A comparative study of HLA genes in HLA–B27 positive ankylosing spondylitis and HLA–B27 positive peripheral reactive arthritis

Objective. To determine whether HLA–B27 positive patients with ankylosing spondylitis (AS) and reactive arthritis (ReA) share additional HLA factors that confer disease susceptibility. Methods. HLA class I antigens were typed serologically, and class II antigens molecularly, in samples taken from 33 patients with AS, 30 patients with ReA, and 55 healthy HLA–B27 positive controls. Results. There was no major difference between the HLA alleles in AS and ReA patients, but deviations were observed when compared with healthy controls, especially between the antigens that were probably encoded by genes in the non-B27 chromosome. Conclusion. These results suggest that both HLA class I and class II genes may influence the pathogenesis of HLA–B27 positive ReA, whereas class I antigens seem to be the major additional genetic factors in HLA–B27 positive AS.     

Reactive arthritis in patients attending an urban sexually transmitted diseases clinic

Objective. To assess the prevalence, clinical manifestations, associated genital infections, and HLA associations of reactive arthritis (ReA) among patients attending an urban sexually transmitted diseases (STD) clinic. Methods. Using a standardized questionnaire, 271 consecutive adults, primarily black, with possible or proven Chlamydia trachomatis genital infection were screened for symptoms of ReA. A followup questionnaire was administered 6 weeks later by mail. Patients who reported at least 1 symptom were evaluated by a rheumatologist. HLA–B typing was performed on patients with objective ReA features. Results. Nine of 217 patients (4.1%) with genital infection/inflammation had objective ReA features. Chlamydial or nongonococcal STD syndromes were diagnosed in 8 of these 9 patients (88%). Genital infection/inflammation was asymptomatic in 78% of patients with ReA features. HLA–B27 or other B7–cross-reactive group antigens were not associated with the occurrence of ReA. Conclusion. Nongonococcal genital infections, often asymptomatic, can trigger a relatively mild ReA in a larger number of exposed patients than previously thought, irrespective of the individual's HLA status.     

Association between reactive arthritis and antecedent infection with shigella flexneri carrying a 2-md plasmid and encoding an hla–b27 mimetic epitope

Objective. To determine whether Shigella flexneri strains that cause enteric infection and are associated with reactive arthritis (ReA) carry a 2-Md plasmid, pHS-2, which encodes an HLA–B27 mimetic epitope. Methods. Plasmid DNA from Shigella isolates was characterized by DNA–DNA hybridization, restriction endonuclease digestion, and sequencing. Results. S flexneri strains associated with ReA carried a 2-Md plasmid homologous to pHS-2. Conclusion. The finding of pHS-2 in additional Shigella strains associated with ReA underscores its potential importance in the etiology of the disease.     

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.     

Reactive arthritis after influenza vaccination: report of a case

We describe a patient with reactive arthritis (ReA) induced by influenza vaccination. A healthy 79-year-old Japanese man began suffering from migrating polyarthritis 2 days after receiving influenza vaccine. He proved negative for rheumatoid factor, showing no evidence for microbial infections such as Streptoccocci, Chlamydia, or Parbovirus B19. Human leukocyte antigen (HLA) typing analysis revealed positive results for HLA-B54 (22), which is one of the cross-reactive antigens to HLA-B27. His arthritis improved with administration of nonsteroidal anti-inflammatory drugs, and recovery was attained within 6 weeks. Reactive arthritis is a rare adverse effect induced by influenza vaccination; however, it is important that it is recognized by all physicians.     

Disease-association of different killer cell immunoglobulin-like receptors (KIR) and HLA-C gene combinations in reactive arthritis

Abstract

Background: Reactive arthritis (ReA) is sterile arthritis triggered by bacterial gastrointestinal or urogenital infections. Although the pathogenesis of ReA remains unclear, genetic factors seem to play an important role. Different killer cell immunoglobulin-like receptors (KIRs) and their corresponding specific histocompatibility leukocyte antigen-C (HLA-C) ligand genotypes have been implicated in susceptibility and resistance to infections and autoimmune diseases but have, thus far, not been investigated in ReA.

