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-α
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 :
-
Bernatsky
S, Hudson S and Suissa S. Anti-rheumatic drug use and risk of
serious infections in rheumatoid arthritis. Rheumatology
2007;46:1157-60.
-
Connor PM
and Morrey BF. Total elbow arthroplasty in patients who have
juvenile rheumatoid arthritis. J. Bone Joint Surg. Am.
80:678-88, 1998.
-
Doran MF,
Crowson CS et al. Predictors of infection in rheumatoid
arthritis. Arthritis & Rheumatism 2002; 46:2294-2301.
-
Gill DRJ
and Morrey BF. The Coonrad-Morrey total elbow arthroplasty in
patients who have rheumatoid arthritis. A ten to fifteen-year
follow-up study. J Bone Joint Surg (Am) 1998;80:1327-35.
-
Gille J,
Ince A, González O, Katzer A, Loehr JF. Single-stage revision
of peri-prosthetic infection following total elbow
replacement. J Bone Joint Surg [Br]. 2006;88-B:1341-6, 2006.
-
Ikavalko
M et al. The Souter-Strathclyde elbow arthroplasty. J Bone
Joint Surg (Br) 2002;84-B:77-82.
-
Kauffman
JI, Chen AL, Stuchin S, Di Cesare PE. Surgical management of
the rheumatoid elbow. J Am Acad Orthop Surg 2003;11:100-8.
-
Kelly EW,
Coghlan J and Bell S. Five- to thirteen-year follow-up of the
GSB III total elbow arthroplasty. J Shoulder Elbow Surg
2004;13:434–40.
-
Khatri M
and Stirrat AN. Souter-Strathclyde total elbow arthroplasty in
rheumatoid arthritis. J Bone Joint Surg (Br) 2005;87-B:950-4.
-
Koopman
WJ. Prospects for Autoimmune Disease: Research Advances in
Rheumatoid Arthritis. JAMA. 2001;285(5):648-650.
-
Kudo H,
Iwano K and Nishin J. Total Elbow Arthroplasty with Use of a
Nonconstrained Humeral Component Inserted without Cement in
Patients Who Have Rheumatoid Arthritis. J. Bone Joint Surg.
Am. 81:1268-80;1999.
-
Landor I
et al. Total elbow replacement with the Souter-Strathclyde
prosthesis in rheumatoid arthritis. J Bone Joint Surg (Br)
2006;88-B:1460-3.
-
Listing
J, Strangfeld A, Kary S, Rau R, von Hinueber U,
Stoyanova-Scholz M, et al. Infections in patients with
rheumatoid arthritis treated with biologic agents. Arthritis
Rheum 2005;52(11):3403-12.
-
Mori T et
al. Kudo type-5 total elbow arthroplasty in mutilating
rheumatoid arthritis. J Bone Joint Surg (Br) 2006;88-B:920-4.
-
Nestor BJ.
Surgical treatment of the rheumatoid elbow. Rheumatic Disease
Clin North Am 1998;24:83-99.
-
Palm TM,
Kaarela K, Hakala MS, Kautiainen HJ, Kröger HP, Belt EA. Need
and sequence of large joint replacements in rheumatoid
arthritis. A 25-year follow-up study. Clin and Exp Rheumatol
2002;20:392-4.
-
Phillips
K, Husni ME, Karlson EW, and Coblyn JS. Experience With
Etanercept in an Academic Medical Center: Are Infection Rates
Increased? Arthritis Care and Research 47:17–21;2002.
-
Salliot
C, Gossec L, et al. Infections during TNF-a blocker therapy
for rheumatic diseases in daily practice: a systematic
retrospective study of 709 patients. Rheumatology 2007; 46:
327-334.
-
Talwalkar
SC et al. Survivorship of the Souter-Strathclyde elbow
replacement in the young inflammatory arthritis elbow. J Bone
Joint Surg (Br) 2005;87-B:946-49.
-
Thillemann TM, Olsen BS, Johannsen HV, Sojbjerg JO.. Long-tem
results with the Kudo type 3 total elbow arthroplasty. J
Shoulder Elbow Surg 2006;15:495-9.
-
van der
Lugt JCT and Rozing PM. Systematic review of primary total
elbow prostheses used for the rheumatoid elbow. Clin Rheumatol
2004;23:291-8
-
van der
Lugt JCT, Geskus RB and Rozing PM. Influence of previous open
synovectomy on the outcome of Souter-Strathclyde total elbow
prosthesis. Rheumatol 2004;43:1240-5.
-
van der
Lugt JCT, Geskus RB and Rozing PM. Primary Souter-Strathclyde
total elbow prosthesis in rheumatoid arthritis. J Bone Joint
Surg (Am) 2004;86:465-73.
-
Wolfe F,
and Zwillich SH. The long-term outcomes of rheumatoid
arthritis: a 23-year prospective, longitudinal study of total
joint replacement and its predictors in 1,600 patients with
rheumatoid arthritis. Arthritis Rheum. 1998;41(6):1072-82.
-
Zandman-Goddard
G. Infection and anti-tumor necrosis factor-alpha therapy.
Israel Med Assoc J 2003:5(11);814-6.
|