Abstract
Background:
Rheumatoid arthritis patients are at increased risk for periprosthetic joint infection after arthroplasty. The reason is multifactorial. Nasal colonization with Staphylococcus aureus is a modifiable risk factor; carriage rates in RA patients is unknown. The goal of this study was to determine the S. aureus nasal carriage rates of RA patients on biologics, RA patients on traditional DMARDs, and osteoarthritis.
Methods:
Consecutive patients with RA on biologics (+/− DMARDs), RA on non-biologic DMARDs, or OA were prospectively enrolled from April 2017 to May 2018 123 patients were determined necessary per group to show a difference in carriage rates. Patients underwent a nasal swab and answered questions to identify additional risk factors. S. aureus positive swabs were further categorized using Spa typing. Logistic regression evaluated the association with S. aureus colonization between the groups after controlling for known risk factors.
Results:
RA patients on biologics, 70% of whom were on DMARDs, had statistically significant increase in S. aureus colonization (37%) compared to RA on DMARDs alone (24%), or OA (20%) p = 0.01 overall. After controlling for glucocorticoids, antibiotic use, recent hospitalization, and diabetes, RA on biologics had a significant increased risk of S. aureus nasal colonization (OR=1.80, 95% CI 1.00-3.22); p=0.047).
Conclusion:
S. aureus colonization risk was increased for RA on biologics compared to RA not on biologics and OA. Nasal S. aureus carriage increases the risk of surgical site infection; this modifiable risk factor should be addressed prior to total joint arthroplasty for this higher risk patient group.
Keywords: S. aureus colonization, rheumatoid arthritis, osteoarthritis, biologics, tumor necrosis factor inhibitors (TNFi), periprosthetic joint infection
Introduction
Patients with rheumatoid arthritis (RA) are at increased risk of periprosthetic joint infection (PJI) and surgical site infection (SSI) after total joint arthroplasty, as compared to patients with osteoarthritis (OA)(1,2). The increased risk of infection is multifactorial and may relate to inherent immunologic dysregulation associated with the disease which may not be modifiable , while treatment with biologics disease modifying anti-rheumatic drugs (DMARDs)medications is a presumptive risk factor for surgical site infection, the association has been hard to define. Although biologics are routinely discontinued at the time of arthroplasty to mitigate the risk of infection, RA patients continue to have an increased risk of complication.
Nasal colonization with S. aureus has been identified as a significant risk factor for surgical site infection (3,4), but the prevalence of nasal colonization in patients with RA, and the factors that increase the risk of S. aureus colonization in patients with RA are not well established. In the general population, the prevalence of S. aureus colonization has been reported at 30% (5). In cross-sectional studies performed in rheumatology outpatient clinics, persistence of S. aureus colonization was shown to be greater in RA patients on tumor necrosis factor inhibitors (TNFi) compared to those not on a TNFi, especially if they were on combination TNFi plus MTX treatment, however the absolute rate of S. aureus colonization was similar to RA patients on DMARDs alone (6-8).
The purpose of this study was to determine if 1.) S. aureus colonization prevalence is different among RA patients on biologics, RA patients on traditional DMARDs, or OA, and 2.) Thereby identify an actionable risk factor for surgical site infection in patients with RA. We also assessed the relative prevalence of methicillin-susceptible (MSSA) and methicillin-resistant S. aureus (MRSA) in the study cohort as well as genetic variations in S. aureus in the study cohort and measured DNA sequence variation in the polymorphic region of S. aureus protein A as genetic marker for strain typing. Our hypothesis is that RA patients, both on or not on a biologic, would have a higher rate of S. aureus colonization than OA patients, and that treatment with a biologic medication would further increase the colonization rate.
Methods and Study Design
Patients
This study prospectively enrolled 369 adults ≥ 18 years of age diagnosed with either RA or OA in 3 equal groups of 123 patients based on an a priori power analysis to detect a relative difference of 20% among groups with 80% power. The 3 groups included: 1.) RA patients on biologics, who could also be on traditional DMARDs, 2.) RA patients not on biologics but could be on traditional DMARDs, and 3.) lower extremity (hip and knee) OA patients. We included the oral small molecule tofacitinib among the biologics in light of the similar mechanism of action as a targeted therapy. For RA patients not on biologics, treatments could include DMARDs or alternative therapies. All patients were seen in outpatient clinics at a tertiary care orthopedic specialty hospital between April 2017 and May 2018. The RA cohort met the ACR 1987 or 2010 criteria for the diagnosis of RA (9,10). Patients in the OA group met 1991 ACR classification criteria for the diagnosis of OA. After inclusion criteria were verified, patients were concurrently enrolled into one of the three groups, assuring that one group did not enroll more than the others during each season to avoid the possibility of S. aureus carrier change with seasonal variation. Patients were excluded if they had systemic lupus erythematosus (SLE) or another autoimmune disease, active infection, or had received antibiotics within the month prior to recruitment. Demographic and clinical data, including age, sex, BMI, smoking history, prior hospitalizations, and medication history (including disease modifying anti-rheumatic drugs (DMARDs), biologics, and history of glucocorticoid use) was collected. The study was approved by our local Institutional Review Board.
