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EDITORIAL

Anti-TNF-alpha use and TEA infection risk

Kasraeian S1, Arkfeld DG2, Fogle EF1, Hatch GF1, Reehal V2, Lee B1 , Itamura JM1.

1Department of Orthopedic Surgery, 2Department of Rheumatology, University of Southern California, Los Angeles, CA

Address for Correspondence:

Daniel Arkfeld, M.D.

Associate Professor of Medicine, University of Southern California,

Keck School of Medicine,Department of Medicine – Rheumatology

2011 Zonal Ave, HMR 711

Phone:  (323) 442-1946
Fax    :  (323) 442-2874
E-mail:
arkfeld@usc.edu

Abstract:

Advancements in total elbow arthroplasty (TEA) have popularized this option for end-stage elbow arthritis in patients with rheumatoid arthritis (RA).  Whether anti-tumor necrosis factor (TNF)-α agents place these patients at increased risk of infection after TEA remains controversial.  The purpose of this study is to determine if anti-TNF-α agent use after TEA is associated with increased infection rates.  We reviewed 36 TEAs, in 34 patients, performed at our institution from 2000 to 2007.  Those exposed to anti-TNF-α agents postoperatively had a 25% infection rate compared to 20% in those unexposed.  Patients using prednisone postoperatively had a 46.2% infection rate compared to 8.7 % in those not on prednisone.  While there was no statistically significant increase in infection rate in patients taking anti-TNF-α agents after TEA, there was a statistically significant increase in the infection rate of patients using prednisone postoperatively.  We conclude that physicians should exercise caution when prescribing prednisone to patients who have recently undergone TEA.  Further investigation is needed regarding infection risks associated with the use of anti-TNF-α agents after TEA.

Level of Evidence: Retrospective study, Level III

J.Orthopaedics 2009;6(3)e1

Keywords: Rheumatoid Arthritis; Total Elbow Arthroplasty, TNF

 

Introduction:

Rheumatoid arthritis (RA) is a potentially devastating condition, afflicting approximately 1-2% of the general population.10,15   Among other organs, joints are targets of inflammation and destruction, resulting in the need for joint replacement in a significant portion of rheumatoid patients.10,15  Wolfe and Zwillich reported that 25% of rheumatoid patients (N=1600) required a major joint replacement over a 23-year period; of those, 3% were upper extremity arthroplasties.24  Palm et al. showed that over a 25-year period, 27% of rheumatoid patients (N=60) underwent some type of arthroplasty, 17% of which were total elbow arthroplasties (TEA).17

Rheumatoid disease involves the elbow in 20-50% of cases and is a major cause of elbow arthritis.10 Although other options exist, advancements in technology have popularized TEA as a viable method of preserving elbow function in RA patients.15,20  As with any type of arthroplasty, however, the risk of potential infections must be realized.  Patients with RA are susceptible to infection given their altered immunoregulation, debility, comorbidities, and disease severity. Long-term immunosuppressive medications also contribute to an increased incidence of infection.4,5,18,25

Anti-tumor necrosis factor (TNF)-α agents, as well as B and T cell directed therapies, have been used to help control rheumatoid disease.  As immunosuppressants, they limit joint inflammation and destruction; however, they also inhibit the body’s ability to resist infection.13   Salliot et al. showed an increased infection risk in patients taking TNF-α blockers, and recommended close monitoring in patients using those medications.16  In a review of recent English literature, TEA studies have noted complication rates of 0% to 50%,2,4,7,9,14,15,20,23 and infection rates of 0% to 6.4%.2,4,5,6,9,11,1214,15,19,21,22,23  Of interest is how the advent of anti-TNF-α agents will affect infection rates in TEA.  To our knowledge, no study to date has addressed this question. The purpose of this pilot study was to compare infection rates among rheumatoid patients, treated with and without anti-TNF-α agents, to determine if the use of TNF-α inhibitors was associated with an increased risk of infection after TEA.

Materials and Methods:

A chart review was performed of all patients who underwent a primary or revision TEA, by the senior author (J.M.I.), from October 2000 to October 2007.  Patients who had a history of RA or inflammatory arthroplasty were included in the study; results of arthroplasties performed by other surgeons were excluded (i.e. infections or complications, etc.).  One patient was excluded due to lack of follow-up data.  A second patient was excluded due to significant wound dehiscence within three weeks due to gross non-compliance with her postoperative instructions (doing push-ups within three weeks of surgery).  Another patient was excluded because her postoperative course was complicated by an open fracture.  In total, 36 TEAs in 34 patients were included in the study.

