Abstract
Objective
Although newly developed immunosuppressive therapies have markedly enhanced disease control in patients with RA, they are associated with an increased risk of various infections, including nontuberculous mycobacterial (NTM) disease and tuberculosis (TB). The anti-glycopeptidolipid (GPL) antibody (Ab) test is used to screen for NTM disease, and the interferon-gamma release assay (IGRA) is used to screen for TB. However, detailed analyses of positive anti-GPL Ab test results from RA patients remain scarce. Therefore, this study examined anti-GPL Ab testing and IGRA positivity in RA patients to determine whether NTM or TB are increased in RA patients.
Methods
Clinical information of Japanese RA patients who underwent anti-GPL Ab testing from 2015 to 2023 or IGRA from 2013 to 2023 was analysed.
Results
The positivity rates of anti-GPL Ab testing were higher in female RA (P = 0.0211) and older RA (P = 0.0050) patients, and increased with time (P = 8.61 × 10−8). The positivity rates of anti-GPL Ab testing in younger female RA patients showed a trend towards being increased. The positivity rates of IGRA decreased with time (P = 0.0015).
Conclusion
The positivity rates of anti-GPL Ab testing increased with time in RA patients and were higher in older RA or younger female RA patients, suggesting the increasing incidences of NTM diseases in Japanese RA patients. The positivity rates of IGRA decreased with time in RA patients.
Keywords: anti-glycopeptidolipid antibodies, interferon-gamma release assay, RA
Key messages.
Detailed analyses of positive anti-glycopeptidolipid (GPL) Ab tests among RA patients remain scarce.
The positive rates of anti-GPL Ab tests increased with time in Japanese RA patients and were higher in older RA and younger female RA patients.
The present study suggests the increasing incidences of nontuberculous mycobacterial (NTM) diseases in Japanese RA patients.
Introduction
RA, a chronic autoimmune disease characterized by synovial inflammation, can also affect multiple organ systems. The recent development of immunosuppressive therapies, including biologics and Janus kinase inhibitors, has markedly enhanced disease control in RA patients. However, these treatments suppress immunological responses and are associated with an increased risk of various infections [1], including nontuberculous mycobacterial (NTM) diseases. Biologics, including TNF-alpha inhibitors, are highly effective for treating RA, but they also increase the risk of NTM infections. Therefore, NTM infection screening is recommended before initiating such treatments [2].
Epidemiological research of NTM diseases conducted in Japan reported an increased incidence, especially in older females [3–6]. Previous studies reported that the risk of NTM disease in RA patients may be higher than that of the general population and might be higher for those treated with biologics [7, 8]. However, there is little epidemiological research on NTM in RA patients. Therefore, obtaining epidemiological information on NTM infections in RA patients is important.
The anti-GPL Ab test is used to screen for Mycobacterium avium complex (MAC) pulmonary disease [9, 10], the most common cause of NTM disease in Japan [11]. The anti-GPL Ab test detects immunoglobulin A Abs against MAC-specific cell wall components. Previous studies reported the clinical usefulness of the anti-GPL Ab testing of RA patients [12–15]. However, few studies have comprehensively examined the association between anti-GPL Ab test positivity and the clinical information of RA patients.
Patients receiving immunosuppressive treatments for RA also have an increased risk of tuberculosis (TB) [1]. For example, TNF inhibitors increase the risk of reactivating latent TB, causing active TB [16]. Therefore, screening for TB infections is recommended before initiating immunosuppressive treatments [2]. The incidence rates of TB in Japan have been decreasing and older males are the predominant infected group. The incidence was 8.1 per 100 000 people in 2023 (https://www.mhlw.go.jp/content/10900000/001295037.pdf). The IGRA, which is used to screen for TB, detects T cell responses to M. tuberculosis-specific antigens. We recently reported that the IGRA positivity rates of patients in the Rheumatology Department of Sagamihara National Hospital had decreased over time [17], However, few longitudinal studies on IGRA positivity rates in rheumatic diseases have been reported [18], and it is not clear whether IGRA positivity rates in Japanese RA patients have decreased over time.
Detailed analyses of positive anti-GPL Ab testing among RA patients remain scarce, highlighting the need for epidemiological analysis to better understand the NTM infection risk in Japan. This multicentre study analysed anti-GPL Ab test positivity in RA patients to examine associations between positivity and patient clinical information. IGRA positivity in RA patients was also analysed in this study. The findings of this study are expected to contribute to the estimation of the incidences of NTM diseases in Japanese RA patients.
