Disease-modifying anti-rheumatic drugs are associated with increased readmission and reoperation rates following anterior cervical discectomy and fusion: a propensity-matched cohort study

Introduction

Anterior cervical discectomy and fusion (ACDF) is a commonly performed surgical procedure indicated for managing cervical spine pathologies such as myelopathy, radiculopathy, and spinal instability. In the United States, ACDF represents the most frequently performed cervical spine operation, with over 137,000 procedures conducted annually (1). The volume of ACDF surgeries continues to rise, with projections estimating a further 13% increase from 2020 to 2040 (2). This upward trend highlights the significance of ACDF as a primary surgical intervention for cervical spine disorders.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, frequently leading to structural damage and functional impairment. Patients with RA exhibit a high prevalence of cervical spine pathology, often necessitating surgical interventions such as ACDF to restore function and alleviate pain (3-5). The emergence of disease-modifying anti-rheumatic drugs (DMARDs) has significantly altered the disease course by reducing inflammation and slowing progression, thereby lessening the need for surgical intervention. However, the perioperative administration of DMARD therapy is especially important in patients undergoing elective spine surgery, given its potential impact on postoperative outcomes such as infection, reoperation, and hospital readmission (6,7). Despite this, considerable variability exists in clinical practice regarding perioperative DMARD management, and no widely adopted guidelines are currently in place (6,7). While outcomes among patients who continue therapy are generally favorable, the immunosuppressive and cytotoxic effects of these medications warrant careful consideration.

Objective of the study

This study evaluates the hypothesis that patients with RA who use DMARDs have a higher risk of postoperative complications following ACDF compared to matched RA patients not on DMARD therapy at all time points. Specifically, the study aims to assess the impact of DMARD use on both short-term (90-day) and long term (2-year) medical and implant related outcomes including infection rates, hospital readmissions, reoperation rates, fusion failure, and reoperation surgery. Clarifying these associations may help guide perioperative DMARD management and inform clinical decision-making for RA patients undergoing ACDF. We present this article in accordance with the STROBE reporting checklist (available at https://jss.amegroups.com/article/view/10.21037/jss-25-134/rc).

Methods

Data source

This study is a matched cohort analysis utilizing data from the TriNetX research network, a comprehensive healthcare database incorporating electronic health records (EHR) from more than 130 million patients, representing a broad spectrum of clinical encounters and health services across over 100 distinct healthcare organizations nationwide. Data for this study was collected in a de-identified process using diagnostic coding systems such as the International Classification of Diseases, Tenth Revision (ICD-10), procedural classifications using Current Procedural Terminology (CPT), and medication classifications. The study was conducted in compliance with institutional and data governance protocols.

Study design and patient selection

The TriNetX database was queried on March 21st, 2025 to identify adult patients diagnosed with RA who underwent ACDF within a 20-year period. Only ACDF procedures were included in the cohort, as defined by CPT codes. Corpectomy and posterior cervical procedures were not included in the analysis. Patients were divided into two cohorts: those receiving DMARD therapy during the perioperative period (n=520), and those who did not receive DMARD therapy (n=1,314). The inclusion criteria included patients with confirmed diagnoses of RA identified by use of ICD-10 codes. To ensure accurate cohort selection, patients under 18 years of age, those with incomplete clinical data, or those without adequate follow-up records within the specified time frame were excluded. A 1:1 propensity score matching (PSM) procedure was performed using TriNetX’s analytics tools which accounted for confounding between the DMARD group (n=507), and those who did not receive DMARD therapy (n=507).

Cohort matching

To eliminate selection bias, control for confounding, and increase compatibility between the groups, 1:1 PSM analysis was employed based on the demographics and clinical antecedents. Matching variables included patient age, sex, BMI, smoking status, diabetes mellitus, hypertension, osteoporosis, chronic kidney disease and the CCI. Propensity scores have been matched using the nearest-neighbor matching algorithm with a caliper width 0.2 standard deviation. The distribution of propensity scores before and after matching is illustrated in Figure 1, demonstrating effective overlap and balance between the cohorts. Subsequent matching provided two groups of 507 patients each, to give the total of 1014 patients for the study. By group matching, there were equal chances of bias control and hence, reducing the risk of potential confounding variables.

Figure 1 Propensity score, before (A) and after (B) matching.

Outcome measures

Postoperative outcomes were assessed at the 90th day and 2 years after operation, reflecting short term and long term respectively. These can be further classified as follows: medical complication, implant related complication, and reoperation rate. All outcomes were defined using ICD-10 and CPT codes in order to classify the postoperative events comprehensively.