Patients who initially presented to our institution with infection (septic elbow or infected TEA) underwent irrigation and debridement, hardware removal (if infected TEA), antibiotic spacer placement and a course of intravenous antibiotics.  Reimplantation was performed after the infection had resolved. 

Patients were separated into two groups, based on use of anti-TNF-α agents (etanercept, infliximab and adalimumab).  Group 1 patients (n=16) were exposed to anti-TNF-α agents after surgery while Group 2 patients (n=20) were not.  Some Group 2 patients were on anti-TNF alpha agents preoperatively, but discontinued those agents weeks to day(s) before surgery.

We compared infection rates of patients taking postoperative anti-TNF-α agents and/or prednisone with patients not on those agents after surgery.  We also evaluated other factors possibly associated with an increased risk of infection, including history of previous infection or previous TEA, comorbidities, preoperative lab values, and the use of other anti-inflammatory medications, such as methotrexate, prednisone, hydroxychloroquine and nonsteroidal anti-inflammatory drugs (NSAIDs).  The type of prosthesis and other surgical details such as blood loss, tourniquet time, length of surgery, use of antibiotics, cement and/or allograft were also compared.

Each patient with a primary TEA underwent similar procedure, with a Depuy (Warsaw, IN), Tornier (Montbonnot, France), or Zimmer (Warsaw, IN) implant using a Bryan-Morrey approach.  Patients who were revised or replanted had incisions based on the previous surgeries.  Follow-up data was obtained through chart review and direct conversations with the patients (two patients) and/or their physicians (one patient), when available for contact.  Endpoint for follow-up was determined by last clinical follow-up or by the occurrence of infection, revision, resection, or re-operation for any reason.

Statistical methods
The following variables were considered as univariate predictors of infection post surgery: primary surgery on joint (yes/no), rheumatologic medication use, including methotrexate, NSAIDs, hydroxychloroquine and use of anti-TNF-α agents both pre- and postoperatively (yes/no), constrained prosthesis (yes/semi/no), allograft use (yes/no), type of prosthesis (CMA/Depuy/Tornier), previous infection (yes/no), sex (m/f), smoking (yes/no), alcohol use (yes/no), surgical approach (previous incision/mb), previous elbow surgeries, radial head replacement (yes/no), preexisting conditions/comorbidities (hypertension, hypothyroidism, etc (yes/no)), preoperative laboratory values divided at less than or equal to the median versus greater than (white blood count (WBC) median 7.5 K/cumm, WBC % median 65.5%, average neutrophil count (ANC) median 4.6, hematocrit median 37.25%, hemoglobin median 12.05 g/dL, platelet median 319 K/cumm as well as WBC divided at less than 5, 5-10 and greater than 10).  The following were also compared with cut time at less than or equal to versus greater than median: operative time (135); tourniquet time (84); estimated blood loss (150) and age (53).  Platelets count was cut at 400/L.

Due to the small sample size, all tables had at least one cell with expected counts less than five.  Thus, Fisher’s exact test was used to test the association between postoperative infection and each of the variables listed above.  Exact confidence limits on ORs for these univariate predictors were computed.  As this was an exploratory study with a small samplesize, an alpha=0.10 was used and two-sided p-values reported.

All confidence intervals reported on rates of infection and ORs were exact confidence intervals.  All analyses were performed with use of SAS software (version 9.1; SAS Institute, Cary, North Carolina).

Results :

Overall patient results
Median follow-up time was 7.59 months (range 0.39 – 58.26).  The overall rate of infection was 22.22% (90% exact confidence interval 11.57 – 36.54).  The infection rate in elbows exposed to anti-TNF-α agents postoperatively was 25% (90% confidence interval 9.03 – 48.44) compared with 20% (90% confidence interval 7.14 – 40.10) in those not exposed. While this equated to 1.33 greater odds of infection (OR) in the anti-TNF-α agents group, the difference was not statistically significant (p = 1.0) (Table 1)

Table 1. Infection rate and anti-TNF-α use after TEA. 

 

Infection

No Infection

Total

anti-TNF-α post

4

12

16

No anti-TNF-α post

4

16

20

Total

8

28

36

The rate of infection in patients exposed to postoperative anti-TNF-a agents was 25% (90% confidence interval 9.03 – 48.44) and 20% (90% confidence interval 7.14 – 40.10) in patients not exposed to postoperative anti-TNF-a agents, OR=1.33 (90% confidence interval 0.26 – 6.67, p = 1.0).