Methods
Patients
This multicentre retrospective cohort study was conducted at Sagamihara National Hospital, Tokyo National Hospital, Asahikawa Medical Center and Tokyo Metropolitan Tama Medical Center. RA patients who underwent anti-GPL Ab testing between 2015 and 2023 or IGRA between 2013 and 2023 were registered in this study. All patients fulfilled the American College of Rheumatology criteria for RA or the Rheumatoid Arthritis Classification Criteria [19, 20]. RA patients with NTM disease fulfilled the criteria for NTM pulmonary disease, and no disseminated NTM disease patients were observed [21]. RA patients were diagnosed with active TB when their sputum or pus smear (microscopic analyses) and/or M. tuberculosis culture and/or genetic analyses were positive [17]. Clinical information of these RA patients was obtained from their medical records and was anonymized.
The study protocol was reviewed and approved by the institutional review boards of all participating institutions, including Sagamihara National Hospital (#2024–008). Consent for participation was obtained using an opt-out approach under the approval of the institutional review boards. This study was conducted in accordance with the principles expressed in the Declaration of Helsinki.
Anti-GPL Ab test and IGRA
Anti-GPL Abs were detected by Capilia MAC Ab ELISA (Tauns Laboratories, Inc., Shizuoka, Japan). A cut-off level of 0.7 U/ml was set with reference to a previous study [9]. T-SPOT.TB (Oxford Immunotec Ltd, Oxford, UK), QuantiFERON-TB 3G (QIAGEN N.V., Venlo, Netherlands) or QuantiFERON-TB Gold Plus (QIAGEN N.V.) were used to measure interferon-gamma levels produced by T cells sensitized to M. tuberculosis-specific antigens. The results of anti-GPL Ab testing were obtained from the patients’ medical records or from a previous study [15]. The results of IGRA were obtained from the patients’ medical records. The result of the first test was used when multiple tests with consistent results were conducted; the result of the first positive test was used when multiple tests with inconsistent results were conducted, as previously reported [17]. Some results of anti-GPL Ab testing and IGRA at Sagamihara National Hospital were previously reported [15, 17].
Statistical analysis
An association of clinical characteristics with positivity of anti-GPL Ab testing or IGRA was verified by Student’s t-test or Fisher’s exact test using 2 × 2 contingency tables. Trends in anti-GPL Ab test or IGRA positivity were analysed using the Cochran–Armitage test for trend. Multiple logistic regression analyses of clinical manifestations were performed to assess independent associations with anti-GPL Ab tests or IGRA positivity. BellCurve for Excel (Social Survey Research Information Co., Ltd, Tokyo, Japan) was used for statistical analyses. P-values < 0.05 were considered statistically significant.
Results
The positivity rates of anti-GPL Ab testing increased with time in RA patients
Of 2027 RA patients who underwent anti-GPL Ab testing, 152 (7.5%) were positive (Table 1). Fewer male RA patients had positive anti-GPL Ab test results compared with those with negative anti-GPL Ab test results (P = 0.0211, n [%], 17 [11.2%] vs. 351 [18.7%]). Thus, the positivity rates of anti-GPL Ab test were higher in female RA patients. RA patients with positive anti-GPL Ab test results were prone to NTM disease, compared with those with negative results (P = 1.48 × 10−43, n [%], 51 [33.6%] vs. 23 [1.2%]).
Table 1.
Characteristics of RA patients with anti-GPL Ab test results.
| Anti-GPL Ab(+) RA | Anti-GPL Ab(-) RA | P-value | |
|---|---|---|---|
| Number | 152 | 1875 | |
| Age, year (SD) | 70.9 (11.7) | 67.1 (12.1) | 0.0002 |
| Male number, n (%) | 17 (11.2) | 351 (18.7) | 0.0211a |
| Disease duration, year (SD) | 15.8 (14.2) | 15.3 (11.8) | 0.5903 |
| Birth year, year (SD) | 1946.2 (11.5) | 1949.0 (12.0) | 0.0063 |
| Examined year with anti-GPL Ab, year (SD) | 2017.2 (2.8) | 2016.1 (2.1) | 1.74 × 10⁻9 |
| NTM disease, n (%) | 51 (33.6) | 23 (1.2) | 1.48 × 10⁻43a |
The average value or number of each group are shown. Standard deviations or percentages are shown in parenthesis. Differences were tested by t-test or Fisher’s exact test using 2 × 2 contingency tables.
Fisher’s exact test was used.
GPL: glycopeptidolipid; Ab: antibody; Anti-GPL Ab(+) RA: RA with anti-GPL Ab positive results; Anti-GPL Ab(-) RA: RA with anti-GPL Ab negative results; NTM: nontuberculous mycobacterium.
