CASE REPORT
Anti-tumor necrosis factor therapy in rheumatoid arthritispatients with a history of deep prosthetic joint infection:a report of four cases
Yuji Hirano • Toshihisa Kojima • Yasuhide Kanayama •
Tomone Shioura • Masatoshi Hayashi •
Seiji Tsuboi • Naoki Ishiguro
Received: 14 December 2010 / Accepted: 10 February 2011 / Published online: 4 March 2011
� Japan College of Rheumatology 2011
Abstract Four rheumatoid arthritis patients (three women
and one man) who had a history of prosthetic joint infection
were treated with anti-tumor necrosis factor (TNF) agents
after treatment of the infection. The anti-TNF therapy was
subsequently discontinued in three patients. The reason for
discontinuation was not the reactivation of infection, but
disseminated tuberculosis, Pneumocystis jiroveci pneumo-
nia, and interstitial pneumonia, respectively. These cases
suggest that a history of prosthetic joint infection may be a
contraindication for treatment with anti-TNF agents.
Keywords Rheumatoid arthritis � Anti-tumor necrosis
factor therapy � Prosthetic joint infection � Disseminated
tuberculosis � Pneumocystis pneumonia
Introduction
The development of anti-tumor necrosis factor (TNF)
agents has dramatically changed the treatment strategy for
patients with rheumatoid arthritis (RA) [1, 2]. The
administration of anti-TNF agents during the early stages
of RA is recommended if disease activity remains high
despite treatment with methotrexate (MTX) [3]. However,
some patients are unable to continue with anti-TNF therapy
due to adverse events. Severe infection is a particular
concern, and the risk factors for developing a severe
infection during anti-TNF therapy are not clear.
Joint destruction has progressed significantly in patients in
the later stages of RA. Joint replacement surgery can improve
the function of the patient’s affected joints and, consequently,
their activities of daily living (ADL). One potential severe
complication of joint replacement surgery is deep infection.
Deep prosthetic joint infections often require lengthy treatment
with antibiotics, and follow-up operations, such as debride-
ment, implant removal, and revision surgery [4]. In addition, it
is difficult to determine when prosthetic joint infections have
been successfully treated because inflammatory signs and
symptoms often disappear, even when bacteria are still present.
Because most RA patients undergoing joint replacement sur-
gery have high disease activity, treatment of their RA is needed
during and after treatment of a deep infection. Due to the small
number of such cases, it is rare that anti-TNF agents are used. It
is unclear whether anti-TNF therapy is appropriate for such
patients and what the outcome of this therapy is in such cases.
Here we report the clinical courses of four RA patients (three
women and one man). All patients had the same RA classifi-
cation (Steinbrocker stage IV, class 3), a history of deep
prosthetic joint infection, and were treated with anti-TNF
agents following treatment of the infection.
Case reports
Case 1
The patient was a 55-year-old woman diagnosed with
RA in 1979 when she was 23 years old. Despite treatment
Y. Hirano (&)
Department of Rheumatology, Toyohashi Municipal Hospital,
50 Hakken-nishi, Aotake-cho, Toyohashi 441-8570, Japan
e-mail: [email protected]
T. Kojima � Y. Kanayama � M. Hayashi � N. Ishiguro
Department of Orthopedic Surgery and Rheumatology,
Nagoya University Graduate School of Medicine, Nagoya, Japan
T. Shioura � S. Tsuboi
Department of Rheumatology, Shizuoka Kosei Hospital,
Shizuoka, Japan
123
Mod Rheumatol (2011) 21:542–547
DOI 10.1007/s10165-011-0437-4
with conventional disease-modifying anti-rheumatic drugs
(DMARDs), her right knee required replacement, and a
total knee arthroplasty (TKA) was performed in December
2002. Although her clinical course after surgery was sat-
isfactory, right gonalgia with localized heat was noted in
January 2003. Blood tests revealed a C-reactive protein
(CRP) level of 8.8 mg/dl. Infection of the TKA was sus-
pected and emergency joint debridement without implant
removal was performed. Although culture from the joint
fluid was negative, signs and symptoms were consistent
with infection, and antibiotic treatment was initiated, first
with cefazolin (CEZ), followed by cefotiam (CTM), cef-
metazon (CMZ), and minocycline (MINO). Blood hemo-
globin (Hb), serum total protein (TP), and serum albumin
(Alb) just before the infection occurred were 12.7, 7.3, and
4.4 g/dl, respectively. The infection was well controlled
and the implant was not removed. RA disease activity
remained high and the disease activity score in 28 joints
using CRP (DAS28-CRP) was 6.11. Treatment with eta-
nercept (ETA) was initiated in April 2007 after consent
was obtained in regard to the risks and benefits of anti-TNF
therapy. Her tuberculin skin test was negative and no
abnormality was found on her chest X-ray. However, ETA
was not effective and she was switched to infliximab (INF)
with tacrolimus (TAC) 2 mg/day in January 2008.