We also evaluated other factors possibly associated with an increased risk of infection, including history of previous infection or previous TEA, comorbidities, preoperative lab values and the use of other anti-inflammatory medications, such as methotrexate, prednisone, hydroxychloroquine and NSAIDs.  We compared the type of prosthesis and other surgical details such as blood loss, tourniquet time, length of surgery, use of antibiotics, cement and/or allograft.  None met the alpha less than or equal to 0.10 threshold except for the use of prednisone and abnormal white cell count (less than 5 or greater than 10).  The clinical significance of the abnormal white count was undetermined (Table 2).

Table 2. Infection rate and preoperative WBC count (K/cumm) in TEAs 

 

Infection

No Infection

Total

WBC 5-10

3

14

17

WBC >10

2

0

2

WBC <5

3

1

4

Total

8

15

23

Infection rate in patients with preoperative WBC 5 -10 was 17.56% (90% confidence interval 4.99 – 39.56), 100% in patients with WBC > 10 (90% confidence interval 22.36 – 100.00) and 75% in patients with WBC < 5 (90% confidence interval 24.86 – 98.73). Patients with preoperative WBC > 10 had a greater risk of infection postoperatively than those with WBC 5-10 (OR=inestimable due to zero cell).  Patients with preoperative WBC < 5 had a greater risk of infection postoperatively than those with WBC 5-10 (OR=14.00, 90% confidence interval 0.97 – 385.20), p=0.0135.

The use of prednisone postoperatively demonstrated statistical significance (p = 0.0157) as a 46.15% infection rate was observed (90% confidence interval 22.40 – 71.30) compared with 8.70% (90% confidence interval 1.57 – 24.92) in those not treated postoperatively with prednisone.  This translated to 9.0 times greater odds of infection (OR=9) (90% confidence interval 1.49 – 69.23) in elbows exposed to postoperative prednisone (Table 3).

Table 3. Infection rate and prednisone use after TEA.

 

Infection

No Infection

Total

Prednisone Post

6

7

13

No Prednisone Post

2

21

23

Total

8

28

36

Infection rate in patients exposed to postoperative prednisone was 46.15% (90% confidence interval  22.40 – 71.30) compared to 8.70% in those not exposed to postoperative prednisone (90% confidence interval 1.57 – 24.92). (OR=9.0, 90% confidence interval 1.49 - 69.23), p=0.0157.

Multivariate analysis
In order to identify the best multivariate set of variables that predicted infection, all variables were initially entered into a multivariate logistic regression using the best subsets maximum likelihood chi-square score method for selection.  The final criteria for selection of the best model were: 1) the model must converge 2) it must increase the chi-square score statistic by more than 1 compared to a model with one less variable, and 3) the p-value for the parameter estimate for each individual variable in the model must be less than or equal to 0.10. No converging model was found that predicted infection better than postoperative prednisone use by itself. 

Primary patient results
The above analysis was also conducted on the subset of patients that underwent primary surgeries.  The rate of infection in primary patients was 21.74% (90% confidence interval 8.98 – 40.39), with a median follow-up time of 7.10 months (range: 12 days to 41 months). Patients on postoperative anti-TNF-α agents had a 30% infection rate (90% confidence interval 8.73 – 60.66), compared to 15.38% in those unexposed (90% confidence interval 0.00 – 31.84) – a 2.4-fold increase in odds of infection (OR=2.4, 90% confidence interval 0.28 – 22.49) in patients exposed to postoperative anti-TNF-α agents (Table 4).  This difference was not statistically significant (p = 0.6175) 

Table 4. Infection rate and anti-TNF-α use after primary TEA. 

 

Infection

No Infection

Total

anti-TNF-α post

3

7

10

No anti-TNF-α post

2

11

13

Total

5

18

23

 Infection rate in patients exposed to postoperative anti-TNF-a agents was 30% (90% confidence interval 8.73 – 60.66) compared to 15.38% in patients not exposed to postoperative anti-TNF-alpha agents  (90% confidence interval 0.00 – 31.84). (OR=7.80, 90% confidence interval 0.62 – 216.02), p= 0.117.