Nasal swab Collection and Processing
Sterile cotton swabs (S/P® Brand CultureSwab Swab, Becton, Dickinson and Company, Cardinal Health, McGraw Park, IL) were used. Patients were instructed on how to perform a nasal swab using the Center for Disease Control’s swabbing protocol and performed the nasal swab themselves in the presence of a research assistant. Patients then placed the swab into its sterile tube which was then immediately transferred to a 4.5-degree Celsius (range 2-8 °C) refrigerator. Swabs were stored in the refrigerator for no more than 14 days and were then sent for plating and evaluation at New York University, Division of Infectious Disease and Immunology lab. There, swabs were inoculated directly onto BBL ChromAgar/ChromID MRSA Staph aureus medium (Becton, Dickenson and Company, Cardinal Health, McGraw Park, IL) and incubated at 37°C for 48 h. Mauve colonies that grew only on ChromAgar plates and protein A were presumptively considered MSSA. Organisms that also grew on ChromID MRSA plates were presumptively identified as MRSA. Individual colonies were streaked onto sheep blood agar (5% on trypticase soy agar; Remel, Lenexa, KS) and incubated overnight at 37°C. The presence of the Protein A and methicillin-resistance genes was confirmed on all suspected S. aureus by polymerase chain reaction analysis of the spa and mecA genes, respectively (11,12).
Bacterial genotyping
The relatedness of S. aureus strains was determined by DNA sequence analysis of the protein A gene variable repeat region (spa typing) (12). spa types were used to identify multilocus sequence typing (MLST) clonal complexes, using the Ridom SpaServer database (available at: http://spa.ridom.de/mlst.shtml) (13).
Statistical analysis
An a priori power analysis determined 123 participants per group were needed to detect a relative difference of 20% S. aureus carriage among groups with 80% power. Mann-Whitney U and Chi-square tests were used to evaluate baseline differences between groups. A univariate analysis was initially performed and significant differences between the groups were identified. An unadjusted subanalysis was also included to explore the association between groups and S. aureus carriage when OA was the reference group. A logistic regression controlling for age, BMI, diabetes, glucocorticoid use, antibiotics within 3 months, and hospitalization, was then used to evaluate the association between the 3 groups and S. aureus carriage. All statistical analyses were performed using SAS Software version 9.3 (SAS Institute, Cary, NC); statistical significance was defined as p<0.05.
Results
Overall 369 patients were prospectively enrolled in the study and underwent nasal swab testing. The mean (standard deviation) age was 66 (SD 13.7), BMI 29 (SD 28.2), 78% were female, 7% had diabetes, 28% received antibiotics 31-90 days prior to the nasal swab, 24% had been hospitalized within the last year, and 18% were actively on glucocorticoids. Patients with osteoarthritis were more likely to have diabetes (p=0.04), to have been hospitalized in the last year (p=0.0001), and to have received antibiotics 31-90 days prior (p=0.0001) than patients in either RA group, whereas RA patients were more likely to be smokers (p=0.009), female (p= <0.0001), and to have received glucocorticoids (p=0.02) (Table 1). For RA patients on biologics, the most common were adalimumab (28%), etanercept (25.2%), abatacept (12.2%), and rituximab (12.2%) (Table 2). 86 (70%) of the biologics group were also on a traditional DMARD.