Although INF with TAC was effective over a 5-month
period, she reported abdominal discomfort in June 2008
after the 5th infusion of INF. She lost 5 kg in 2 months just
before the occurrence of abdominal discomfort. Abdominal
computed tomography (CT) imaging showed apparent
ascites (Fig. 1a, b), and chest X-ray showed fluid in the
right pleural cavity (Fig. 1c). The treatment with INF and
TAC was discontinued. A QuantiFERON-TB2G test (QFT;
Cellestis, Carnegie, Victoria, Australia) was positive and
culture examination of sputum and stomach fluid was
positive for Mycobacterium tuberculosis. A pleural biopsy
was performed and showed granulomas with Langhans
giant cells. She was diagnosed with disseminated tuber-
culosis (TB), and anti-tuberculosis chemotherapy was ini-
tiated with isoniazid (INH), ethambutol (EB), rifampicin
(REP), and pyrazinamide (PZA). Signs and symptoms of
TB were well controlled with the combination drug
therapy.
Case 2
The patient was a 34-year-old woman diagnosed with
juvenile idiopathic arthritis (JIA) in 1986 when she was
12 years old. Total hip arthroplasty (THA) was performed
for her right hip joint in April 2001 (Fig. 2a) and for her
left hip joint in July 2001. Late infection of the right THA
occurred in July 2002, and this was treated with antibiotics
and surgical debridement without implant removal. Blood
Hb, serum TP, and serum Alb just before the infection
occurred were 8.3, 6.6, and 3.5 g/dl, respectively. Staphy-
lococcus aureus was detected by culture examination.
Fig. 1 Radiological images of
the patient in Case 1. a,
b Abdominal computed
tomography (CT) before
treatment of disseminated
tuberculosis (TB). c Chest X-ray
before treatment of TB.
d Abdominal CT after treatment
of TB
Mod Rheumatol (2011) 21:542–547 543
123
Although the infection seemed to be well controlled,
reactivation of infection occurred in March 2004 and was
treated again by surgical debridement without implant
removal. The implants loosened in July 2005, resulting in
implant removal and treatment with cement beads
(Fig. 2b). Revision surgery of the right hip joint was per-
formed in February 2006 (Fig. 2c). RA disease activity
remained high, and DAS28-CRP was 5.71. ETA with MTX
was initiated in May 2006 after consent was obtained in
regard to the risks and benefits of anti-TNF therapy. Her
chest X-ray was normal before ETA administration.
Although eight injections of ETA were given, Herpes
zoster infection and Pneumocystis jiroveci pneumonia
(PCP) were evident after a month (Fig. 3) and ETA with
MTX was discontinued. PCP was diagnosed by a positive
polymerase chain reaction test of bronchial alveolar lavage
fluid. The Herpes zoster infection and PCP were success-
fully treated with aciclovir, trimethoprim-sulfamethox-
azole, and subsequently, with pentamidine. No signs of
infection around the right THA have been seen to date. She
is currently being treated with MTX (8 mg/week), TAC
(0.5 mg/day), and prednisolone (PSL) (2.5 mg/day).