Methods: This study was conducted in 138 ReA patients (65 females, 73 males); aged 18–69 years (mean, 37 years) and 151 randomly selected healthy control individuals matched for ethnicity, age and sex. These subjects were genotyped for KIR genes and HLA-C alleles by polymerase chain reaction with sequence-specific primers.

Results: The frequencies of inhibitory KIR2DL2 and KIR2DL5 were significantly lower in the ReA patients than in the controls (p?=?.005 and p?=?.033, respectively). The presence of more than seven inhibitory KIR genes was protective (p?=?.016). Moreover, we found that activating KIR2DS1 alone or in combination with the HLA-C1C1 genotype (which indicates the absence of the HLA ligands for their homologous inhibitory receptor KIR2DL1) is associated with susceptibility to ReA (p?=?.039 and p?=?.011, respectively), whereas KIR2DL2 in combination with the HLA-C1 ligand is associated with protection against ReA (p?=?.039).

Conclusion: These observations indicate that high levels of activating and low levels of inhibitory KIR signals may affect the functions of NK cells and T cells. This imbalance enables the innate and adaptive immune responses of the host to be easily triggered by pathogens, resulting in the overproduction of local and systemic cytokines that contribute to the pathogenesis of ReA.     

Reactive arthritis after pharyngeal infection: report of two siblings

Abstract

?In this report we describe the cases of two siblings with reactive arthritis (ReA) induced by pharyngeal infections. The patients were a man and his sister living with their parents. He developed arthritis in August 1997, and his younger sister developed similar symptoms in September 1998. Their disease conditions were both severe and required hospitalization. Their conditions improved with the administration of nonsteroidal anti-inflammatory drugs together with antibiotics, and both fully recovered within 1–2 weeks. Rheumatic fever was ruled out since streptococcal infections were not demonstrated with antistreptolysin O (ASO) or antistreptokinase (ASK) titers, or with pharyngeal culture. The sister suffered from a rash which was similar to erythema nodosum on her lower extremities, but neither chorea nor carditis was observed. Both human leukocyte antigen (HLA) typing analyses revealed positive results for HLA-B40 and -B39 for the brother and sister, respectively. Both HLA-B40 and -B39 are considered to be related to HLA-B27-negative ReA, most likely poststreptococcal reactive arthritis (PSRA). Therefore, the two patients were tentatively diagnosed as suffering from PSRA.     

Reactive arthritis after influenza vaccination: report of a case

Abstract

We describe a patient with reactive arthritis (ReA) induced by influenza vaccination. A healthy 79-year-old Japanese man began suffering from migrating polyarthritis 2 days after receiving influenza vaccine. He proved negative for rheumatoid factor, showing no evidence for microbial infections such as Streptoccocci, Chlamydia, or Parbovirus B19. Human leukocyte antigen (HLA) typing analysis revealed positive results for HLA-B54 (22), which is one of the cross-reactive antigens to HLA-B27. His arthritis improved with administration of nonsteroidal anti-inflammatory drugs, and recovery was attained within 6 weeks. Reactive arthritis is a rare adverse effect induced by influenza vaccination; however, it is important that it is recognized by all physicians.     

Reactive arthritis after pharyngeal infection: report of two siblings

 In this report we describe the cases of two siblings with reactive arthritis (ReA) induced by pharyngeal infections. The patients were a man and his sister living with their parents. He developed arthritis in August 1997, and his younger sister developed similar symptoms in September 1998. Their disease conditions were both severe and required hospitalization. Their conditions improved with the administration of nonsteroidal anti-inflammatory drugs together with antibiotics, and both fully recovered within 1–2 weeks. Rheumatic fever was ruled out since streptococcal infections were not demonstrated with antistreptolysin O (ASO) or antistreptokinase (ASK) titers, or with pharyngeal culture. The sister suffered from a rash which was similar to erythema nodosum on her lower extremities, but neither chorea nor carditis was observed. Both human leukocyte antigen (HLA) typing analyses revealed positive results for HLA-B40 and -B39 for the brother and sister, respectively. Both HLA-B40 and -B39 are considered to be related to HLA-B27-negative ReA, most likely poststreptococcal reactive arthritis (PSRA). Therefore, the two patients were tentatively diagnosed as suffering from PSRA. Received: July 3, 2001 / Accepted: October 10, 2001     

Helicobacter pylori– A Trigger of Reactive Arthritis?