Primary outcomes

Medical complications

Medical complications included sepsis (ICD-10 codes: A41.9, T81.44), pulmonary embolism (PE) (ICD-10 code: I26), deep vein thrombosis (DVT) (ICD-10 code: I82.40), myocardial infarction (MI) (ICD-10 code: I21), renal failure (ICD-10 codes: N17, N19, N99.89), and all-cause mortality. Hospital readmissions were defined based on the discharge summaries and coding with the CPT code 1013699/SNOMED codes 737481003 and 394656005. Postoperative infection (ICD-10 codes: T81.4, T81.43XA) was defined as chronic infection due to device, spine infection (intraspinal abscess or discitis of the intervertebral space or osteomyelitis of the vertebrae). The list of ICD codes with associated complications is listed in Table 1, which has been templated from similar TriNetX studies (8).

Surgical site and implant-related complications

Surgical site and implant-related complications were also assessed, including reoperations (CPT codes: 22551, 22552, 22830, 22548, 22590, 22595, 22554, 22600), chronic infections related to the surgical site (ICD-10 code: T84.7XXD), seroma or hematoma formation (ICD-10: L76.32, L76.34, M96.840, M96.842, G97.61, G97.62, G97.63, G97.64), wound disruption (ICD-10 code: T81.31XA), spine infections (ICD-10 codes: M46.4, M46.2, G06.1), and pseudarthrosis (ICD-10 code: M96.0). The occurrence of these complications was then compared in the two groups. Kaplan-Meier estimator was used to estimate the probability of reoperation-free survival at 2 years. Complications of each outcome are available in Table 1.

Statistical analysis

The effectiveness of postoperative complications of DMARD and No DMARD group were analyzed statistically at 90 days and at 2 years. Categorical data were analyzed using chi-squared (χ²) tests, with risk ratios (RRs) and 95% confidence intervals (CIs) calculated for each outcome measure in order to establish the risk conferred by the DMARDs. The reoperation-free survival was conducted using the Kaplan-Meier curves up to 2 years, and the intergroup comparisons were performed using the log-rank test. For all the comparisons made in this study, the statistical significance was established at P<0.05.

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Publication of this retrospective review was waived from patient consent according to the HIPPA privacy rule defined in Section §164.514(a). The data reviewed is a secondary analysis of existing data, does not involve intervention or interaction with human subjects, and is de-identified per the de-identification standard defined.

Results

90-day outcomes

Medical complications

The rates of major medical complications, including sepsis, infection, PE, DVT, MI, renal failure, and mortality, were identical in both cohorts. Each of these complications occurred in 2.0% of patients in both the DMARD and non-DMARD groups, with a RR of 1.00 (95% CI: 0.42–2.38) and a P value of >0.99, indicating no statistically significant differences as seen in Table 2.

However, hospital readmission rates were significantly higher in the DMARD group (4.3%, 22 patients) compared to the non-DMARD group (2.0%, 10 patients), with a RR of 2.2 (95% CI: 1.05–4.60). The risk difference was 0.024 (P=0.03), indicating an additional 24 readmission per 1,000 patients. Patients on DMARD therapy were more likely to require readmission within 90 days post-surgery.

Surgical site and implant-related complications

Among “Surgical site and implant-related complications”, the reoperation rate was significantly higher in the DMARD group (4.1%, 21 patients) than in the non-DMARD group (2.0%, 10 patients), with a RR of 2.1 (95% CI: 1.00–4.41). The risk difference was 0.022 (P=0.045), suggesting that DMARD use may contribute to a higher likelihood of early reoperation within 90 days. Comprehensive outcomes are listed in Table 3.

Chronic infection related to the surgical device was observed only in the non-DMARD group (2.0%, 10 patients), while no cases were recorded in the DMARD group, leading to a statistically significant negative risk difference (RD: −0.02, P=0.001). This finding may suggest that patients on DMARDs were not more susceptible to chronic device infections within 90 days. However, due to TriNetX’s de-identification protocols, any non-zero cohort count below 10 is rounded to 10, meaning the true count in the non-DMARD group could range from 1–10. The apparent difference should therefore be interpreted cautiously. Other Surgical site and Implant-related complications, including seroma, hematoma, wound disruption, and pseudarthrosis, did not demonstrate statistically significant differences between the two cohorts.

2-year outcomes

Surgical site and implant-related complications

The RR of 2.0 (95% CI: 1.20–3.33, P=0.006) indicates a strong association between DMARD use and the need for reoperation within two years. Chronic device-related infections, seroma, hematoma, wound disruption, and spine infection showed no significant differences between groups, with all P values equal to or greater than 1.0 as highlighted in Table 4.