Table 1:
Characteristics of the cohort and differences between the groups
| Variable | All Patients (n=369) |
RA + Biologic (n=123) |
RA no Biologic (n=123) |
OA (n=123) | p-value |
|---|---|---|---|---|---|
| Age (Mean ± SD) | 65.63 ± 13.77 | 59.15 ± 14.4 | 65.82 ± 13.86 | 71.91 ± 9.51 | <0.0001 |
| Sex: female, n (%) | 289 (78.32) | 108 (87.8) | 106 (86.18) | 75 (60.98) | <0.0001 |
| BMI, kg/m2 (Mean ± SD) | 28.17 ± 7.00 | 27.98 ± 7.12 | 26.36 ± 6.08 | 30.19 ± 7.25 | <0.0001 |
| Ethnicity, Hispanic or Latino, n (%) | 27 (7.32) | 8 (6.5) | 14 (11.38) | 5 (4.07) | - |
| Race, White, n (%) | 294 (79.67) | 87 (70.73) | 97 (78.86) | 110 (89.43) | - |
| Synthetic DMARDS n (%) | |||||
| Methotrexate | 139 (37.67) | 59 (47.97) | 80 (65.04) | - | - |
| Leflunomide | 30 (8.13) | 17 (13.82) | 13 (10.57) | - | - |
| Hydroxychloroquine | 29 (7.86) | 9 (7.32) | 20 (16.26) | - | - |
| Sulfasalazine | 3 (0.81) | 1 (0.81) | 2 (1.63) | - | - |
| Smoker (ever), n (%) | 148 (40.11) | 43 (34.96) | 42 (34.15) | 63 (51.22) | - |
| Smoker (current), n (%) | 19 (12.84) | 10 (23.26) | 6 (14.29) | 3 (4.76) | - |
| Diabetes, n (%) | 27 (7.32) | 6 (4.88) | 6 (4.88) | 15 (12.2) | 0.04 |
| Hospitalization in past year n (%) | 89 (24.12) | 22 (17.89) | 14 (11.38) | 53 (43.09) | <0.0001 |
| Glucocorticoids, n (%) | 67 (18.16) | 32 (26.02) | 18 (14.63) | 17 (13.82) | 0.02 |
| Antibiotics in past 3 months, n (%) | 104 (28.18) | 29 (23.58) | 21 (17.07) | 54 (43.90) | <0.0001 |
| Years since RA diagnosis (Mean ± SD) | 11.55 ± 10.70 | 13.55 ± 11.01 | 9.55 ± 10.03 | 0 | - |
| Years since OA diagnosis (Mean ± SD) | 24.17 ± 176.99 | 0 | 0 | 25.54 ± 181.94 | - |
| Positive S. aureus growth, n(%) | 99 (26.83) | 45 (36.59) | 29 (23.58) | 25 (20.33) | 0.01 |
Table 2:
Biologic Use among RA patients
| Biologic | Frequency (%) |
|---|---|
| Adalimumab | 35 (28.5) |
| Etanercept | 31 (25.2) |
| Abatacept | 15 (12.2) |
| Rituximab | 15 (12.2) |
| Tocilizumab | 9 (7.3) |
| Infliximab | 7 (5.7) |
| Golimumab | 4 (3.3) |
| Tofacitinib | 4 (3.3) |
| Certolizumab | 2 (1.6) |
| Sarilumab | 1 (1.0) |
In the RA group not on biologics, 65% were on methotrexate, 16% on hydroxychloroquine, 11% on leflunomide, and 1.6% on sulfasalazine (Table 3).
Table 3:
Synthetic DMARD Use in Patients with RA, RA + Biologics, and OA
| Synthetic DMARDS n (%) | RA + Biologics | RA | OA |
|---|---|---|---|
| Methotrexate | 59 (47.97) | 80 (65.04) | 0 |
| Leflunomide | 17 (13.82) | 13 (10.57) | 0 |
| Hydroxychloroquine | 9 (7.32) | 20 (16.26) | 0 |
| Sulfasalazine | 1 (0.81) | 2 (1.63) | 0 |
S. aureus colonization and characteristics
In all three groups combined, 99 (26.83%) had a positive cultures for S. aureus. A univariate analysis was performed and demonstrated significant differences between the groups in S. aureus carriage S. aureus carriage was most prevalent in RA patients on biologics (37%), followed by RA not on a biologic (24%), and OA (20%). For patients taking both biologics and traditional DMARDs combined, 35% grew S. aureus, of which 17% were MRSA. There was no difference in MRSA prevalence for those on combination therapy (p=0.55) compared to those on biologics alone. In an unadjusted sub analysis using OA as the reference group, there was no significant increase in S.aureus risk for RA (OR 1.2 (95% CI 0.66-2.2), while for RA+ biologics, the risk was increased OR 2.3(95%CI 1.3-4.0) (Table 4). After multivariate adjustment, the RA+ biologics group was found to have a significant increased odds of S. aureus colonization (OR=1.80, 95% CI 1.00-3.22); p=0.047) compared to the RA group not on biologics (Table 5). The OA group had a trend towards decreased odds of S. aureus growth when compared to the RA group; however this was not found to be statistically significant (p=0.99). Use of glucocorticoids, antibiotics, recent hospitalization, or diabetes did not influence the odds of S. aureus carriage in the multivariable regression analysis.
