Tuberculosis in rheumatic and musculoskeletal diseases: An epidemiological overview

To the Editor: Tuberculosis (TB) persists as one of the leading causes of death from a single infectious agent worldwide and has regained prominence following the Coronavirus Disease 2019 pandemic.1 Patients with rheumatic and musculoskeletal diseases (RMDs) constitute a particularly vulnerable population because of underlying immune dysregulation and the frequent need for long-term immunosuppressive therapy.1 In this context, RMDs are defined as chronic inflammatory rheumatic conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis, and systemic vasculitis, which commonly necessitate sustained immunosuppression. Here, we provide a concise, data-driven narrative synthesis of the epidemiological burden of tuberculosis in RMD populations, drawing on epidemiological studies, observational cohorts, clinical trials, and international guideline documents, with emphasis on quantitative risk stratification and clinically relevant diagnostic and therapeutic considerations. Epidemiological data consistently demonstrate that patients with RMDs carry a substantially higher burden of TB than the general population. A large multicenter cross-sectional study conducted in 13 tertiary hospitals across China reported a standardized prevalence of active TB of 882 per 100,000 among patients with RMDs, nearly twice that observed in matched healthy controls.2 This issue is of particular relevance in countries such as China, where, although TB incidence has declined in recent years China continues to rank among the leading contributors to global incident TB cases, accounting for approximately 6.5% of the worldwide total, alongside the increasing use of immunosuppressive therapies.1 Similar trends have been reported across different regions and disease subtypes. Cohort studies from East Asia and Europe indicate that patients with SLE, RA, psoriasis or psoriatic arthritis, and systemic vasculitis consistently exhibit higher TB incidence than background populations, with standardized incidence ratios commonly ranging from approximately 1.2 to over 5, depending on disease type, treatment exposure, and regional TB burden.3,4 Beyond absolute prevalence, longitudinal data further highlight the sustained and cumulative risk of TB over time in RMD cohorts. Population-based studies from Sweden have reported that the incidence rate of TB in patients with RA exceeds that in the general population.3 In SLE, the incidence of TB is frequently even higher, reflecting both disease-related immune abnormalities and intensive immunosuppressive regimens.2 Importantly, these elevated risks persist over time despite improvements in TB control programs, suggesting that advances in public health alone are insufficient to offset disease- and treatment-related susceptibility in RMD populations. Collectively, these findings underscore that TB risk in RMDs extends beyond individual disease entities and is consistently observed across different healthcare systems and geographic regions, supporting its characterization as a globally observed phenomenon. Risk factors for TB in RMD patients can be broadly divided into demographic, socioeconomic, and treatment-related domains, with immunosuppressive therapy exerting the strongest and most modifiable effect. Being male and older age are consistently associated with increased risk of TB, reflecting trends observed in the general population but often exacerbated in patients with autoimmune disease.5 Socioeconomic context and regional TB endemicity further modify risk, as evidenced by the higher incidence of TB among RMD patients residing in high-burden countries or highly urbanized areas characterized by elevated population density and increased migration and exposure opportunities. These background factors interact with the host’s immunity and treatment exposure to determine the individual TB risk.5 Over the past two decades, the widespread adoption of biologic agents and Janus kinase (JAK) inhibitors has substantially altered the risk profile of TB in patients with RMD. Different choices of therapeutic preparations, including glucocorticoids, tumor necrosis factor (TNF) inhibitors, and JAK inhibitors, are associated with distinct and hierarchically different levels of TB risk. Glucocorticoids demonstrate a clear dose-dependent association with TB, with higher daily or cumulative doses linked to both incident TB and reactivation of latent TB infection (LTBI). In SLE cohorts, daily prednisone doses of 30 mg or higher have been associated with markedly elevated risk of TB,6 emphasizing