Fig. 3 Chest computed
tomography (CT) at the onset of
Pneumocystis jirovecipneumonia in Case 2. A ground-
glass pattern is seen bilaterally
in the lungs
Fig. 2 Radiological images of
the right hip joint of the patient
in Case 2. a Primary total hip
arthroplasty (THA).
b Treatment of infection with
cement beads following implant
removal. c Revision THA
544 Mod Rheumatol (2011) 21:542–547
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Case 3
The patient was a 67-year-old man diagnosed with RA in
1989 when he was 48 years old. A total elbow arthroplasty
(TEA) was performed on his left elbow in February 2002.
Infection of the TEA occurred in November 2002. Blood
Hb and serum TP just before the infection occurred were
11.2 and 7.6 g/dl, respectively. Emergency surgical
debridement without implant removal was performed and
culture examination was positive for S. aureus. The infec-
tion was well controlled with antibiotic treatment (CEZ,
CTM, and CMZ), but reactivation occurred in January
2003, and the implants were removed. Revision surgery was
not performed (Fig. 4) and orthosis was used to stabilize the
left elbow. RA disease activity remained high, and DAS28-
CRP was 5.65. INF with MTX was initiated in August 2004
after consent was obtained in regard to the risks and benefits
of anti-TNF therapy. Bronchiectasis was noted prior to the
initiation of INF administration. He was referred to another
hospital because of a change of address. After that, deteri-
oration, with interstitial pneumonia (IP), occurred in 2006,
and INF and MTX were discontinued (Fig. 5). The total
duration of treatment with INF was 24 months.
Case 4
The patient was a 69-year-old woman diagnosed with RA
when she was 30 years old. Disease activity remained high
despite treatment with MTX (6 mg/week), bucillamine
(BUC; 100 mg/day), and PSL (5 mg/day). DAS28-CRP
was 5.70. INF was added to MTX, BUC, and PSL in
November 2005. She had right gonalgia, which worsened,
and joint space narrowing was apparent on X-ray images.
TKA was performed on her right knee in January 2007
(Fig. 6). The duration of INF treatment was 1 year and
2 months, with the last dose administered 21 days before
the surgery. She had a high fever just after the surgery, and
discharge from the wound continued, although bacteria
were not detected by culture examination. Finally, surgical
debridement without implant removal was performed, and
Capnocytophaga was detected from a synovial specimen
taken during surgery. Blood Hb, serum TP, and serum Alb
just before the infection occurred were 11.0, 6.4, and 3.2 g/dl,
respectively. Ampicillin/sulbactam (ABPC/SBT) 6 g/day
was administered for 4 weeks and this effectively treated the
infection. INF was discontinued after the infection of the
TKA. She was treated with oral levofloxacin (LVFX) for
6 months, and reactivation did not occur after the LVFX
treatment ended. RA disease activity remained high, and
DAS28-CRP was 5.47. Administration of ETA with MTX
was initiated in August 2008 after consent was obtained in
regard to the risks and benefits of anti-TNF therapy. DAS28-
CRP had decreased to 3.73 1 month after the initiation of
ETA and MTX. No signs of infection around her right TKA
have been seen to date, and the anti-TNF therapy was
re-initiated 1 year and 8 months after it was discontinued.
Discussion
In this case series, we have described the clinical courses of
four patients with RA who had a history of prosthetic joint
infection and were treated with anti-TNF therapy. Anti-
TNF therapy was discontinued in three of the four patients
Fig. 4 Radiological images of the left elbow after implant removal in
Case 3. No revision surgery was performed, and orthosis was used to
stabilize the left elbow
Fig. 5 Chest X-ray of the patient in Case 3. Infliximab was
discontinued due to interstitial pneumonia
Mod Rheumatol (2011) 21:542–547 545
123
for reasons other than reactivation of the infection, showing
that the prosthetic joint infections were treated success-
fully. We are very interested in the fact that these patients
could not continue anti-TNF therapy for other reasons. The
causes for discontinuation were disseminated TB in Case 1,
PCP in Case 2, and IP in Case 3. These findings suggest
that patients with a history of prosthetic joint infection may
be at higher risk of adverse events during treatment with
anti-TNF agents. Although immunological factors in such
patients may be one of the reasons for the failure of anti-
TNF therapy, the precise mechanisms of this failure are
currently unknown. Prospective studies including more
patients with a history of prosthetic joint infection are
needed.