As in the overall patient analysis, the infection rate of patients taking prednisone postoperatively was greater than in those who were not.  Those on prednisone postoperatively had a 42.86% infection rate (90% confidence interval 12.88 – 77.47) compared with 12.50% in patients not taking postoperative prednisone (90% confidence interval 2.27 – 34.38), with OR = 5.25 (90% confidence interval 0.56 – 51.39).  However, this difference did not meet statistical significance (p = 0.1421) (Table 5).

Table 5. Infection rate and prednisone use after primary TEA.

  Infection No Infection Total
Prednisone Post 5 4 7
No Prednisone Post 2 14 16
Total 5 18 23

Infection rate in patients taking postoperative prednisone was 42.86% (90% confidence interval 12.88-77.47) compared to 12.50% in patients not exposed to postoperative prednisone (90% confidence interval 2.27 - 34.38). (OR=5.25, 90% confidence interval 0.56 - 51.39, p=0.1421).

In terms of other investigated variables, only patients with a preoperative platelet level greater than 400/L met the alpha less than or equal to 0.10 threshold (Table 6).  Once again, the clinical significance of the abnormal laboratory values was undetermined.  No multivariate model met the previously mentioned criteria for model selection, most likely due to the small sample size.

Table 6. Infection rate and preoperative platelet count in primary TEAs 

 

Infection

No Infection

Total

Platelet cont > 400

3

1

4

Platelet count <= 400

2

11

13

Total

5

12

17

Infection rate in patients with preoperative platelet count > 400/L was 75.00% (90% confidence interval 24.86 – 98.73) compared to 15.38% (90% confidence interval 2.81 – 41.01) in those with platelet count < 400 (OR=16.50, 90% confidence interval .97 – 461.45, p=0.0525). Of the 23 primary elbows, 6 were missing platelet data.

Discussion :

To our knowledge, this is the first report specifically assessing the use of anti-TNF-α agents in patients with RA undergoing TEA as a potential risk factor for infectious complications.  Our data did not show a statistically significant increase in infection rate among patients on anti-TNF-alpha agents following TEA.  While the use of prednisone was more predictive of postoperative infection, methotrexate and hydroxychloroquine did not impose this risk.

The increase in infection rates found with prednisone use is consistent with other prednisone studies.  Doran et al. reviewed 609 patients previously diagnosed with RA for development of infections.  Among the factors predicting infection, use of corticosteroids was a strong predictor, while use of disease-modifying anti-rheumatic drugs (DMARDs) was not associated with increased risk.3   Bernatsky et al. evaluated 23,733 patients with rheumatoid arthritis and showed an elevated risk of infection associated with anti-rheumatic medications such as systemic glucocorticoids (RR 2.56) and cyclophosphamide (RR 3.26).1 

Our study was limited by its low power and its short follow-up period.  Additionally, there was a large variability in the medication regimens with regard to administration and discontinuation of medication protocols, pre-, peri- and postoperatively.  Another limitation was the small number of patients who were candidates for primary TEA (i.e. no previous TEA or infection).  Although our specific test population was intrinsically small in number, we considered 36 elbows a clinically significant number, especially for an exploratory study such as this one.  Further research with a larger number of subjects and a longer follow-up period is needed to fully explore the effect of perioperative use of anti-TNF-α agents in TEA.  There is also a critical need to standardize anti-TNF-α medication protocols for patients with RA who are candidates for TEA. 

This study addresses an important matter regarding treatment protocols in patients with RA and other inflammatory conditions, undergoing TEA, and perhaps other types of arthroplasty.  While our data demonstrate a statistically significant increase of infection in patients with RA undergoing TEA while on postoperative prednisone, we did not find a similar relationship with postoperative anti-TNF-α agent use.  Despite the limitations previously discussed, this study raises an important concern in the perioperative surgical care of patients with rheumatoid and other inflammatory conditions.  It also suggests the need for future studies with a larger number of subjects, a more rigid medication protocol, and longer follow-up period.  In the meantime, our data suggest that physicians should use great caution when administering prednisone to patients who have recently undergone TEA.  Further studies are needed before a more solid recommendation can be made regarding the use of anti-TNF-α agents after TEA.

Acknowledgements: 

We thank Dr. S. Da Costa for editing the manuscript, Sarah Cole for statistical analysis and Steve Kang MD for help with data collection.

Reference :

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This is a peer reviewed paper 

Please cite as: Daniel Arkfeld: Anti-TNF-alpha use and TEA infection risk.

J.Orthopaedics 2009;6(3)e1

URL: http://www.jortho.org/2009/6/3/e1

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