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Successful treatment of reactive arthritis with a humanized antiinterleukin-6 receptor antibody tocilizumab.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 61, No. 12, December 15, 2009, pp 1762–1764
DOI 10.1002/art.24899
© 2009, American College of Rheumatology
CASE REPORT
Successful Treatment of Reactive Arthritis With a
Humanized Anti–Interleukin-6 Receptor Antibody,
Tocilizumab
TOSHIO TANAKA, YUSUKE KUWAHARA, YOSHIHITO SHIMA, TORU HIRANO, MARI KAWAI,
MASAKO OGAWA, JUNSUKE ARIMITSU, KEISUKE HAGIHARA, MASASHI NARAZAKI,
ATSUSHI OGATA, ICHIRO KAWASE, AND TADAMITSU KISHIMOTO
Introduction
Reactive arthritis is a disease with the clinical triad of
arthritis, urethritis, and conjunctivitis (1). The onset of
the disease is often preceded by bacterial infections of
Campylobacter, Chlamydia, Salmonella, Shigella, or Yersinia, either in the urogenital or gastrointestinal tract (2,3).
HLA–B27 is strongly associated with reactive arthritis, so
that this disease is considered as one of the HLA–B27positive spondylarthropathies. Although the pathogenesis
of reactive arthritis remains imperfectly understood, bacterial infections trigger systemic immunoreactions, and
overproduction of proinflammatory cytokines has been
shown to contribute to sterile joint inflammation (1– 4).
Several kinds of drugs are used for the management of
reactive arthritis, including nonsteroidal antiinflammatory
drugs (NSAIDs); disease-modifying antirheumatic drugs
(DMARDs) such as sulfasalazine, methotrexate, and leflunomide; corticosteroids; and immunosuppressive drugs,
including azathioprine and cyclosporine, whereas the use
of antibiotics remains controversial (1– 4). Infliximab, a
chimeric anti–tumor necrosis factor ␣ (anti-TNF␣) antibody, and etanercept, a 75-kd TNF receptor fusion protein,
Supported by the Program for Promotion of Fundamental
Studies in Health Sciences of the National Institute of Biomedical Innovation.
Toshio Tanaka, MD, PhD, Yusuke Kuwahara, MD, PhD,
Yoshihito Shima, MD, PhD, Toru Hirano, MD, PhD, Mari
Kawai, MD, PhD, Masako Ogawa, MSc, Junsuke Arimitsu,
MD, PhD, Keisuke Hagihara, MD, PhD, Masashi Narazaki,
MD, PhD, Atsushi Ogata, MD, PhD, Ichiro Kawase, MD, PhD,
Tadamitsu Kishimoto, MD, PhD: Osaka University, Osaka,
Japan.
Dr. Kishimoto holds a patent for tocilizumab and receives
royalties for Actemra.
Address correspondence to Toshio Tanaka, MD, PhD, Department of Respiratory Medicine, Allergy and Rheumatic
Diseases, Osaka University Graduate School of Medicine,
2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. E-mail:
ttanak@imed3.med.osaka-u.ac.jp.
Submitted for publication June 1, 2009; accepted in revised form July 28, 2009.
1762
reportedly ameliorated symptoms in patients with reactive
arthritis (5– 8), as well as other HLA–B27-positive spondylarthropathies (9). However, to our knowledge, there have
been no reports regarding the efficacy of the humanized
anti–interleukin-6 (IL-6) receptor antibody, tocilizumab
(10), for reactive arthritis. Here we report a case of reactive
arthritis treated successfully with tocilizumab.
Case Report
A 20-year-old woman presenting with urethritis, arthritis
of the knee, ankle, and shoulder joints, and left conjunctivitis was diagnosed as having reactive arthritis in 2004.