Table 4:
Unadjusted sub-analysis using OA as a reference group
| Group | OR (Unadjusted) | p-value |
|---|---|---|
| OA vs. RA | 1.2 (0.66-2.2) | 0.54 |
| OA vs. RA+B | 2.3 (1.3-4.0) | 0.01 |
Table 5:
Multivariable Regression of the Risk of S. aureus colonization
| Effect | OR | 95% Wald Confidence Limits |
p-value | |
|---|---|---|---|---|
| OA vs. RA no biologics | 0.99 | 0.50 | 1.96 | 0.98 |
| RA + biologics vs. RA no biologics | 1.80 | 1.01 | 3.22 | 0.047 |
| Age | 0.99 | 0.97 | 1.01 | 0.21 |
| BMI | 1.01 | 0.97 | 1.04 | 0.66 |
| Sex (Male vs. Female) | 0.80 | 0.43 | 1.50 | 0.49 |
| Diabetes (Yes vs. No) | 1.29 | 0.52 | 3.19 | 0.59 |
| Glucocorticoids use (Yes vs. No) | 0.79 | 0.42 | 1.48 | 0.46 |
| Antibiotics in past 3 months (Yes vs. No) | 0.88 | 0.50 | 1.56 | 0.66 |
| Hospitalized in past year (yes vs. no) | 0.82 | 0.44 | 1.53 | 0.52 |
Multivariable analysis controlling for age, BMI, Diabetes, Glucocorticoid use, antibiotics within 3 months, and hospitalization. Bold values indicate significant data.
Overall, among 100 S. aureus-colonized patients, 8% were colonized by MRSA and 92% were colonized by MSSA. All isolates underwent PCR-sequencing of the staphylococcal protein A (spa) repeat region to determine the genetic relatedness of S. aureus isolates (12). This method, known as spa typing, is a front line DNA sequence-based typing method to determine the genetic relatedness of S. aureus isolates. Sixty-eight different spa types were identified, with no one genotype accounting for more than 8% of the strains. The distribution of the four predominant spa clusters, based on the pattern of the repeat region, is similar to that recently described for MSSA in the United States (spa cluster frequencies: t002, 17%; t012, 16%; t008, 11%; t084, 8%)(14). Thus, genotypic diversity was high, consistent with the high proportion of MSSA in the study population and the high degree of genetic diversity associated with MSSA compared to MRSA strains (14). Comparison of spa type diversity among nasal isolates from 74 RA patients with those of 25 OA patients demonstrated that both groups were nonclonal and equally diverse. Thus, there was no evidence of clustering of spa types by diagnosis, and colonizations did not reflect dissemination of an outbreak strain, which could skew results.
Discussion:
This study demonstrates that patients with RA treated with biologics have an increased risk of S. aureus nasal colonization. While S. aureus carriage was most prevalent in patients with RA on biologics (37%), nasal S. aureus carriage was present in 24% of RA not on biologics, and 20% of patients with OA. RA treated with traditional DMARDs without biologic therapy was not an independent risk factor for S. aureus carriage, but treatment with biologics increased the risk of nasal S. aureus carriage by 80%. Moreover, those patients taking both biologics and traditional DMARDs have the same risk for S. aureus carriage as those on biologics alone; suggesting that the heightened risk of colonization is associated with use of biologic medications. While more patients with RA on biologics also received glucocorticoids, glucocorticoid use was not an independent risk factor for S. aureus carriage. It was surprising that OA patients were significantly more likely to have diabetes, to have received a prior antibiotic, and to have been hospitalized during the 3 months prior to obtaining the culture; nonetheless, fewer OA patients had positive S. aureus nasal carriage. Neither antibiotic use, hospitalization, nor diabetes were independent risk factors for S. aureus colonization.
