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:
[email protected]. Submitted for publication June 1, 2009; accepted in revised form July 28, 2009.
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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
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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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