HLA–B27 was positive and no bacterial growth was found
in the joint fluid culture. Due to the persistence of arthritis,
she had been treated with corticosteroids, followed by
DMARDs such as methotrexate, sulfasalazine, or bucillamine, or with immunosuppressive drugs such as cyclosporine or mizoribine, but the disease activity remained
high in conjunction with the presence of arthritis and
C-reactive protein (CRP) level elevation (2.7–5.1 mg/dl,
normal value ⬍0.2 mg/dl). She was admitted to our hospital for tocilizumab treatment in November 2008. At admission, she presented with swelling of the right knee
joint and pain in the bilateral knee and ankle, left shoulder, and right pelvic joints, but there were no gastrointestinal, mucocutaneous, or ocular symptoms. Her lymphatic,
respiratory, cardiac, and neuropsychiatric findings were
unremarkable. Laboratory test results showed the following: white blood cell count of 10,890 cells/ml, hemoglobin
level of 12 gm/dl, platelet count of 414,000 cells/ml, CRP
level of 4.68 mg/dl, IgG level of 2,436 mg/dl, IgA level of
737 mg/dl, and IgM level of 249 mg/dl. Urinalysis indicated aseptic pyuria. The serum concentrations of serum
amyloid A (SAA) and matrix metalloproteinase 3 (MMP-3)
were elevated to 270 mg/liter (normal value ⬍8) and
692 ng/ml (normal range 17– 60), respectively. Antinuclear
antibodies, rheumatoid factor, and anti– cyclic citrullinated peptide antibodies were all negative. A radiographic
examination of radiographs showed no erosive damage or
joint space narrowing in shoulder, ankle, pelvic, and knee
Tocilizumab Therapy for Reactive Arthritis
1763
joints, whereas gallium (Ga) citrate scintigraphy showed a
marked uptake in the bilateral shoulders and ankles, as
well as in the bilateral sacroiliac, pelvic, and right knee
joints (Figure 1A). Serum IL-6, TNF␣, and IL-1␤ levels
were 15.4 pg/ml (normal value ⬍4), 8.4 pg/ml (normal
range 0.6 –2.8), and 1.9 pg/ml (normal value ⬍10), respectively.
Informed consent by the patient and approval by the
Ethics Committee of Osaka University Hospital were obtained for the injection of tocilizumab at 8 mg/kg every 4
weeks, starting from November 2008 in conjunction with
oral administration of prednisolone (5 mg/day), bucillamine (200 mg/day), and the NSAID naproxen (200 mg/
day). After one injection of tocilizumab, serum CRP and
SAA levels normalized (Figure 2). The visual analog scale
(VAS) score for the general health of the patient (range
0 –10) decreased from 5.6 to 1, whereas swollen and tender
joint counts changed from 1 to 3 and from 6 to 5, respectively. Two administrations of tocilizumab led to the disappearance of joint swelling and pain and complete reso-
Figure 2. Clinical course of reactive arthritis. The administration
of tocilizumab was started on day 0. Changes in serum levels of
C-reactive protein (CRP), serum amyloid A (SAA), matrix metalloproteinase 3 (MMP3), and the Disease Activity Score in 28 joints
using the CRP level (DAS28-CRP) score, based on the numbers of
tender and swollen joints, CRP level, and visual analog scale, are
indicated.
lution of symptoms, with a VAS score of 0 (Figure 2).
When disease activity was evaluated with the Disease
Activity Score in 28 joints (DAS28) using the CRP level
score, usually employed to assess rheumatoid arthritis activity, the score was initially 4.79 and became 3.06 after
one injection of tocilizumab. Successive administrations
of tocilizumab every 4 weeks rendered the patient symptom free, and the DAS28-CRP score remained at 1.08. In
February 2009, naproxen was stopped, and in March,
prednisolone could be tapered to 4 mg/day. The serum
concentration of MMP-3 decreased from 692 to 118, and
after 5 injections of tocilizumab, Ga-citrate scintigraphy
showed a marked reduction in uptake for the bilateral
pelvic and ankle joints as well as for the left shoulder and
right knee joints (Figure 1B). Concentrations of serum IgM
decreased from 249 to 164 mg/dl, of IgG from 2,463 to
1,403 mg/dl, and of IgA from 737 to 409 mg/dl, and became normalized. During the tocilizumab treatment, there
were no infectious episodes, including urethritis, and no
adverse effects. Persistent pyuria observed before the tocilizumab treatment also disappeared.