When the positivity rates of anti-GPL Ab tests in RA patients were stratified by year, these rates increased over time (P = 8.61 × 10−8, Fig. 1A, Table S1, available at Rheumatology Advances in Practice Online). When the positivity rates of anti-GPL Ab tests in RA patients were stratified by birth year, these rates decreased from the 1920s to 1960s, and increased from the 1960s to 1980s (Fig. 1B). When the positivity rates of anti-GPL Ab tests in RA patients were stratified by age at examination, these rates decreased from those in their 20s to 50s, and increased from those in their 50s to 90s (Fig. 1C). Thus, the positivity rates of anti-GPL Ab tests increased over time for patients with RA and the positivity rates of anti-GPL Ab tests were higher in older RA patients.
Figure 1.
Positivity rates of anti-GPL Ab tests in RA patients. Positivity rates of anti-GPL Ab tests were sorted by year with anti-GPL Ab test (A), birth year (B), age at examination by anti-GPL Ab test (C) and disease duration of RA (D). The Cochran–Armitage test was used to evaluate trends in positivity rates. GPL: glycopeptidolipid; Ab: antibody
When the positivity rates of anti-GPL Ab tests in RA patients were stratified by birth year and sex, these rates increased from the 1960s to 1980s in females (Fig. S1F, available at Rheumatology Advances in Practice Online). When the positivity rates of anti-GPL Ab tests in RA patients were stratified by age at examination and sex, these rates decreased from those in their 20s to 50s in females (Fig. S1G, available at Rheumatology Advances in Practice Online). These data suggest increased positivity rates of anti-GPL Ab tests in younger female RA patients.
Multiple logistic regression analysis was performed to evaluate independent associations of patient clinical characteristics with anti-GPL Ab test results in RA patients (Table 2). The association of sex (P = 0.0132, odds ratio [OR] 0.50, 95% CI 0.29–0.87), birth year (P = 0.0046, OR 0.98, 95% CI 0.96–0.99) and year examined (P = 1.43 × 10⁻⁷, OR 1.20, 95% CI 1.12–1.28) with anti-GPL Ab test results in RA patients remained significant when conditioned on the patient clinical characteristics, suggesting the independent association of these available clinical characteristics with anti-GPL Ab test positivity.
Table 2.
Multiple logistic regression analysis of clinical manifestations for anti-GPL Ab test positivity in RA patients.
| Unconditioned |
Conditioned on other factors |
|||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P | ORadjusted | 95% CI | P adjusted | |
| Male | 0.55 | (0.33–0.92) | 0.0222 | 0.50 | (0.29–0.87) | 0.0132 |
| Disease duration, year | 1.00 | (0.99–1.02) | 0.5901 | 1.00 | (0.99–1.02) | 0.9386 |
| Birth year, year | 0.98 | (0.96–0.99) | 0.0065 | 0.98 | (0.96–0.99) | 0.0046 |
| Examined year with anti-GPL Ab, year | 1.19 | (1.12–1.27) | 7.78 × 10⁻9 | 1.20 | (1.12–1.28) | 1.43 × 10⁻7 |
P, OR, 95% CI, Padjusted and ORadjusted were calculated by logistic regression analysis of RA patients. GPL: glycopeptidolipid; Ab: antibody; OR: odds ratio.
The positivity rates of IGRA decreased with time in RA patients
Of 4030 RA patients who underwent IGRA, 228 (5.7%) were positive (Table 3). Those with positive IGRA results were predominantly male RA patients (P = 1.60 × 10⁻7, n [%], 100 [37.0%] vs. 1022 [22.4%]). RA patients with positive IGRA results were prone to have active TB (P = 1.58 × 10⁻13, n [%], 11 [4.1%] vs. 1 [0.0%]), compared with those with negative results. Thus, the positivity rates of IGRA were higher in male RA patients.
Table 3.
Characteristics of RA patients with IGRA results.
| IGRA(+) RA | IGRA(-) RA | P | |
|---|---|---|---|
| Number | 270 | 4555 | |
| Age, year (SD) | 71.9 (9.9) | 64.9 (14.1) | 1.89 × 10⁻15 |
| Male number, n (%) | 100 (37.0) | 1022 (22.4) | 1.60 × 10⁻7a |
| Disease duration, year (SD) | 8.5 (12.4) | 10.6 (14.0) | 0.0359 |
| Birth year, year (SD) | 1945.1 (10.0) | 1952.6 (14.0) | 8.50 × 10⁻18 |
| Examined year with IGRA, year (SD) | 2017.0 (2.7) | 2017.5 (2.9) | 0.0041 |
| Active TB, n (%) | 11 (4.1) | 1 (0.0) | 1.58 × 10⁻13a |
The average value or number of each group are shown. Standard deviations or percentages are shown in parenthesis. Differences were tested by t-test or Fisher’s exact test using 2 × 2 contingency tables. IGRA: interferon-gamma release assay; IGRA(+) RA: RA with positive IGRA results; IGRA(-) RA: RA with non-positive IGRA results; TB: tuberculosis.
