) of 82 subjects examined had confirmed ReA. Enthesitis was the most frequent finding; arthritis was less common. The estimated incidence of ReA following culture-confirmed Campylobacter, E coli O157, Salmonella, Shigella and Yersinia infections in Oregon was 0.6-3.1 cases/100,000."

Townes - Ann Rheum Dis 2008 abstract / PubMed

Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis. JD Carter, HC Gérard, LR Espinoza, LR Ricca, J Valeriano, J Snelgrove, C Oszust, FB Vasey, AP Hudson. Arthritis Rheum 2009 May;60(5):1311-1316. 26 undifferentiated spondylarthritis patients, 167 osteoarthritis patient controls. "Sixteen of them (62%) were positive for C trachomatis and/or C pneumoniae DNA (10 for C trachomatis, 4 for C pneumoniae, and 2 for both). PCR analysis of ST revealed the presence of Chlamydia significantly more frequently in patients with uSpA than in OA controls (P<0.0001). No specific clinical characteristics differentiated Chlamydia-positive from Chlamydia-negative patients. PBMCs from 4 of the 26 uSpA patients (15%) were positive for Chlamydia, and Chlamydia was found in ST from 2 of these 4 patients."

Carter - Arthritis Rheum 2009 full article / PubMed Central
Carter / Arthritis Rheum 2009 full article

Prevalence of antibodies against Chlamydia trachomatis and incidence of C. trachomatis-induced reactive arthritis in an early arthritis series in Finland in 2000.E Savolainen, A Kettunen, A Närvänen, H Kautiainen, U Kärkkäinen, R Luosujärvi, O Kaipiainen-Seppänen. Scand J Rheumatol 2009;38(5):353-356. 122 patients, 78 adults without any joint symptoms. "Of 122 patients, with the baseline diagnosis of rheumatoid arthritis (RA) in 11, spondyloarthropathy (SpA) in 28, and undifferentiated arthritis (UA) in 83 cases, 42 (34%) showed immunoglobulin (Ig)G or IgA antibodies against at least one serotype C, E, or G. Among the patients with UA the prevalence was significantly increased compared with the controls (p = 0.010)."

Savolainen - Scand J Rheumatol 2009 abstract / PubMed

Endogenous processing and presentation of T-cell epitopes from Chlamydia trachomatis with relevance in HLA-B27-associated reactive arthritis. JJ Cragnolini, N García-Medel, JA de Castro. Mol Cell Proteomics 2009 Aug;8(8):1850-1859. "A predicted T-cell epitope, from the CT610 gene product, was presented by HLA-B27. This is, to our knowledge, the first endogenously processed epitope involved in HLA-B27-restricted responses against C. trachomatis in reactive arthritis. A second predicted epitope, from the CT634 gene product, was not detected. Instead a non-predicted nonamer from the same protein was identified. Both bacterial peptides showed very high homology with human sequences containing the HLA-B27 binding motif."

Cragnolini - Mol Cell Proteomics 2009 full article / PubMed Central
Cragnolini - Mol Cell Proteomics 2009 full article

Interferon-γ contributes to HLA-B27-associated unfolded protein response in spondyloarthropathies. Y Feng, J Ding, CM Fan, P Zhu. J Rheumatol 2012 Mar;39(3):574-582. "Tumor necrosis factor-α (TNF-α) and IFN-α, IFN-ß, and IFN-γ were found to have activated the HLA-B27 promoter in the U937 cell line (p < 0.05). Following stimulation with IFN-γ, the expressions of GRP78, CHOP and XBP-1 in HLA-B27-transfected U937 cells and PBMC of HLA-B27-positive AS patients were more intense than those in A2-U937 cells, HLA-B27-negative AS patients, or healthy controls (p < 0.05)."