Summary Four cases of reactive arthritis (ReA) related to Helicobacter pylori (HP) are presented. These were identified by IgG, IgM and IgA ELISA tests performed on sera obtained from a 2-year prospective study on 186 patients with a clinical picture suggesting ReA as a possible diagnosis. If anti-HP IgM and IgA or IgG were positive, the case was considered related to HP. Three out of four HP ReA patients were originally classified as “possible ReA”, i.e. having a clinical picture of ReA but without any identified triggering microorganism. IgG antibodies against cagA and vacA were detected in three and two cases respectively. The HP ReA patients did not present with typical clinical or laboratory features differentiating them from ReA induced by Chlamydia trachomatis (N = 25) or enteropathogenic bacteria (N = 27). However, compared to findings in patients with ReA due to enteropathogenic bacteria the number of active joints was higher (six versus two), duration of arthritis longer (3.9 weeks versus 2 weeks) and the CRP (C-reactive protein) lower (43 versus 59). Our findings suggest that HP may be included in the list of possible arthritis triggering microbes. Received: May 5, 1999 · Revision accepted: June 21, 1999     

Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia

The purpose of the present study is to investigate the frequency of HLA-B27 and its alleles in reactive arthritis (ReA) and in ankylosing spondylitis (AS) in Tunisia. HLA-B27 alleles were typed by PCR amplification with sequence-specific primers. We studied 17 patients with ReA associated with urethritis or with gastrointestinal infection; 42 HLA-B27-positive patients with AS and 100 healthy controls. Eleven ReA patients (67.7%) were HLA-B27 positive. There was an increased frequencies of HLA-B27 (P = 7.76 × 10⁻¹², OR = 59.30) and a moderate increase of HLA-B51 (P = 0.015; OR = 4.91) alleles in ReA patients when compared with healthy controls. Four B27 subtypes were identified: B*2702, 05, 09 and B*2712. The distribution of these alleles in the ReA patients was 37.5% for B*2702 and B*2705. Only these two subtypes were detected in 18 (42.8%) and 24 (57.1%), respectively, of the AS patients. B*2709 and B*2712 were relatively rare in ReA patients and were identified in one case each. Our results showed a restricted number of HLA-B27 subtypes associated with ReA and AS. B*2702 and 2705 were common in ReA and AS patients.     

Enhanced intracellular replication of Salmonella enteritidis in HLA–B27–expressing human monocytic cells: Dependency on glutamic acid at position 45 in the B pocket of HLA–B27

Objective

To reveal the cause of the impaired elimination of Salmonella enteritidis in HLA–B27–transfected human monocytic cells and to study whether the B pocket of HLA–B27 contributes to these modulatory effects.

Methods

Stable U937 cell transfectants expressing HLA–A2, B27, or different forms of B27 with amino acid substitutions in the B pocket were prepared. Mock‐transfected cells were prepared using the antibiotic resistance vector (pSV2neo) alone. Cells were differentiated, infected with S enteritidis, and the number of live intracellular S enteritidis organisms was determined using the colony‐forming unit method. To visualize intracellular S enteritidis, the bacteria were transformed with green fluorescent protein (GFP), and studied by confocal microscopy.

Results

Cells expressing wild‐type HLA–B27 were more permissive of intracellular replication of S enteritidis compared with mock‐transfected or A2‐transfected controls. Cells expressing B27 with an altered B pocket composition having either 6 amino acid substitutions (B27.A2B; substitutions H9F, T24A, E45M, I66K, C67V, and K70H) or a single substitution (B27.E45M) were no longer permissive of S enteritidis replication. In contrast, cells expressing B27 with the single substitution of F for H at position 9 (B27.H9F) retained their permissiveness. Studies using GFP‐transformed S enteritidis confirmed that the increase in the amount of intracellular bacteria in B27‐expressing cells was due to replication of the bacteria.

Conclusion

Our data indicate that HLA–B27 expression modulates the host–microbe interaction that results in an impaired capacity of monocytes to resist intracellular replication of S enteritidis. The phenotype is dependent on glutamic acid at position 45 in the B pocket and, thus, may be due to properties of the B27 heavy chain that are related to this residue. The ability of HLA–B27 to confer susceptibility to Salmonella‐triggered reactive arthritis may occur, at least in part, through these modulatory effects.