S. aureus is the most common cause of overall hospital acquired infections (4,15-18), and is the most common pathogen identified in skin and soft tissue infection in patients with RA being treated with either TNFis or traditional DMARDs (4,18,19). In addition, where microbiologic diagnosis for septic arthritis including PJI was available, S. aureus was the most frequently reported organism in RA patients whether they were treated with TNFi (57%) or a traditional DMARDs (43%) (20). DMARDs and biologics are known to increase infection risk and are often in use by RA patients at the time of arthroplasty (21,22), but the association of DMARDs and biologics with surgical arthroplasty infections has not been directly established through randomized controlled trials performed in patients undergoing surgery (23,24). However, in a registry database study, the risk of septic arthritis including PJI was doubled for RA patients treated with TNFi, and a meta-analysis of surgical site infection in patients exposed to TNFi also showed an elevated infection risk (OR 2.47, 95% CI 1.66, 3.68) (20,25). However, a pharmaco-epidemiologic study using a large insurance database did not find an association between infliximab use and infection after arthroplasty (23). Altered immune function in active RA increases the risk of infection, and active RA at the time of arthroplasty may contribute to increased risk of PJI infection in these patients (26,27).
While prior studies have not demonstrated a difference in S. aureus colonization for patients with RA overall, small numbers, or possibly inclusion of patients with less severe RA, may have prevented identification of medication-associated risks (7,8). However, in this study, neither recent hospitalization nor glucocorticoid use, surrogate measures for disease severity, influenced the risk of S. aureus carriage.
Only 8 of the 99 (8%) nasal swab colonized patients had MRSA. This is comparable to the results seen in earlier studies demonstrating a low frequency of MRSA colonization among individuals in the community (28). Indeed, community acquired (CA)-MRSA USA300 (spa type 1/t008, positive for staphylococcal cassette chromosome mec type IV [SCCmec IV], pvl, and the arginine catabolic mobile element [ACME]) was identified in isolates from 2% of patients in recent studies (29-31).
This study has certain limitations. Cultures were only obtained by nasal swab, as the association with surgical site infections is strongest with nares cultures; however, while the addition of other sites such as the throat or the surgical site might increase in culture yield, the increase is unlikely to be large (4, 32-34). Moreover, a difference in carriage would likely affect all three tested groups equally. In addition, patients performed the swabs, which might have introduced error, although they were instructed and observed by a member of the research team. While the low baseline colonization rate of 20% among OA patients might indicate our assay was not sensitive, this would indicate a higher rate among RA patients as the assay sensitivity would affect all groups equally. We were unable to analyze colonization risk differences between the biologics due to small number in each group. We also found little differences in genetic variation; however, this may be due to limitations in sample size as genetic associations require much larger samples. Finally, as with all observational studies, although we controlled for known risk factors, unmeasured confounders may also play a role.
We believe that our findings may have clinical impact in the perioperative care of RA patients. Decolonization of surgical patients may reduce risks of surgical site infection, but implementation of institutional programs to decolonize all perioperative patients empirically, or to screen and treat, can be cumbersome and have not been shown to be cost-effective (35). Common decolonization techniques include mupirocin and chlorhexidine at home, versus single-application treatment with a commercial iodine preparation just prior to incision. RA patients on biologics, who we have identified as higher risk of S. aureus colonization, as well as an increased baseline risk of infection, are a cohort which might benefit maximally from such a universal perioperative decolonization protocol.
In conclusion, this study demonstrates that patients with RA treated with biologics have an increased prevalence of S. aureus nasal colonization. Since nasal S. aureus carriage may play a role in the pathogenesis of surgical infections, our results help explain the increase in surgical infections in RA patients on TNF inhibitors, and support the use of decolonization protocols in order to potentially decrease the increased risk of PJI seen in patients with RA undergoing joint replacement surgery.
Supplementary Material
Acknowledgements
The content is solely the responsibility of the authors and does not necessarily represent the official views of the Complex Joint Reconstruction Center.
Funding
This work was supported by the National Center For Advancing Translational Science of the National Institute of Health [UL1TR002384]; The Weill Cornell Clinical and Translational Science Center [UL1-TR000457-06]; The Complex Joint Reconstruction Center at Hospital for Special Surgery; The National Institutes of Health [R01 AI103268 (to B.S.)]; and National Institute of Allergy and Infectious Diseases [HHSN272201400019C (to B.S)].
Footnotes
Disclosure statement: The authors disclose the following conflicts of interest: royalties are received from Lima- total elbow and Exactech; paid consultants for Wishbone, Lima Corporate, Novartis, Pfizer, and UCB; stock in Wishbone, insight and mekanika; research support recieved from Karius Inc., Intellijoint Surgical, Novartis; Board Members for the American College of Rheumatology, Rheumatology research foundation BOD, Guidelines Committee for the American College of Rheumatology, Knee Society Board Member.
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