the importance of steroid-sparing strategies and careful tapering whenever feasible. TNF inhibitors are regarded as the drug with the highest-risk in relation to TB. Large registry studies and meta-analyses consistently report a 2.5- to 4.0-fold increase in TB risk compared with non-biologic therapy.7,8 Importantly, risk varies within the TNF inhibitor class. Infliximab and adalimumab are associated with substantially higher TB incidence than etanercept, a difference that was thought to reflect their broader neutralization of both soluble and membrane-bound TNF, which plays a critical role in granuloma maintenance.9 Although the absolute incidence of TB in patients treated with JAK inhibitors appears low, case series and observational data indicate that TB may occur at rate higher than background in endemic regions, particularly with tofacitinib and baricitinib exposure, underscoring a clinically meaningful risk.10 Diagnosis of TB in patients with RMDs is frequently challenging. Clinical presentations of these patients may be atypical, extrapulmonary involvement is common, and symptoms can overlap with autoimmune disease flares or treatment-related adverse events. In addition, immunosuppressive therapy may reduce the sensitivity of immunological screening tests. The 2022 European League Against Rheumatism (EULAR) recommendations therefore advocate interferon-gamma release assays (IGRAs) over the tuberculin skin test for LTBI screening in patients with autoimmune inflammatory rheumatic diseases.11 IGRAs offer higher specificity in Bacille Calmette-Guérin (BCG)-vaccinated populations; however, false-negative results have been reported in patients receiving high-dose glucocorticoids or those with high disease activity, particularly in SLE.12 In such settings, reliance on a single screening modality may be insufficient, and combined strategies incorporating IGRAs, chest radiography or computed tomography, and individualized clinical risk assessment may improve diagnostic accuracy and reduce missed diagnoses. Prevention of TB is a central component of clinical management in patients with RMDs receiving long-term immunosuppression. Preventive treatment for LTBI is strongly recommended before initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs, most commonly using isoniazid- or rifampin-based regimens.11 For active TB, standard multidrug regimens remain effective; however, immunosuppressive therapies are generally withheld until at least two months of effective anti-TB treatment have been completed and clear clinical improvement is evident.11 Particular attention is warranted for central nervous system TB, which appears disproportionately represented in SLE and is associated with substantial morbidity and mortality. Early imaging-based diagnosis, prolonged anti-TB therapy, and close multidisciplinary collaboration are essential in these cases. In conclusion, TB remains a clinically significant and largely preventable complication in patients with RMDs Figure 1. The magnitude of risk varies according to demographic context and, most importantly, immunosuppressive treatment exposure, with TNF inhibitors conferring the highest risk, followed by glucocorticoids and JAK inhibitors. Emerging evidence and recent practice guidelines underscore that TB risk in this population is not random but predictable and amenable to structured prevention.13 Accordingly, implementation of rigorous LTBI screening, careful risk stratification before initiating high-risk immunosuppressive therapies, and integration of regional epidemiological context into clinical decision-making are essential to reduce TB-related morbidity and mortality in this growing patient population.Figure 1: Relationship between RMD and tuberculosis. ATB: Active tuberculosis; DMARDs: Disease-modifying antirheumatic drugs; IGRA: Interferon-gamma release assays; INH: Isoniazid; JAK: Janus kinase; LTBI: Latent tuberculosis infection; MRI: Magnetic resonance imaging; MTB: Mycobacterium tuberculosis; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; RI: Rifampicin (RMP, RIF) + Isoniazid (INH); RIPE: Rifampicin (RMP, RIF) + Isoniazid (INH) + Pyrazinamide + Ethambutol; RMP/RIF:Rifampicin; RMD: Rheumatic and musculoskeletal diseases; SLE: Systemic lupus erythematosus; TAK: Takayasu arteritis; TB: Tuberculosis; TNF: Tumor necrosis factor; vs: Versus.Acknowledgments We thank all the researchers and clinicians whose work contributed to the data and insights presented in this review. We acknowledge the support of the institutions that facilitated access to relevant literature and resources. Conflicts of interest None.