Kaplan-Meier survival analysis at 90 days and 2 years

The probability of remaining free from reoperation at 90 days was slightly lower in the DMARD group (95.82%) compared to the non-DMARD group (97.99%). The log-rank test yielded a P value of 0.046, confirming statistical significance. This is illustrated in Table 5 and further supported by the Kaplan-Meier survival curves presented in Figure 2 (1-year) and Figure 3 (2-year), which visually demonstrate the divergence in reoperation-free survival between the two cohorts over time. This further supports the finding that DMARD use is associated with an increased likelihood of reoperation within the early postoperative period.

Figure 2 One-year Kaplan-Meier survival curve.

Figure 3 Two-year Kaplan-Meier survival curve.

The probability of remaining free from reoperation at 2 years was lower in the DMARD group (90.94%) compared to the non-DMARD group (95.12%). The log-rank test yielded a P value of 0.008, confirming statistical significance. This is illustrated in Table 5. and further supports the association between DMARD use and an increased likelihood of requiring additional surgery over time.

Reoperation rate comparison at 90 days and 2 years for DMARD vs. NO DMARD groups

A comparison of reoperation rates at 90 days and 2 years for patients with and without DMARD treatment is presented in Table 6. These results revealed a significantly higher reoperation rate among DMARD patients at both the time points of assessment with the difference being more evident at two-year follow-up period.

Discussion

This study aimed to assess the efficacy of DMARDs on postoperative outcome of patients who underwent ACDF. The results suggest that DMARD use preoperatively increases the risk of both readmission and reoperation for RA patients undergoing ACDF. There is no apparent increase in the frequency of most medical complications of surgery within 90 days postoperatively.

Hospital readmissions

The DMARD cohort demonstrated a higher 90-day readmission rate compared to the non-DMARD group (4.3% vs. 2.0%; RR 2.2, 95% CI: 1.05–4.60; P=0.03), possibly reflecting the immunosuppressive effects of DMARD therapy and its impact on postoperative recovery (Table 2). Specific biologic DMARDS, particularly subtypes that inhibit TNF alpha, increase risk of perioperative infection which may contribute to these patients returning to the hospital at a higher rate (5,9). It is important to note that 90-day hospital readmissions were all-cause and not limited to cervical spine-related complications. Therefore, some readmissions may not be directly attributable to surgical or device-related issues.

Although no device-related infections were documented in the DMARD group at 90 days, the higher readmission rate observed may reflect broader immunosuppression-related complications, such as superficial surgical site infections (SSIs), or systemic rheumatic disease flare, rather than deep or chronic implant-related infections. Immunosuppressive therapy and surgical outcomes were investigated in a retrospective analysis (5) of 50,359 orthopedic surgery cases reported an increased risk of postoperative infections in patients using DMARDs, a known contributor to hospital readmissions. DMARDs also functionally weaken the immune system of a patient, potentially contributing to the decreased rate of wound healing and increasing the overall risk of developing other associated complications and subsequent readmission rates (10). A similar analysis (5) of patients with inflammatory rheumatic diseases treated with immunosuppressive drugs found an elevated risk of postoperative infections, further supporting the role of DMARDs as a risk factor for delayed recovery. Moreover, complications in relation to the use of DMARDs including slowed healing of the wound and increased risk of developing an infection are well known, both of which stand as strong predictors of readmissions (10). Notably, these findings contrast with those reported in a study of major non-spine surgeries (11), which found no significant increase in readmission associated with DMARD use. The discrepancy may reflect factors unique to ACDF, despite cautious perioperative practices such as strict fusion protocols and sterile wound care, the immunosuppressive effects of DMARDs may still compromise wound healing and early recovery, thereby increasing the risk of readmission.

Reoperations

The DMARD cohort demonstrated a higher 90-day reoperation rate compared to the non-DMARD group (4.1% vs. 2.0%; RR 2.1, 95% CI: 1.00–4.41; P=0.045), as well as a higher 2-year reoperation rate (8.3% vs. 4.1%; RR 2.04, 95% CI: 1.20–3.33; P=0.006), suggesting that immunosuppressive therapy may contribute to delayed surgical recovery and an increased need for reoperation (Tables 3,4). Reoperation rates in spine surgery are considered critical outcome measures, as they are particularly linked to increased perioperative morbidity and adverse surgical outcomes. Prior research has demonstrated that revision surgeries accounted for 5.84% of all spine procedures and are associated with significantly higher odds of complications such as infection, dural tears, and neurological deficits, as well as longer hospital stays and increased 30-day readmission rates (12,13).

