A Case of Tuberculous Arthritis Following the Use of
Seung Won Choi1, Jong Joon Ahn1, Young Tae Hwang1, Sang Hoon Koh2, and Sung Do Cho2
Departments of 1Internal Medicine and 2Orthopedic Surgery, Ulsan University Hospital, Ulsan University College of Medicine,
Etanercept is a tumor necrosis factor (TNF) inhibitor that has been used for the treatment of chronic
inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Because of its
immunosuppressive activity, opportunistic infections have been noted in treated patients, most notably caused by
Mycobacterium tuberculosis. Tuberculosis may present in an extrapulmonary or disseminated form. Since TNF-α
inhibitors have been used in Korea, a few cases of TNF-α inhibitor associated tuberculosis have been described.
However, tuberculous arthritis has not been previously reported. We describe a case of tuberculous arthritis in a
57-year-old woman with rheumatoid arthritis who was treated with etanercept. (Korean J Intern Med 2009;24:
Keywords: Tumor necrosis factor-alpha; Arthritis, rheumatoid; Tuberculosis, osteoarticular
Received: May 5, 2007
Accepted: August 9, 2007
Correspondence to Seung Won Choi, M.D.
Department of Internal Medicine, Ulsan University Hospital, 290-3 Cheonha-dong, Dong-gu, Ulsan 682-714, Korea
Tel: 82-52-250-7029, Fax: 82-52-251-8235, E-mail: email@example.com
Tumor necrosis factor (TNF) is a proinflammatory
cytokine that plays an important role in the pathogenesis
of a variety of autoimmune diseases. The biologic effects
of TNF-α include the mediation of systemic inflammatory
responses as well as the response to a variety of infections,
particularly Mycobacterium tuberculosis and other intra-
cellular pathogens . TNF-αalso stimulates the recruitment
of inflammatory cells and the formation of granulomas
TNF-α inhibitors have demonstrated clinical benefit in
the treatment of autoimmune and inflammatory disorders
including rheumatoid arthritis (RA), ankylosing spondylitis
and Crohn’s disease . Occasionally, these agents have
been associated with infectious complications [5,6].
TNF-α inhibitors have been suggested to increase the risk
of tuberculosis; this is not surprising considering the role
of TNF-αin the defense mechanisms against mycobacterium
. Therefore, physicians must be vigilant in the prevention
and early detection of tuberculosis, in patients that receive
TNF-α inhibitors, particularly with unusual manifestations
of the disease.
Although several complications have been described
following treatment with TNF-α inhibitors, tuberculous
arthritis has not been reported previously in Korea .
We describe a 57-year-old woman who developed severe
tuberculous arthritis in the elbow joint following etanercept
administration for RA.
A 57-year-old woman was admitted to the hospital
because of swelling, pain and warmth noted at the right
elbow. The patient had seropositive RA diagnosed 15
years ago. The involved joints included wrist, elbow, knee,
and ankle, bilaterally. She underwent bilateral knee
arthroplasty9 years previously and right ankle arthrodesis
2 years ago. Recently, the patient was treated with naproxen,
prednisolone, methotrexate and cyclosporine A. Despite
treatment, the symptoms remained active. Three months
prior to admission she was started on etanercept injections
(25 mg, twice weekly) combined with methotrexate, pred-
nisolone and aceclofenac. A purified protein derivative
(PPD) skin test performed before administration of
etanercept was negative with 3 mm induration and a chest
X-ray revealed no evidence of tuberculosis. The patient
did not have a history of tuberculosis nor any known
exposure to persons with active tuberculosis. The articular
symptoms improved gradually after the etanercept
injections. The serial laboratory tests showed improvement
during the use of etanercept (Table 1). However, one month
before admission, the patient began to experience swelling
and pain of the right elbow joint. Intermittent fever and
anorexia were also reported to be present. Her temperature
was 38˚C, blood pressure 130/80 mmHg, and pulse 80/
minites. Physical examination revealed swelling with
moderate tenderness and local heat around the right
elbow. The range of motion was very limited. There was
no lymphadenopathy. Chest and abdominal examinations
were normal. Laboratory evaluation showed an increase
in acute phase reactants. Renal and liver function tests
were normal (Table 1). Blood and urine cultures were
negative. The aspirates from the elbow joint showed
cloudy yellow fluid with a white blood cell 75,000/mm3
(95% of neutrophil). Gram staining of the synovial fluid
revealed no bacteria. A chest radiograph demonstrated
no new infiltrates. Plain radiography of the elbow joint
disclosed extensive osteolytic bony destruction (Fig. 1).
Arthroscopic debridement and synovectomy were
performed. Severe inflammatory changes in the synovium
with destruction of cartilage and subchondral bone
were noted (Fig. 2). Pathology examination of the biopsy
398 The Korean Journal of Internal Medicine Vol. 24, No. 4, December 2009
Table 1. Laboratory tests before and during the use of etanercept
Before the use
During the use
Hemoglobin (12-16 g/dL)
ESR (<20 mm/hr)
CRP (<0.5 mg/dL)
Creatinine (0.6-1.5 mg/dL)
AST (0-40 IU/L)
ALT (0-40 IU/L)
Figures in parenthesis refer to reference values.
WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine
Figure 1. Plain radiography of the right elbow. Extensive
osteolytic bony lesions is shown.
