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: yu-hr@sf.commufa.jp

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

123

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.

References

1. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman

M, et al. Infliximab (chimeric anti-tumor necrosis factor alpha

monoclonal antibody) versus placebo in rheumatoid arthritis

patients receiving concomitant methotrexate: a randomized phase

III trial. Lancet. 1999;354:1932–9.

2. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleisch-

mann RM, Fox RI, et al. A trial of etanercept, a recombinant

human tumor necrosis factor: Fc fusion protein in patients with

rheumatoid arthritis receiving methotrexate. N Engl J Med.

1999;340:253–9.

3. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR,

et al. American College of Rheumatology 2008 recommendations

for the use of nonbiologic and biologic disease-modifying

antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum.

2008;59:762–84.

4. Tsukayama DT, Estrada R, Gustilo RB. Infection after total hip

arthroplasty. J Bone Jt Surg Am. 1996;78:512–23.

5. Darouiche RO. Treatment of infections associated with surgical

implants. N Engl J Med. 2004;350:1422–9.

6. Bongartz T, Halligan CS, Osmon DR, Reinalda MS, Bamlet WR,

Matteson EL, et al. Incidence and risk factors of prosthesis joint

infection after total hip or knee replacement in patients with

rheumatoid arthritis. Arthritis Rheum. 2008;59:1713–20.

7. Schrama JC, Espehaug B, Hallen G, Engesaeter LB, Furnes O,

Havelin LI, et al. Risk of revision for infection in primary total

hip and knee arthroplasty in patients with rheumatoid arthritis

compared with osteoarthritis: a prospective, population-based

study on 108,786 hip and knee joint arthroplasties from the

Norwegian Arthroplasty Register. Arthritis Care Res (Hoboken).

2010;62:473–9.

8. Bibbo C, Goldberg JW. Infectious and healing complications after

elective orthopaedic foot and ankle surgery during tumor necrosis

factor-alpha inhibition therapy. Foot Ankle Int. 2004;25:331–5.

9. den Broeder AA, Creemers MCW, Fransen J, de Jong E, de Rooij

DR, Wymenga A, et al. Risk factors for surgical site infections

and other complications in elective surgery in patients with

rheumatoid arthritis with special attention for anti-tumor necrosis

factor: a large retrospective study. J Rheumatol. 2007;34:689–95.

10. Hirano Y, Kojima T, Kanayama Y, Kaneko A, Eto Y, Ishiguro N,

et al. Influences of anti-tumour necrosis factor agents on post-

operative recovery in patients with rheumatoid arthritis. Clin

Rheumatol. 2010;29:495–500.

11. Giles JT, Bartlett SJ, Gelber AC, Nanda S, Fontaine K, Ruffing V

et al. Tumor necrosis factor inhibitor therapy and risk of serious

postoperative orthopedic infection in rheumatoid arthritis.

Arthritis Rheum. 2006;55:333–337.

12. Kawakami K, Ikari K, Kawamura K, Tsukahara S, Iwamoto T,

Momohara S, et al. Complications and features after joint surgery

in rheumatoid arthritis patients treated with tumour necrosis

factor-alpha blockers: perioperative interruption of tumour

necrosis factor-alpha blockers decreases complications? Rheu-

matology (Oxford). 2010;49:341–7.

13. Cid J, Aguinaco R, Sanchez R, Garcia-Perdo G, Liorente A.

Neutrophil CD64 expression as marker of bacterial infection: a

systematic review and meta-analysis. J Infect. 2010;60:313–9.

Mod Rheumatol (2011) 21:542–547 547

123