Feng - J Rheumatol 2012 abstract / PubMed

Risk and prognosis of campylobacteriosis in relation to polymorphisms of host inflammatory cytokine genes. H Nielsen, R Steffensen, T Ejlertsen. Scand J Immunol 2012 Apr;75(4):449-454. 105 patients with Campylobacter jejuni/coli gastroenteritis. "After 6 months, RA had developed in 15 subjects and IBS in 20 subjects. RA was significant more frequent in patients with IL-18(-137G/G) (22%) than IL-18(-137C/C) (0%), P = 0.03, with INFG(+874 T/T (32%) than INFG(+874A/A) (0%), P = 0.007, and with INFG(+2197 A/A) (22%) than INFG(+2197G/G) (0%), P = 0.02. The development of IBS was not linked to gene polymorphisms."

Nielsen - Scand J Immunol 2012 abstract / PubMed

Phosphorylation of STAT-1 serine 727 is prolonged in HLA-B27-expressing human monocytic cells. M Ruuska, AS Sahlberg, K Granfors, MA Penttinen. PLoS One 2013;8(1):e50684. "We discovered that the phosphorylation of STAT-1 serine 727 is prolonged in cells expressing misfolding forms of HLA-B27 after S. enteritidis infection, whereas in mock cells and in cells expressing mutated, non-misfolding HLA-B27 the phosphorylation of serine 727 is transient. Interestingly, STAT-1 serine 727 phosphorylation is partly dependent on PKR. In addition, more STAT-1 is localized in the nucleus of HLA-B27-expressing cells, even before an external trigger, when compared to mock cells... This is of interest since the phosphorylation of serine 727 on STAT-1 is suggested to contribute to macrophage activation and promote inflammatory responses."

Ruuska - PLoS One 2013 full article / PubMed Cemtral
Ruuska / PLoS One 2013 full article

Identification of immunogenic HLA-B*27:05 binding peptides of salmonella outer membrane protein in patients with reactive arthritis and undifferentiated spondyloarthropathy.AK Singh, A Aggarwal, S Chaurasia, R Misra. J Rheumatol 2013 Feb;40(2):173-185. 23 patients with ReA/uSpA, 10 with rheumatoid arthritis (RA), and 10 healthy individuals. "Nineteen of 23 SFMC from ReA/uSpA showed a significant proliferative response to salmonella OMP, with minimal response of PBMC (1/10) from ReA/uSpA, SFMC from RA (1/10), or PBMC from controls (1/10). Nine salmonella OMP peptides... were identified. Response to QRAEMLPTL was seen in 6/7 HLA-B*27:05-positive patients. All immunogenic peptides had sequence similarity with peptides from arthritogenic bacterial proteins, while 5 had similarity with peptides from human proteins."

Singh - J Rheumatol 2013 abstract / PubMed

Reactive arthritis following Salmonella infection: a population-based study. R Tuompo, T Hannu, L Mattila, A Siitonen, M Leirisalo-Repo. Scand J Rheumatol 2013;42(3):196-202. 4.4% (22/496) had ReA and 13.7% (68/496) had other reactive musculoskeletal symptoms [tendinitis, enthesopathy, or bursitis (ReTe)]. 42% of patients with ReA were HLA-B27 positive. All 22 patients with ReA and all 68 patients with ReTe were in O antigen groups B, C, D1, or E.

Tuompo - Scand J Rheumatol 2013 abstract / PubMed

Normal inflammasome activation and low production of IL-23 by monocyte-derived macrophages from subjects with a history of reactive arthritis.E Välimäki, S Aittomäki, L Karenko, J Kantonen, T Pettersson, U Turunen, S Matikainen, M Leirisalo-Repo, H Repo. Scand J Rheumatol 2013;42(4):294-298. 10 HLA-B27-positive subjects with previous ReA triggered by Yersinia enterocolitica O:3 infection and 20 healthy controls (10 HLA-B27 positive). "TNF-α production from macrophages upon co-stimulation of LPS and MDP increased in the order ReA group < HLA-B27-positive reference group < HLA-B27-negative reference group (p for a trend = 0.027). Similarly, Yersinia-induced TNF-α and IL-23 production increased in the same order (p for trend for TNF-α = 0.036; p for trend for IL-23 = 0.026)."