Figure 2. Arthroscopic view of the elbow joint. Severe inflam-
matory changes in hypertrophic synovium is observed.
specimen revealed numerous granulomas composed of
epithelioid cells and giant cells (Fig. 3). Eventually,
cultures of the joint tissue specimen and joint fluid grew
Mycobacteriumtuberculosis. The patient was treated with
rifampin, isoniazid, pyrazinamide and ethambutol. The
treatment with etanercept was discontinued. Three weeks
later, there was significant decrease in the swelling and
tenderness over the joint. The elbow discomfort continues
TNF-α stimulates the production of proinflammatory
cytokines and influences the maturation of inflammatory
cells . It promotes recruitment of inflammatory cells to
the area of infection, and stimulates the formation and
maintenance of a granuloma. In addition, TNF-α directly
activates macrophages, which engulf and kill the
mycobacterium and other pathogens. Thus, it is a key
component of host defenses against Mycobacterium
tuberculosis. TNF-αacts in a number of ways to influence
the course of an infection. Early in the process, TNF-α
promotes the influx of cells into the infected area to control
the inciting agent, and later it helps to limit the extent of
damage by inducing apoptosis and maintaining
granuloma formation . However, these functions may
be disturbed in the presence of a TNF-α inhibitor, making
the host vulnerable to tuberculosis [9,10].
At present, three types of TNF-α inhibitors are available
in Korea: infliximab, etanercept and adalimumab. These
agents have been recommended as treatment for RA
in patients who are not adequately controlled by at least
two other disease modifying anti-rheumatic agents [1,11].
Etanercept is a fusion protein that consists of two soluble
p75 TNF-α receptors linked to an immunoglobulin Fc
domain. It functions as a soluble receptor of TNF-α,
competing with TNF-α on the cell membrane receptors
and blocking the biological activity [12,13]. Its efficacy
is demonstrated within the first week of treatment and
tends to be sustained throughout the duration of therapy.
Several side effects have been reported, including injection
site reactions, headache, demyelinating disorders, lupus,
and infections .
Use of TNF-α inhibitors have been implicated in the
reactivation of tuberculosis or in the progression of recently
acquired tuberculosis. In a recent report, Mohan et al. 
reviewed 25 cases of tuberculosis in patients who were
treated with etanercept. Thirteen (54%) patients were
diagnosed with extrapulmonary tuberculosis, including
three cases of disseminated disease, two of lymphadenitis
and one with articular tuberculosis. These atypical clinical
presentations may result in a delay of diagnosis and
Tuberculous arthritis commonly presents with chronic
pain accompanied by swelling and progressive loss of
joint function . The diagnosis is often delayed,
especially if it involves the same joints affected by RA. The
typical radiological findings are periarticular osteoporosis,
peripherally located bony erosions, gradual narrowing
of the joint space, and periarticular bone destruction .
In this case, the plain film showed extensive bony destruc-
tion, which prompted us to perform an invasive procedure.
The identification of Mycobacterium tuberculosis is
essential for the diagnosis of tuberculous arthritis.
However, acid-fast stains of the synovial fluid smears are
positive in only 20-25%. On the other hand, cultures of
joint fluid are positive in about 90% of cases . The
diagnosis in this patient was established by isolation of
Mycobacterium tuberculosis in the culture of the synovial
tissue and joint fluid and the histological findings of the
synovium. The therapy for articular tuberculosis is the
same as for other forms of tuberculosis. If the patient is
not responding to drug therapy, synovectomy, debridement,
joint arthrodesis, or joint replacement may be considered
The risk of reactivation of tuberculosis by a TNF-α
inhibitor depends on many factors including the underlying
Choi SW, et al. Tuberculous arthritis following the use of etanercept 399
Figure 3. Histologic examination of synovial tissue. Chronic
inflammation with granuloma composed of epithelioid cells and
giant cells is shown (H&E, ×200).
immune status of the patient and the immunomodulating
effects of the therapy. In patients with RA, the use of cor-
ticosteroids has been associated with an increased risk of
tuberculosis, presumably due to its effects on cell-mediated
immunity [17,18]. Physicians should be aware of the
increased risk of reactivation of tuberculosis in patients
who are receiving a TNF-α inhibitor and, in particular, of
the unusual clinical manifestations. Assessment of the risk
factors and the PPD test are recommended to determine
the presence of latent tuberculosis and the risk for active
disease [19-21]. Individuals with positive PPD tests must
be thoroughly assessed for active tuberculosis. Active
tuberculosis must be treated appropriately before initiation
of TNF-α inhibitor therapy. Patients with a positive PPD
test, without evidence of active tuberculosis, should have
the anti-TNF agent withheld until the patient has been
adequately treated for at least one month. To screen and
treat patients with evidence of latent tuberculosis infection,
the PPD skin test may be insufficient. In addition, there can
be some difficulty evaluating the results as a false-positive
in patients who received a BCG vaccination. Recently, the
introduction of a whole blood interferon (IFN)-γ assay,
QuantiFERON®-TB Gold test (Cellestis, Victoria,
Australia) or T-SPOT.TB (Oxford Immunotec, Abingdon,
UK) may add to the accuracy for the detection of latent
tuberculosis. However, there are limited data on the use of
whole blood IFN-γ assays in immunosuppressed subjects.
By contrast, PPD skin tests may have false-negative results
in immune compromised or severely ill patients;
meticulous assessment of the risk of tuberculosis should be
performed in every patient. Furthermore, many patients
with RA treated with immunosuppressive therapy, can
have false-negative results on PPD tests. Chest radiography
is a useful tool for screening active tuberculous infection.
As the use of TNF-α antagonists becomes more
widespread, additional cases of tuberculosis associated
with TNF-α inhibitor treatment are expected. If infection
does develop, early detection and appropriate treatments
are mandatory to obtain a good outcome.
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