Fisher’s exact test was used.
When the positivity rates of IGRA in RA patients were stratified by year, these rates decreased over time (P = 0.0015, Fig. 2A, Table S2, available at Rheumatology Advances in Practice Online). When the positivity rates of IGRA in RA patients were stratified by birth year, these rates decreased (P < 1.00 × 10⁻15, Fig. 2B). When the positivity rates of IGRA in RA patients were stratified by age at examination, these rates increased by age (P = 3.11 × 10⁻14, Fig. 2C). When the positivity rates of IGRA in RA patients were stratified by sex, similar tendencies were observed in both groups (Fig. S2, available at Rheumatology Advances in Practice Online). Thus, the positivity rates of IGRA decreased over time in RA patients and the positivity rates of IGRA were higher in older RA patients.
Figure 2.
Positivity rates of IGRA in RA patients. Positivity rates of IGRA were sorted by year with IGRA (A), birth year (B), age at examination by IGRA (C) and disease duration of RA (D). The Cochran–Armitage test was used to evaluate trends in positivity rates. IGRA: interferon-gamma release assay
Multiple logistic regression analysis was performed to evaluate independent associations of RA patient clinical characteristics with IGRA (Table 4). The association of sex (P = 0.0001, OR 1.79, 95% CI 1.33–2.41), disease duration (P = 0.0107, OR 0.98, 95% CI 0.97–1.00), birth year (P = 5.37 × 10⁻14, OR 0.95, 95% CI 0.94–0.96) and year examined (P = 0.0349, OR 0.95, 95% CI 0.90–1.00) with IGRA in RA patients remained significant when conditioned on the patient clinical characteristics, suggesting the independent association of these available clinical characteristics with IGRA positivity.
Table 4.
Multiple logistic regression analysis of clinical manifestations for IGRA positivity in RA patients.
| Unconditioned |
Conditioned on other factors |
|||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P | ORadjusted | 95% CI | P adjusted | |
| Male | 2.03 | (1.57–2.63) | 5.94 × 10⁻8 | 1.79 | (1.33–2.41) | 0.0001 |
| Disease duration, year | 0.99 | (0.98–1.00) | 0.0365 | 0.98 | (0.97–1.00) | 0.0107 |
| Birth year, year | 0.95 | (0.94–0.96) | 3.50 × 10⁻17 | 0.95 | (0.94–0.96) | 5.37 × 10⁻14 |
| Examined year with IGRA, year | 0.94 | (0.90–0.98) | 0.0042 | 0.95 | (0.90–1.00) | 0.0349 |
P, OR, 95% CI, Padjusted and ORadjusted were calculated by logistic regression analysis of RA patients. IGRA: interferon-gamma release assay; OR: odds ratio.
Discussion
This study provides a multicentre retrospective analysis of anti-GPL Ab test positivity among 2027 patients with RA, as well as their associated clinical background factors. The positivity rates of anti-GPL Ab testing in RA patients increased over time, and fewer male RA patients had positive anti-GPL Ab test results compared with female RA patients, and the positivity rates of anti-GPL Ab tests were higher in older RA patients. The stratified analyses also suggested the increasing positivity rates of anti-GPL Ab tests in younger female RA patients. Multiple logistic regression analysis suggested the independent association of these available clinical characteristics with anti-GPL Ab test positivity. To the best of our knowledge, this is the first longitudinal study on the positivity rates of anti-GPL Ab tests in Japanese RA patients, suggesting increasing incidence rates of NTM diseases in older RA and younger female RA patients.
The present study also analysed IGRA positivity among 4030 patients with RA. The positivity rates of IGRA in RA patients decreased over time. Male and older RA patients predominantly had positive IGRA results. Multiple logistic regression analysis suggested the independent association of these available clinical characteristics with IGRA positivity. Of note, these tendencies in RA are concordant with those of the general Japanese population [22].