Immunosuppression is again a likely contributor to these outcomes. There is substantial evidence that continuation of DMARD therapy during the perioperative period increases the risk of SSIs, which may in turn contribute to higher revision rates (14,15). However, not all DMARDs confer equal risk. Conventional agents such as methotrexate and leflunomide have not been shown to significantly increase postoperative infection rates (16,17). Whereas biologic DMARDs such as TNF alpha, stated prior, have been associated with a higher incidence of perioperative infection and delayed recovery (14,15). These findings underscore the importance of carefully timed management of biologic therapy in surgical planning. The European Alliance of Associations for Rheumatology (EULAR) has endorsed an individualized, case-based approach to perioperative DMARD management to balance infection risk against the possibility of RA flare (18,19). Effective control of RA disease activity plays a central role in reducing postoperative risk. In a large cohort of RA patients (20), high disease activity was independently associated with an increased risk of infection, emphasizing that disease control regardless of DMARD use is a critical factor in mitigating surgical complications. A clear consensus remains lacking within the spine surgery community, and further investigation is needed to establish evidence-based guidelines specific to spinal fusion procedures.

Other medical complications

No statistically significant differences were observed between DMARD and non-DMARD groups with respect to sepsis, infection, pulmonary embolism, deep vein thrombosis, renal failure, and mortality at the 90-day follow-up period.

Surgical site and implant-related complications

The DMARD cohort did not demonstrate a higher 90-day rate of device-related infections compared to the non-DMARD group (0.0% vs. 2.0%; P=0.001), a finding that may reflect differences in perioperative risk profiles or surgical selection bias (Table 3). The DMARD cohort also did not demonstrate a higher rate of pseudarthrosis compared to the non-DMARD group (16.6% vs. 14.0%; P=0.26), suggesting that fusion integrity was not adversely affected by immunosuppressive therapy.

It is important to note that due to TriNetX’s de-identification protocol, any cohort size less than 10 is reported as 10, and therefore the exact number of device-related infections in the non-DMARD group is unknown, though the DMARD group’s count of zero remains accurate and notable. While this suggests that DMARD therapy was not associated with an increased risk of chronic implant-related infections in this cohort, it contrasts with prior literature (5,9,12,13), showing that biologic DMARDs, particularly TNF-alpha inhibitors, are associated with increased perioperative infection risk.

A possible explanation for this discrepancy is that patients on biologic DMARDs may have undergone more perioperative screening for infection prevention, given the immunocompromised state of the DMARD group. Furthermore, implant-related infections represent a subset of postoperative infections, and may be less frequent or differently influenced by immunosuppressive therapy than superficial SSIs. Nevertheless, the complexity of infection risk in this population underscores the importance of individualized perioperative management when balancing disease control and immunosuppression. Additionally, no significant differences were observed between the groups in other Surgical site and Implant-related complications, including seroma, hematoma, wound disruption, or pseudarthrosis.

Kaplan-Meier survival analysis

There were significant differences in reoperation-free survival probability between patients who received DMARDs and those who did not, as determined by Kaplan-Meier analysis. At 90 days, the probability of reoperation-free survival was lower for patients on DMARD therapy compared to those not on DMARDs (95.82% vs. 97.99%; P=0.046). Similarly, at 2 years, patients treated with DMARDs had a significantly lower reoperation-free survival probability compared to those not on DMARDs (90.94% vs. 95.12%; P=0.008). These findings indicate that DMARD therapy is associated with an increased likelihood of repeat surgical interventions. It must be considered that the decreased survival of these operations are specifically associated with DMARD use despite the possible sequelae faced by patients with autoimmune diseases such as other unrelated infections and disease flares. Clinically, the results of this Kaplan-Meier analysis underscore the necessity of tailored perioperative management strategies, particularly vigilant monitoring, and close management for patients undergoing DMARD treatment.

Clinical implications

The findings of this study suggest that RA patients on DMARD therapy undergoing ACDF are at increased risk for readmission and reoperation, emphasizing the need for individualized perioperative planning. This should include careful consideration of the timing of immunosuppressive medications and enhanced postoperative monitoring. There were no significant medical complications which indicate surgeons may follow routine DVT, PE, and sepsis protocol in patients on DMARD therapy. Implant related failure was also not significantly increased with the use of DMARDs. The isolated significant finding was the decreased rate of device-related infections in the DMARD group compared to the non DMARD group which may be attributable to more intensive perioperative monitoring and follow-up commonly employed in immunosuppressed patients. Kaplan-Meier survival analysis suggests that DMARD use negatively affects reoperation-free survival, further highlighting the importance of individualized perioperative risk assessment and management strategies in RA patients undergoing ACDF.

