HLA-B27 and Salmonella Infection: The Other Side of the Coin
abstract & commentary
Synopsis: HLA-B27 positivity, which predisposes to the development of reactive arthritis after Salmonella infection, had no apparent effect on the duration of fecal Salmonella excretion or upon the severity of the infection.
Source: Ekman P, et al. Modification of disease outcome in Salmonella-infected patients by HLA-B27. Arthritis Rheum 2000;43:1527-1534.
Individuals who are hla-b27 positive have an in-creased risk of developing reactive arthritis after infection with one of a number of pathogens, including Salmonella. Ekman and colleagues examined the opposite side of the coin in attempting to determine if the course of Salmonella infection is itself affected by the presence of HLA-B27.
A total of 198 consecutive consenting adults in Helsinki and Turku, Finland, who had a positive stool culture for Salmonella between May 1998 and June 1999, had follow-up monthly stool cultures until two consecutive samples failed to yield this pathogen. Their blood, as well as that of healthy blood donor controls, was also examined for the presence of HLA-B27 by flow cytometry after immunofluorescent staining and as well as by PCR.
S. enteritidis was the most commonly isolated serotype (38.4%), followed by S. infantis (8.6%), S. typhimurium (7.6%), S. hadar (5.1%), and S. stanley (4.0%). Five of the eight patients who developed reactive arthritis were infected with S. enteritidis, while one each were infected with S. typhimurium, S. stanley, and an untypeable strain.
Thirteen of 100 (13%) controls and 38 of 198 (19.2%) Salmonella-infected patients were HLA-B27 positive (P = 0.13). The median duration of recovery of Salmonella from stool culture was 49.0 days in both HLA-B27-positive and HLA-B27-negative patients. The time to clearance of Salmonella was not affected by the presence or absence of joint symptoms. Men excreted the organism for a significantly longer duration than did women: 57.0 days vs. 49.0 days (P < 0.02). In contrast to previous studies, receipt of antibiotics (a fluoroquinolone in 90% of cases) was associated with a shortened median duration of stool excretion of Salmonella (38.0 vs 56.0 days; P < 0.02).
Associated joint pain was significantly more frequent and severe in HLA B-27-positive patients than in those who were negative for this antigen. Eight (4%) patients had reactive arthritis; six were HLA-B27-positive. Furthermore, the mean duration of Salmonella-triggered joint pain was 126.2 ± 30.7 days in patients who were HLA-B27-positive and only 26.0 ± 7.7 days in those who were HLA-B27-negative (P < 0.002).
Comment by Stan Deresinski, md, facp
The association between HLA-B27 and genetic susceptibility to the seronegative spondyloarthropathies, including ankylosing spondylitis, Reiter’s syndrome, and reactive arthritis, is well accepted. Some recent in vitro evidence suggests that the presence of HLA-B27 on the cell surface may also be associated with an altered interaction of Salmonella with cells expressing this antigen.
While studies of the effect of HLA-B27 expression on cellular invasion by Salmonella have yielded conflicting results,1-4 it appears that expression of this antigen may be associated with prolongation of intracellular survival of this organism. This same group of researchers, using both HLA-B27 transfected murine fibroblasts and U937 cells (derived from human promonocytes), found that HLA-B27 was associated with prolongation of intracellular persistence of S. enteritidis, possibly as the result of impaired nitric oxide production.4,5 Despite these findings, however, the current study found no apparent significant effect of HLA-B27 positivity on the duration of Salmonella excretion in feces, or on the duration of clinical symptoms, other than those affecting the joints.
One surprising finding of the study reviewed here was the apparent shortening of the duration of excretion of Salmonella in patients who had received antibiotic therapy. It must be recognized, however, that treatment was not assigned by randomization and that stool cultures were only performed monthly.
Early studies concluded that antibiotic therapy provided no benefit in the treatment of uncomplicated enteric non-typhoid salmonellosis, while at the same time, prolonging fecal excretion of the organism.6 Therefore, a comparison of trimethoprim-sulfamethoxazole, ciprofloxacin, and placebo confirmed a lack of benefit from antibiotic therapy, but failed to demonstrate prolonged intestinal carriage as a consequence of such therapy.7 A recent comparison of azithromycin, cefixime, and no treatment in children with salmonellosis also found no benefit from antibiotic therapy, but did not observe prolonged excretion of the pathogen.8 These and other studies, however, were of small size and, thus, highly underpowered. However, a recent Cochrane meta-analysis of 12 trials with 778 participants has confirmed an apparent lack of benefit of antibiotic therapy and also confirmed an apparent prolongation of intestinal Salmonella carriage after their administration.9
While it appears that antibiotic therapy does indeed fail to produce clinical benefit in most patients, the issue of prolongation of fecal excretion of Salmonella by such therapy does remain open to question, especially with regard to antibiotics with intracellular activity. In the two small studies cited before, treatment with azithromycin, ciprofloxacin, or cefixime was not associated with prolonged fecal carriage. Azithromycin and ofloxacin have been demonstrated, in contrast to beta-lactam antibiotics, to have bactericidal activity against intracellular Salmonella.10 Such activity may be potentially more effective in the elimination of Salmonella from the gastrointestinal tract.
The mechanism by which HLA-B27 predisposes to seronegative arthropathies remains unclear. HLA-B27 appears to play a modulatory role in the early signal transduction events induced by Salmonella invasion.11 It was recently reported that Salmonella invasion leads to serologically recognizable changes in the B27-bound peptide repertoire, possibly as the result of modulation of proteosmal proteins.12
Finally, what about the value of antibiotic treatment of reactive arthritis? In a randomized, double-blind study, Sieper and colleagues randomized 126 patients with seronegative arthritis or undifferentiated oligoarthritis to receive either ciprofloxacin or placebo for three months.13 Ciprofloxacin administration was not beneficial.
References
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11. Ikawa T, et al. Expression of arthritis-causing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium. J Clin Invest 1998;101:263-272.
12. Maksymowych WP, et al. Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27. Infect Immun 1998;66:4624-4632.
13. Sieper J, et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: A three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum 1999;42:1386-1396.
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