ARTHRITIS & RHEUMATISM Vol. 58, No. 4, April 2008, pp 1197–1200 DOI 10.1002/art.23373 © 2008, American College of Rheumatology
Successful Treatment of a Patient With Takayasu Arteritis Using a Humanized Anti–Interleukin-6 Receptor Antibody Norihiro Nishimoto,1 Hideko Nakahara,2 Naoko Yoshio-Hoshino,1 and Toru Mima1 appear to result from the overproduction of cytokines with proinflammatory properties, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) (3,4). TNF induces inflammatory responses as well as granuloma formation, and one study showed that antiTNF therapy provided benefits in patients with TA, although it was an open-label study (5). On the other hand, strong expression of IL-6 has been shown to occur in the aortic tissue of patients with TA (6). Serum IL-6 levels have been reported to be greatly elevated in patients with TA and to correlate positively with disease activity (4,6,7). This indicates that IL-6 may be a good target molecule in the treatment of TA. At the time that the patient described here required treatment, it was not yet known whether anti-TNF therapy had clinical benefits for patients with TA. We therefore used a humanized anti–IL-6 receptor (IL-6R) antibody, tocilizumab (8), to treat the patient. This is the first study to show the successful treatment of a TA patient with tocilizumab. In addition, the profiles of cytokines with proinflammatory properties were assessed during tocilizumab treatment.
Takayasu arteritis (TA) is a chronic inflammatory disease that involves the aorta and its major branches. Since overproduction of interleukin-6 (IL-6) seems to play a pathogenic role in TA, we used the anti–IL-6 receptor (IL-6R) antibody tocilizumab to treat a 20-year-old woman with refractory active TA complicated by ulcerative colitis (UC). Treatment with tocilizumab improved the clinical manifestations of TA and the abnormal laboratory findings in this patient and ameliorated the activity of UC. These results indicate that IL-6R inhibition with tocilizumab might be a future treatment option for TA. Takayasu arteritis (TA) is a chronic inflammatory disease of unknown pathogenesis that involves large and medium-sized arteries, primarily the aorta and its major branches (1). Histopathologic analysis has revealed inflammatory cell infiltration in the adventitia and the media, and granulomatous changes of the vessel walls (2), which, together with the resultant organ ischemia, induce various clinical manifestations, such as decreased arterial pulses, episodes of syncope, discrepancies in blood pressure (BP) between both arms, and arterial bruit. Fever, leukocytosis, anemia, and increased levels of acute-phase proteins, such as C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen, are often found in patients with TA. These abnormalities
CASE REPORT The patient, a 20-year-old woman, was diagnosed as having TA in August 1996, at the age of 15 years, based on the presence of decreased brachial artery pulse, discrepancies in BP, arterial bruit, and arteriographic abnormalities, according to the American College of Rheumatology criteria for the classification of TA (1). The patient also had ulcerative colitis (UC). She was treated with prednisolone at an initial dosage of 60 mg/day. Although immunosuppressants such as cyclosporin A (150 mg/day) and cyclophosphamide (50 mg/ day) were used in combination with prednisolone, a subsequent reduction in the prednisolone dosage to 30 mg/day was followed by a recurrence of the symptoms. Betamethasone (1 mg/day) and 7 cycles of leukapheresis were ineffective. Since 2001, the patient had been
Supported by the Takeda Science Foundation and the Ministry of Health, Labor, and Welfare of Japan. 1 Norihiro Nishimoto, MD, PhD, Naoko Yoshio-Hoshino, MD, Toru Mima, MD, PhD: Osaka University, Osaka, Japan; 2Hideko Nakahara, MD, PhD: NTT West Osaka Hospital, Osaka, Japan. Drs. Nishimoto and Mima have received consulting fees (more than $10,000) from Chugai Pharmaceutical Company, Ltd., Tokyo, Japan. Address correspondence and reprint requests to Norihiro Nishimoto, MD, PhD, Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-Oka, Suita-City, Osaka 565-0871, Japan. E-mail:
[email protected]. ac.jp. Submitted for publication August 14, 2007; accepted in revised form January 4, 2008. 1197
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Figure 1. Computed tomography of the chest of a patient with Takayasu arteritis. A, Before tocilizumab treatment, thickening of the vessel walls of the ascending and descending aorta was seen (arrows). B, After treatment, there was a reduction in the thickening of the walls of the aorta (arrows).