Strengths

This study consists of several methodological and clinical strengths that contribute to the validity of the study findings. One key strength is the fact that the study uses the TriNetX database that is comprehensive, multi-institutional to support a diverse population of patients. In an attempt to reduce selection bias and make the two groups similar in terms of baseline characteristics, the PSM analysis was utilized. Furthermore, by assessing patient outcomes at both 90-day and 2-year follow-up intervals, this study provides a robust understanding of the short- and long-term effects of DMARD therapy on ACDF outcomes. This extended duration of follow up assists in identifying the early postoperative morbidity and mortality and implant related failure such as reoperation and pseudarthrosis. Additionally, the addition of Kaplan-Meier survival analysis also enhances the robustness of this research endeavor since it helps to provide a clear difference in the re-operation free survival probability between the two groups over a span of time.

Limitations

This study has several important limitations. First, as a retrospective observational study rather than a randomized controlled trial, the potential for residual confounding remains despite the use of PSM. Additionally, TriNetX relies on aggregated EHR data, which may be subject to documentation errors, coding variability, and differences in clinical practice patterns across institutions. A significant limitation is the lack of detailed information on DMARD subtypes, treatment duration, medication adherence, and perioperative management strategies. Disease activity and severity, which are known independent risk factors for postoperative infection in RA patients, could not be captured in the dataset, and thus their potential influence on outcomes could not be assessed. The dataset also did not differentiate between types of ACDF procedures (multilevel vs. single level ACDF), surgical techniques, or fusion materials, all of which may affect complication rates. Spinal infections were defined as discitis, osteomyelitis, or implant associated infections that assess for post-surgical infection. Importantly, since the same ICD code is utilized for native infection, there was no definitive way to know if the infections were directly related to the index ACDF or from another native etiology. Nonetheless, we felt that it would be appropriate to analyze these infections in both cohorts as they may pose an overall increased morbidity regardless of etiology. Additionally, due to the de-identified nature of the TriNetX database, we could not determine the exact year of surgery for individual patients or evaluate whether the type or class of DMARD therapy changed over time. As such, temporal variation in surgical techniques or immunosuppressive regimens may have influenced outcomes and should be considered when interpreting these findings. Another important limitation of this study is that reoperations were defined by procedural codes that capture any cervical spine surgery, regardless of anatomical level or clinical indication. As such, the database does not distinguish between reoperations performed at the index level versus those related to adjacent pathology or new indications. This restricts our ability to infer causality or attribute reoperations directly to complications from the index ACDF procedure. Consequently, some of the observed statistical differences, including in reoperation-free survival, should be interpreted cautiously and may not reflect a clinically substantial divergence in surgical durability. Additionally, while the use of a large multi-institutional database strengthens generalizability, it also limits clinical granularity. We are unable to determine specific causes of reoperation, index-level involvement, perioperative medication management, or disease activity at time of surgery. These unmeasured confounders may influence both outcomes and their interpretation. Therefore, while associations are robust, causality cannot be inferred. Lastly, although this study included a two-year follow-up, certain long-term complications, such as pseudarthrosis, may manifest beyond this window and were therefore not fully captured. Future prospective studies with extended follow-up and granular clinical data are necessary to validate these findings and further refine perioperative strategies for RA patients undergoing ACDF.

Conclusions

This study supports the hypothesis that RA patients receiving DMARDs undergoing ACDF experience higher reoperation rates and hospital readmissions at 90 days and 2 years postoperatively. Although DMARD use was not associated with increased rates of systemic infection, their relationship with increased reoperation risk underscores the need for careful preoperative evaluation and vigilant postoperative monitoring. Further studies should explore certain questions concerning the overall implication of ACDF in RA patients, specific sorts of DMARDs, the ideal course of action before and after surgery, and the long-term repercussions of the intervention beyond the two-year mark. Future multicenter randomized trials and prospective studies should be carried out and help to specify the factors influencing such parameters as length of hospital stay, recurring costs, and to confirm these outcomes. Ultimately, this study emphasizes the importance of case specific surgical management for RA patients undergoing ACDF surgery and highlights the need for a multidisciplinary collaboration between primary care physicians, rheumatologists and spine surgeons to optimize patient care and improve clinical outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-25-134/rc

Data Sharing Statement: Available at https://jss.amegroups.com/article/view/10.21037/jss-25-134/dss

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-25-134/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-25-134/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Publication of this retrospective review was waived from patient consent according to the HIPPA privacy rule defined in Section §164.514(a). The data reviewed is a secondary analysis of existing data, does not involve intervention or interaction with human subjects, and is de-identified per the de-identification standard defined.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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