Discussion
Figure 1. Gallium citrate scintigraphy of the entire body. A, Before tocilizumab treatment, a marked uptake in the bilateral shoulder, ankle, sacroiliac, pelvic, and right knee joints was observed.
B, After treatment, there was a marked reduction in uptake in the
bilateral pelvic and ankle joints, as well as in the left shoulder and
right knee joints.
In this study, we demonstrated the prompt and sustained
ameliorative effect of tocilizumab on symptoms caused by
reactive arthritis. To the best of our knowledge, this is the
first case to evince the efficacy of tocilizumab for HLA–
B27-positive spondylarthropathies, which include ankylosing spondylitis, psoriatic arthritis, arthritis manifestations of inflammatory bowel diseases, and reactive
1764
arthritis (9). In addition to NSAIDs, DMARDs, and immunosuppressive drugs, the TNF antagonists infliximab and
etanercept and the fully humanized anti-TNF␣ antibody
adalimumab have shown impressive ameliorative effects
for patients with ankylosing spondylitis and psoriatic arthritis (9). The efficacy of TNF antagonists such as infliximab and etanercept for reactive arthritis has also been
reported (5– 8). The literature shows that 4 patients with
reactive arthritis responded well to infliximab, as well as
10 patients with reactive or undifferentiated arthritis who
responded well to etanercept treatment. This response was
assessed in terms of tender and swollen joint counts, a
10-point VAS for pain, and the disability index of the
Health Assessment Questionnaire. In addition, these antiTNF antagonists were found to be well tolerated without
clinical exacerbation of any suspected underlying infections. However, we selected tocilizumab rather than any of
the TNF antagonists as an alternative treatment for the
patient for two reasons. First, most bacteria responsible for
reactive arthritis are intracellular and therefore, an adequate induction of Th1 response is required for the elimination of reactive arthritis–associated bacteria. Since
TNF␣ has been shown to augment Th1 response (11), we
were concerned that anti-TNF biologics might cause worsening of intracellular bacteria growth. Because IL-6 appears to be less active in Th1 response than TNF␣, it was
considered that tocilizumab might be safer than TNF antagonists. Second, it has been reported that serum concentrations of IL-6 in reactive arthritis were elevated (12,13).
Moreover, synovial fluid concentrations of IL-6 were significantly higher in patients with reactive arthritis or undifferentiated spondylarthropathy than those in patients
with rheumatoid arthritis, so that oversynthesis of IL-6
was considered to be related to the development of arthritis in reactive arthritis (14).
The same study also demonstrated increased synovial
fluid levels of IL-17, transforming growth factor ␤, and
interferon-␥ in patients with reactive arthritis or undifferentiated spondylarthropathy, suggesting that the Th1 and
Th17 cells could be the major cells in inflammation in
reactive arthritis (14). In mouse models, anti–IL-6 receptor
antibody inhibits the differentiation of Th17 cells, which
may contribute to its effect in preventing and ameliorating autoimmune diseases (15). Therefore, it is possible
that this inhibitory action of tocilizumab may lead to ameliorating clinical symptoms in our patient with reactive
arthritis.
As reported here, the ameliorative effect of tocilizumab
on arthritis in our patient with reactive arthritis was
prompt and striking. Only two injections of tocilizumab
led to complete clinical remission in association with a
reduction in MMP-3 concentration. Our case therefore suggests that for refractory cases of reactive arthritis, tocili-
Tanaka et al
zumab treatment can be an option for alternative treatment.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr.
Tanaka had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.
Study conception and design. Tanaka, Shima, Hagihara, Ogata,
Kawase, Kishimoto.
Acquisition of data. Tanaka, Kuwahara, Hirano, Narazaki.
Analysis and interpretation of data. Tanaka, Kawai, Ogawa,
Arimitsu, Kishimoto.
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