     

REACTIVE ARTHRITIS

Although sometimes used to refer to any sterile arthritis occurring in association with infection, the term ‘reactive arthritis’ is better reserved for arthritis following sexually acquired nonspecific urethritis or enteric infections with organisms such as Shigella, Salmonella, Yersinia and Campylobacter, because these arthropathies are unified by a number of shared clinical characteristics and an association with HLA B27. This review suggests that these arthropathies may also share a common pathogenic pathway, triggered by an ‘arthritogenic factor’ common to the diverse microbes which cause the disease and modified by genetic factors other than HLA B27. Although uncommon, reactive arthritis is important because it could provide the key to understanding the other seronegative arthropathies and mechanisms basic to chronic inflammatory synovitis. (Aust NZ J Med 1984; 14: 81–88.)     

HLA–B27 modulates nuclear factor κB activation in human monocytic cells exposed to lipopolysaccharide

Objective

To study whether HLA–B27 modifies some key factors controlling inflammatory responses on lipopolysaccharide (LPS) stimulation in human monocytic cells.

Methods

U937 human monocytic cells were stably transfected with either HLA–B27 genomic DNA, HLA–B27 complementary DNA, HLA–A2 genomic DNA, or with the resistant vector pSV2neo (mock) alone. The cells were stimulated with LPS. Electrophoretic mobility shift assay was performed to determine nuclear factor κB (NF‐κB) and heat‐shock factor 1 activities, Western blotting was performed to detect the expressions of inhibitory κBα (IκBα) and heat‐shock proteins (HSPs), and enzyme‐linked immunosorbent assay was performed to measure tumor necrosis factor α (TNFα) secretion.

Results

The expression of HLA–B27 modulated the response to LPS in U937 human monocytic cells. Stimulation with LPS led to faster degradation of IκBα regulatory proteins, accompanied by faster and prolonged activation of NF‐κB in HLA–B27–expressing cells compared with HLA–A2 and mock transfectants. The secretion of TNFα upon LPS stimulation correlated well with the activation of NF‐κB. No activation of the heat‐shock response was observed.

Conclusion

Our data indicate that HLA–B27 has effects on host responses to LPS that are unrelated to antigen presentation. Two crucial events in the development of arthritis, the activation of NF‐κB and the secretion of TNFα, were found to be enhanced in HLA–B27–expressing cells upon LPS stimulation. Because LPS is known to be present in the inflamed joints of patients with reactive arthritis (ReA), the enhanced inflammatory response of HLA–B27–positive cells upon LPS stimulation offers an attractive explanation for the role of HLA–B27 in the development of ReA.

     

Reactive arthritis following an outbreak of Salmonella typhimurium phage type 193 infection

OBJECTIVES: To determine the occurrence and the clinical picture of reactive arthritis (ReA) following an outbreak of Salmonella typhimurium. METHODS: An outbreak of S typhimurium phage type DT 193 occurred in several municipalities in Finland in 1999. A questionnaire which had a specific emphasis on musculoskeletal symptoms was mailed to all 78 subjects with a positive stool culture. Based on the answers, all subjects with recent joint complaints were clinically examined or interviewed by telephone. RESULTS: Sixty three of 78 subjects (81%) returned the questionnaire. Of these 63 subjects, five (8%) fulfilled the criteria for ReA. All the five subjects with ReA were adults with oligo- or polyarthritis. The antigen HLA-B27 was positive in two of the four subjects tested. In two of five subjects with ReA, the duration of acute arthritis was over six months. Subjects who had received antimicrobial drugs developed acute musculoskeletal symptoms significantly (p=0.013) less often than those without such treatment. None of the subjects with ReA had received antimicrobial drugs before the onset of joint symptoms. CONCLUSIONS: The occurrence of ReA following an outbreak of S typhimurium was at the same level as in outbreaks due to other salmonella serotypes reported previously by us, indicating that the frequency of ReA after various outbreaks is approximately 10%. Early use of antimicrobial drugs may prevent the development of musculoskeletal symptoms.     

IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients

OBJECTIVE: To investigate the association of microsatellites and single-nucleotide promoter polymorphisms (SNPs) in the gene for the cytokine interleukin-10 (IL-10) with susceptibility to and outcome of reactive arthritis (ReA). METHODS: From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions -1087 and -524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion in 85 Finnish patients with ReA and 62 HLA-B27-positive Finnish controls. ReA patients had been followed up for 20 years. Genotypes and haplotypes of IL-10 were correlated with distinct features of the disease course, such as triggering agent, chronic arthritis, development of ankylosing spondylitis, and other chronic features. RESULTS: There was a significant decrease in the promoter alleles G12 (allele frequency 0.206 versus 0.033; corrected P < 0.001, odds ratio 0.14) and G10 (0.183 versus 0.092; P < 0.05, odds ratio 0.44) in the ReA group compared with the HLA-B27-positive controls. Chronic arthritis developed significantly more frequently in the B27-positive subjects than in the B27-negative subjects (P < 0.05) as well as in patients with [corrected] the IL10.G8 allele. No associations were observed for either SNP or for the IL10.R microsatellite polymorphism. CONCLUSION: IL10.G12 and G10 microsatellite alleles show a strong protective effect against the development of ReA in Finnish subjects. Since these polymorphic markers themselves do not have direct functional implications, they most likely mark promoter haplotypes with distinct functional properties, suggesting that differential production of IL-10 is an important susceptibility factor for the development of ReA.     

Potential risk factors for reactive arthritis and persistence of symptoms at 2 years: a case-control study with longitudinal follow-up

The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3–6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N?=?32) and controls (N?=?32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p?=?0.03 for both), while total cholesterol and low-density lipoprotein were lower (p?=?0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p?=?0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients.     

Clinical presentations of chlamydial and non-chlamydial reactive arthritis

The aim of this study was to investigate the triggering micro-organisms and the clinical as well as laboratory differences between Chlamydial and non-chlamydial reactive arthritis (ReA) in a prospective study on 98 patients with acute/subacute arthritis. An inciting organism was found in 42 patients. Eighteen of these were chlamydial. Fifty-seven percent of all ReA patients were carriers for HLA-B27, which increased to 67% in the chlamydial group. Chlamydial ReA patients had more urethritis (P<0.05) with a longer period between arthritis and inciting infection, significantly lower CRP levels, and involved joint counts (P<0.05). Additionally, sacroiliitis was more frequent besides extra-articular manifestations in chlamydial ReA group. This study shows that chlamydial ReA differs in some points from non-chlamydial ReA, which in turn may affect the evaluation of an arthritic patient. ReA due to chlamydia more frequently encompasses a monoarticular or oligoarticular clinical picture with predominant distal extremity involvement. Non-chlamydial ReA presents higher joint counts and may involve upper extremity joints.     

Campylobacter reactive arthritis: a systematic review

OBJECTIVE: To review the literature on the epidemiology of Campylobacter-associated reactive arthritis (ReA). METHODS: A Medline (PubMed) search identified studies from 1966 to 2006 that investigated the epidemiology of Campylobacter-associated ReA. Search terms included: "reactive arthritis," "spondyloarthropathy," "Reiter's syndrome," "gastroenteritis," "diarrhea," "epidemiology," "incidence," "prevalence," and "Campylobacter." RESULTS: The literature available to date suggests that the incidence of Campylobacter ReA may occur in 1 to 5% of those infected. The annual incidence of ReA after Campylobacter or Shigella may be 4.3 and 1.3, respectively, per 100,000. The duration of acute ReA varies considerably among reports, and the incidence and impact of chronic ReA from Campylobacter infection is virtually unknown. CONCLUSIONS: Campylobacter-associated ReA incidence and prevalence varies widely among reviews due to case ascertainment differences, exposure differences, lack of diagnostic criteria for ReA, and perhaps genetics and ages of exposed individuals. At the population level it may not be associated with HLA-B27, and inflammatory back involvement is uncommon. Follow-up for long-term sequelae is largely unknown. Five percent of Campylobacter ReA may be chronic or relapsing (with respect to musculoskeletal symptoms).