Prosthetic joint infection is one of the most miserable
complications of joint replacement surgery. Its prevalence
in patients in the United States was reported to be 2% [5].
The risk of prosthetic joint infection is higher for patients
with RA than for patients with osteoarthritis [6, 7]. In the
present report, bacteria were not detected in Case 1, and
Capnocytophaga, an opportunistic pathogen, was detected
in Case 4. Although prostheses were not removed in Cases
1 and 4, successful treatment of the infection required both
surgical debridement and the administration of antibiotics.
In clinical studies, the influence of anti-TNF therapy on
the manifestations of surgical site infection (SSI) is con-
troversial. Bibbo and Goldberg [8] reported that the use of
anti-TNF agents might be safely undertaken in the peri-
operative period without increasing risks to healing or risks
of infectious complications in RA patients undergoing
elective foot and ankle surgery. den Broeder et al. [9]
investigated postoperative SSIs in 1,219 operations carried
out in 768 patients, and found that the crude infection risks
were 4.0, 5.8, and 8.7% in patients who did not use anti-
TNF agents, patients who did but then stopped, and
patients who continued anti-TNF preoperatively, respec-
tively. However, there were no significant differences in
infection rates among the three groups. Also, we previously
reported that anti-TNF therapy did not increase the rates of
postoperative infection of orthopedic surgery sites in
patients with RA [10]. By contrast, Giles et al. reported that
anti-TNF agents increased the rate of infection in elective
orthopedic operations [11]. Kawakami and Momohara also
reported that anti-TNF therapy was a risk factor for SSI
following major orthopedic surgery [12]. Reactivation of
the infection may be induced if anti-TNF therapy is initi-
ated. There is currently no definitive treatment strategy for
patients with very active RA who have a history of pros-
thetic joint infection.
Anti-TNF agents have revolutionized the treatment of
severe RA [1, 2], but they are not indicated for all patients
with RA. For example, they are contraindicated in patients
with signs of infection. However, it is difficult to decide
whether anti-TNF therapy should be initiated in RA
patients with a history of prosthetic joint infection, because
it is difficult to determine whether the infection has been
successfully treated. The usefulness of inflammatory
markers, such as CRP or the erythrocyte sedimentation rate
(ESR), is limited in patients with RA. We decided that anti-
TNF agents could be administered after a long observation
period without reactivation of infection. Neutrophil CD64
expression is a promising candidate for use as a marker of
bacterial infection when using anti-TNF agents to treat RA
patients with a history of prosthetic joint infection [13].
Fig. 6 Total knee arthroplasty
of the patient in Case 4. High
fever and discharge from the
right (R) knee continued
immediately after surgery.
Capnocytophaga was detected
from a specimen of synovial
tissue
546 Mod Rheumatol (2011) 21:542–547
123
In conclusion, we have reported the clinical courses of
four RA patients with a history of deep prosthetic joint
infection who were treated with anti-TNF agents following
treatment of the infection. Anti-TNF therapy could not be
continued in three of the four patients, not because the
infection had reactivated, but because of disseminated
tuberculosis, Pneumocystis jiroveci pneumonia, and dete-
rioration of interstitial pneumonia (IP), respectively. This
case series suggests that a history of prosthetic joint
infection is a contraindication for treatment with anti-TNF
agents, possibly due to abnormalities in the immune sys-
tems of such patients.
Conflict of interest Y. Hirano has received speaking fees from
Abbot Japan Co. Ltd.; Eisai Co. Ltd.; Mitsubishi Tanabe Pharma
Corporation; and Pfizer Co. Ltd. T. Kojima has received speaking fees
from Mitsubishi Tanabe Pharma Corporation; Takeda Pharmaceutical
Company Limited; Pfizer Co. Ltd.; and Wyeth K.K. N. Ishiguro has
received speaking fees from Abbot Japan Co. Ltd.; Eisai Co. Ltd.;
Mitsubishi Tanabe Pharma Corporation.; Takeda Pharmaceutical
Company Limited; and Pfizer Co. Ltd. The other authors have
declared no conflict of interest.
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