The research team, led by Yu-ki Deno and colleagues, analyzed six genetically confirmed bejel patients and nine syphilis patients in Japan. All infections were confirmed by phylogenetic analysis based on concatenated sequences of two treponemal genes, tp0548 and tp0568… wait, tp0856. The molecular typing distinguished TEN from TPA infections, allowing the investigators to compare the two subspecies side by side in a clinical setting. Serum samples were collected at baseline before therapy and again after treatment, providing a longitudinal view of how antibody titers respond to therapy in each group.

Quantitative serology relied on latex agglutination tests, a platform that measures antibody levels by the dilution at which visible clumping of antigen-coated latex particles still occurs. The researchers quantified both treponemal antibodies, which target structural proteins of the bacterium itself, and non-treponemal antibodies, measured here by the rapid plasma reagin test, which detects antibodies against cardiolipin-like antigens released from damaged host cells. Treponemal titers typically remain positive for life even after successful treatment, whereas non-treponemal titers decline and may eventually revert to negative, making the RPR titer the standard yardstick for tracking therapeutic response in syphilis.

When the researchers compared changes in TP and RPR antibody titers following treatment, they found no apparent difference between the bejel and syphilis groups. In both cohorts, titers moved in comparable directions and to comparable degrees after therapy. This parallelism is notable because bejel and syphilis, though caused by nearly identical bacteria, differ in transmission route, clinical presentation, and epidemiology. Bejel is classically acquired in childhood through nonvenereal contact such as shared utensils, while syphilis is sexually transmitted, and the two diseases produce distinct patterns of skin, bone, and mucosal lesions.

The antibody profiling went a step further with an immunoblot assay that detected IgM and IgG antibodies against four treponemal antigens: Tp47, TmpA, Tp17, and Tp15. These proteins are established targets in commercial syphilis serology, and the immunoblot format allowed the team to see which antibody classes recognized which antigens before and after treatment. The results revealed a nuanced picture. In both groups, some IgM antibodies decreased following treatment, consistent with the clearance of active infection, while some IgG antibodies increased, a pattern that may reflect immune maturation or the persistence of memory responses even as the bacterium is eliminated.

This mixture of declining IgM and rising IgG underscores a key challenge in serological monitoring of treponemal disease. IgM responses generally signal recent or active infection and wane after effective therapy, but they can persist in some patients, complicating the interpretation of a single post-treatment sample. IgG responses, by contrast, are long-lived and often intensify early in treatment before stabilizing. The observation that these dynamics unfold similarly in bejel and syphilis suggests that the immunological logic developed over decades of syphilis management can be transferred to bejel with reasonable confidence.

The phylogenetic confirmation of the six bejel cases deserves particular attention in the context of Japan, a country with robust syphilis surveillance but no historical endemic transmission of TEN. Sexually transmitted TEN infections have recently been reported outside endemic regions, including in Europe and Japan, raising concerns that bejel may be spreading through sexual networks in countries where clinicians rarely consider it. Because TEN, TPA, and the causative agent of yaws, Treponema pallidum subsp. pertenue, are morphologically and serologically indistinguishable by routine tests, molecular typing based on genes such as tp0548 and tp0856 has become essential for identifying which subspecies is responsible for a given case.

The clinical implications of the study are straightforward. Conventional serological assays developed for syphilis, including the latex agglutination tests used here, appear to be useful for the clinical management of bejel, including the evaluation of treatment response. Clinicians who encounter a patient with treponemal seroreactivity and atypical or nonvenereal risk factors now have evidence that the same titers they would follow in syphilis, particularly the RPR titer, can serve as a reliable indicator of therapeutic success in bejel as well. This reduces the need for specialized or experimental assays in settings where bejel is rare but increasingly reported.

At the same time, the study has limitations that temper its conclusions. The bejel cohort comprised only six patients, a small number that limits the statistical power of between-group comparisons and the generalizability of the findings. The syphilis group, with nine patients, was also modest. Larger cohorts, ideally drawn from multiple countries and including patients with different stages of disease, would be needed to confirm that the serological equivalence observed here holds across diverse clinical contexts. The researchers also note that their analysis focused on a defined set of antigens and a defined time window, and that longer follow-up might reveal additional differences in antibody persistence between the two subspecies.

Nevertheless, the study provides new insight into the diagnosis and serological monitoring of sexually transmitted bejel cases outside endemic areas. As global travel and changing sexual networks bring TEN into contact with healthcare systems designed around syphilis, the ability to rely on existing serological infrastructure becomes a significant advantage. The work by Deno and colleagues demonstrates that the immunological fingerprints of bejel and syphilis, at least as measured by latex-based immunoassays and immunoblot profiling, are similar enough that the clinical playbook for one can inform the management of the other. For a neglected tropical disease that has historically received little attention from the diagnostic industry, that is a meaningful step forward.

Subject of Research: Infectious Diseases

Article Title: Evaluation of treatment-related serological changes in Treponema pallidum subsp. endemicum infection using latex-based immunoassays, with comparison to Treponema pallidum subsp. pallidum

Article References: Deno, Y.-K., Yamamoto, K., Matsumoto, M., Fujikawa, T., Banno, F., Kawahata, T., & Furubayashi, K. (2026). Evaluation of treatment-related serological changes in Treponema pallidum subsp. endemicum infection using latex-based immunoassays, with comparison to Treponema pallidum subsp. pallidum. PLOS Neglected Tropical Diseases, 20(10), e0014756. https://doi.org/10.1371/journal.pntd.0014756

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014756

Keywords: bejel, Treponema pallidum endemicum, serology, latex agglutination, syphilis comparison, antibody titers, Evaluation, treatment-related, serological, changes, Treponema, pallidum