Välimäki - Scand J Rheumatol 2013 abstract / PubMed

High frequency of reactive arthritis in adults after Yersinia pseudotuberculosis O:1 outbreak caused by contaminated grated carrots. M Vasala, S Hallanvuo, P Ruuska, R Suokas, A Siitonen, M Hakala. Ann Rheum Dis 2014 Oct;73(10):1793-1796. 49 case patients. "Among 37 adults, reactive arthritis (ReA) was found in 8 (22%) and three adults had probable ReA. Six (67%) out of nine human leucocyte antigen (HLA) typed patients with ReA were HLA-B27 positive. Erythema nodosum was found in 42% of the 12 children, whereas none of them had definite ReA."

Vasala - Ann Rheum Dis 2013 abstract / PubMed

The role of intracellular organisms in the pathogenesis of inflammatory arthritis. A Singh, S Karrar. Int J Inflam 2014;2014:158793. Review. "The classic bacteria associated with ReA are Gram-negative obligate or facultative intracellular aerobic bacteria with a lipopolysaccharide-containing outer membrane. The primary focus of infection is thought to be through the mucus membrane, either in the gut or in the urogenital tract. Gastrointestinal microbes commonly include Salmonella, Shigella, and Campylobacter jejuni. Less frequently diagnosed infections include Campylobacter lari, Chlamydia psittaci, and Clostridium difficile. Chlamydia trachomatis is the most common cause of genital infection and the most common triggering infection for ReA."

Singh - Int J Inflam 2014 full article / PubMed Central
Singh / Int J Inflam 2014 full article

The source of infection and the most frequent causes of reactive arthritis in Kosovo. A Lahu, IH Bajraktari, S Lahu, V Saiti, A Kryeziu, F Sherifi, B Durmishi. Mater Sociomed 2016 Jun;28(3):201-204. 100 patients, 66 male, 34 female. "The study concludes that: urogenital tract was the source of infection with 66% of cases, nasopharyngeal tract with 19% of cases, and enteral tract with 15% of cases respectively. Predominantly presents bacteria are E. Coli with 21%, Staphylococcus aureus with 20%, Streptococcus B. hem. gr. A with 16% of cases respectively and other species."

Lahu - Mater Sociomed 2016 full article / PubMed Central

Gut Microbiota Perturbations in Reactive Arthritis and Postinfectious Spondyloarthritis. J Manasson, N Shen, HR Garcia Ferrer, C Ubeda, I Iraheta, A Heguy, JM Von Feldt, LR Espinoza, A Garcia Kutzbach, LN Segal, A Ogdie, JC Clemente, JU Scher. Arthritis Rheumatol 2018 Feb;70(2):242-254. Number of subjects not in abstract. "Subjects with ReA showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas and an increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were enriched in Erwinia and unclassified Ruminococcaceae, respectively; both were enriched in Dialister. Host genetics, particularly HLA-A24, were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co-occurring taxa that were also predictive of HLA-A24 status."

Manasson - Arthritis Rheumatol 2018 abstract / PubMed

Chlamydia Trachomatis Associated Reactive Arthritis: A Urinary PCR Based Study. M Sharma, S Sharma, A Sharma, K Sharma. Indian Dermatol Online J 2020 Jan 13;11(1):21-24. "C. trachomatis DNA was detected from urinary samples with PCR in 24 (36%) of 65 ReA patients. PCR was negative in the patients of other inflammatory arthritis as well as in normal healthy control group."

Sharma - Indian Dermatol Online J 2020 full article / PubMed Central
Sharma / Indian Dermatol Online J 2020 full article

Reactive arthritis and other musculoskeletal symptoms associated with acquisition of diarrhoeagenic Escherichia coli (DEC). R Tuompo, T Lääveri, T Hannu, SH Pakkanen, J Kirveskari, M Leirisalo-Repo, A Kantele. Ann Rheum Dis 2020 Mar 16 [Epub ahead of print]. 224 volunteers. "38 (17.0%) reported MSK symptoms. Multivariate analysis revealed that acquisition of DEC was associated with MSK symptoms (OR 3.9; 95% CI 1.2 to 13.3)."

Tuompo - Ann Rheum Dis 2020 abstract / PubMed
Tuompo / Ann Rheum Dis 2020 full article

cast 03-24-20