The anti-GPL Ab test was reported to have a relatively low sensitivity and high specificity [12, 14, 15, 23]. Positive anti-GPL Ab test results are influenced by disease spectrum or severity; patients with mild or non-cavitary disease are more often seronegative [24], and anti-GPL Ab titers decrease after successful treatment [25]. Cases with disseminated NTM disease following biologic treatment and cases associated with anti-interferon-γ auto-Abs have been reported [2]. However, their clinical information was not available in this study; therefore, the effects of biologic treatment and anti-interferon-γ auto-Ab production in RA patients could not be estimated in the present study. Further studies using precise clinical information and the auto-Ab profiles of RA patients should be conducted.
T-SPOT.TB, QuantiFERON-TB 3G or QuantiFERON-TB Gold Plus were used in this study. The different methods might influence the results on the IGRA positivity, though the positivity rates of IGRA were rapidly decreasing.
In this study, anti-GPL Ab test positivity was more prevalent in older RA patients and the possibility of increasing incidence rates of NTM diseases in younger female RA patients was suggested. These findings may have been influenced by the effects of increased estrogen or progesterone levels in younger females, or decreased androgen levels in older males, on the immune reactions of neutrophils or macrophages against NTMs [26, 27]. Younger female RA patients might clean bathtubs or wash muddy clothes of children, and therefore, might be at higher risk of exposure to NTMs. Because the prevalence of TB is rapidly decreasing in Japan, younger individuals are likely to have reduced exposure to mycobacterial antigens, leading to fewer immunological reactions against mycobacterial pathogens, resulting in the increased prevalence of NTM diseases in the younger generations. The genetic and phenotypic differences of younger age onset and elder age onset RA might also influence immunological reactions against NTMs [28, 29].
This study had several limitations. It was conducted in four institutions in different regions and may not fully reflect the nationwide distribution patterns of NTM. Because no guidelines on anti-GPL testing were developed on RA patients and the anti-GPL Ab test was performed on selected subsets of RA patients, the possibility of selection bias could not be excluded. Information related to the medication administered to RA patients was not available in this study and it may influence the results of the anti-GPL Ab testing or IGRA. Although sex, disease duration, birth year and year examined were adjusted in the analyses, residual confounding factors could not be eliminated in logistic regression analyses. This study did not provide incidence rates or prevalences of NTM diseases in RA patients. Thus, future large-scale epidemiological studies of the incidence rates and prevalences of NTM diseases in RA patients should be performed in broader range of regions of Japan to elucidate the trends of NTM diseases in RA patients.
Supplementary Material
Contributor Information
Yusuke Yano, Department of Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Shinichi Nogi, Department of Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Hirokazu Taguchi, Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
Takashi Higuchi, Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan.
Fuminori Hirano, Department of Internal Medicine, NHO Asahikawa Medical Center, Asahikawa, Japan.
Shomi Oka, Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan; Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Kota Shimada, Department of Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan; Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan.
Toshihiro Matsui, Department of Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan; Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Shigeto Tohma, Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan; Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Kenji Itoh, Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan.
Hiroshi Furukawa, Department of Rheumatology, NHO Tokyo National Hospital, Kiyose, Japan; Clinical Research Center for Allergy and Rheumatology, NHO Sagamihara National Hospital, Sagamihara, Japan.
Supplementary data
Supplementary data are available at Rheumatology Advances in Practice online.
Data availability
Data supporting the study findings have been presented in the manuscript and supplementary data. Other data are available from the corresponding authors on reasonable request. However, anti-GPL Ab and IGRA data as well as clinical information related to individual participants are not available, based on the Act on the Protection of Personal Information enforced in Japan.
Author contributions
Shigeto Tohma, Kenji Itoh and Hiroshi Furukawa designed and conceived experiments. Yusuke Yano, Shinichi Nogi, Hirokazu Taguchi, Takashi Higuchi, Fuminori Hirano and Hiroshi Furukawa analysed the data. Yusuke Yano, Shinichi Nogi, Hirokazu Taguchi, Takashi Higuchi, Fuminori Hirano, Shomi Oka, Kota Shimada, Toshihiro Matsui, Shigeto Tohma, Kenji Itoh and Hiroshi Furukawa provided reagents and materials. Yusuke Yano, Shinichi Nogi, Kenji Itoh and Hiroshi Furukawa wrote the manuscript. All authors read and approved the final version of the manuscript.
Funding
The work was supported by Grants-in-Aid for Clinical Research from National Hospital Organization. The funders had no role in study design, data collection and analysis, decision to publish or preparing the manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
AI usage in the preparation of manuscript
AI was used for a grammatical and typographical check of the manuscript prepared by the authors. All the authors reviewed and confirmed the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data supporting the study findings have been presented in the manuscript and supplementary data. Other data are available from the corresponding authors on reasonable request. However, anti-GPL Ab and IGRA data as well as clinical information related to individual participants are not available, based on the Act on the Protection of Personal Information enforced in Japan.