treated intermittently with high-dose methylprednisolone (1,000 mg/day for 3 consecutive days) and daily doses of oral azathioprine (100 mg/day) and mycophenolate mofetil (2 gm/day) or methotrexate (17.5 mg/ week), together with oral corticosteroids at a dosage of at least 30 mg/day, but none of these medications fully controlled the disease activity. In September 2001, the patient experienced continuous left cervical pain, left chest pain, several episodes of syncope, and a 5-kg weight loss in 1 month. She had no aortic valve disease or arrhythmia. An examination using computed tomography (CT) and singlephoton–emission CT showed no intracranial involvement. The episodes of syncope were considered to be a symptom of ischemia due to vessel stenosis in both the right common carotid artery and the left subclavian artery. Serum CRP levels were elevated to 126 mg/liter, and chest CT showed marked thickening of the wall of the ascending aorta, of 3 branches of the aortic arch (right brachiocephalic artery, left common carotid artery, and left subclavian artery), and of the descending aorta (Figure 1A), as well as stenosis of the left subclavian artery. Vessel stenosis of the right common carotid artery was also suspected. Because the disease activity was not fully controlled by conventional therapies such as immunosuppressants and leukapheresis, tocilizumab was considered as a therapeutic option. The ethics committee of Osaka University Hospital approved the use of tocilizumab for this patient, and informed consent was obtained from the patient and her family members. After a single tocilizumab dose of 4 mg/kg, the
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patient’s serum CRP level decreased rapidly from 126 mg/liter to 26 mg/liter within 1 week. Initially, 4 mg/kg of tocilizumab was administered once every week in an attempt to rapidly increase the blood concentration of tocilizumab, and 8 mg/kg every 4 weeks was not an established dosing schedule at that time. Since that time, phase II clinical trials of tocilizumab in patients with rheumatoid arthritis have shown that 8 mg/kg every 4 weeks is an optimal dosage for maintaining appropriate serum levels of the drug (9). With this treatment regimen, tocilizumab blood concentrations were maintained above 20 g/ml. Within 3 weeks of the start of treatment, the CRP level was completely normalized (Figure 2). Fibrinogen and SAA levels were normalized after 1 month of tocilizumab treatment. The cervical pain, chest pain, and
Figure 2. White blood cell (WBC), C-reactive protein (CRP), fibrinogen, serum amyloid A (SAA), and cytokine profiles in the serum of a Takayasu arteritis patient during tocilizumab treatment. The treatment improved the WBC, CRP, fibrinogen, and SAA levels and reduced the serum interleukin-6 (IL-6) level. Serum tumor necrosis factor (TNF) levels fluctuated in the first 3 years and then became undetectable (⬍5 pg/ml). Serum IL-1 levels were undetectable (⬍10 pg/ml) throughout the treatment. PSL ⫽ prednisolone.
USE OF TOCILIZUMAB IN THE SUCCESSFUL TREATMENT OF TA
episodes of syncope disappeared, and Doppler echocardiography showed an increase in blood flow in the cervical artery (results not shown). Enhanced CT analysis revealed a reduction in the thickening of the wall of the ascending and descending aorta (Figure 1B). At the time tocilizumab treatment was initiated, the prednisolone dosage was not increased and no other immunosuppressants were added. Therefore, this rapid clinical and surrogate marker response seemed to be produced by tocilizumab. To allow for outpatient treatment, the infusion schedule of tocilizumab was changed from once a week to once every 2 weeks after the sixth dose of the drug, maintaining a dose of 4 mg/kg per infusion. This dosing schedule provided a tocilizumab blood concentration that was sufficient to suppress TA activity. After the twenty-sixth treatment (46 weeks after the start of treatment), the tocilizumab dose was increased from 4 mg/kg to 8 mg/kg in order to extend the infusion interval from 2 to 3 weeks. Using this regimen, trough concentrations of tocilizumab in the blood were maintained at ⬃20 g/ml with no change in efficacy. Tapering of prednisolone from 30 mg/day at the tenth dose (14 weeks) to 17.5 mg/day at the eighteenth dose (30 weeks) was accomplished without a disease flare, as shown in Figure 2. Before starting tocilizumab treatment, the patient’s left brachial artery pulse was very weak. The crude BP in the right brachial artery was 112/70 mm Hg and that in the left brachial artery was 102/74 mm Hg when she was admitted to the hospital. The BP fluctuated from day to day, and the BP in the left brachial artery was not always detectable. At the first tocilizumab injection, the BP was 142/88 mm Hg in the right brachial artery and 116/78 mm Hg in the left brachial artery. At 30 weeks, it was 109/65 mm Hg and 99/72 mm Hg, respectively. Although there were some discrepancies in BP between the arms, her left brachial artery pulse became steadily more palpable and recordable, even with an automatic sphygmomanometer. During that time, the concomitant UC also improved with tocilizumab treatment, as demonstrated by findings on occult hemoglobin tests of the stool and colonoscopy. Profiles of proinflammatory cytokines, including TNF, IL-6, and IL-1, were assessed during tocilizumab treatment. At the start of treatment, the serum IL-6 level was 1,720 pg/ml. The concentration gradually decreased to 114 pg/ml by the twenty-sixth dose (46 weeks after the start of tocilizumab treatment) and to 13.6 pg/ml at 173 weeks (Figure 2). The serum TNF level was 8 pg/ml (the lowest detectable level was 5 pg/ml) at the start of
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tocilizumab treatment and fluctuated (range 5–41) during treatment, as shown in Figure 2. Although the serum TNF level continued to be elevated during tocilizumab treatment, there was no relapse of TA as long as IL-6 signaling was blocked with tocilizumab. The serum TNF level decreased to an undetectable level (⬍5 pg/ml) 155 weeks after the start of tocilizumab treatment and has not been detected since then. Serum IL-1 was undetectable (⬍10 pg/ml) throughout the course of tocilizumab treatment. The patient’s clinical symptoms and laboratory findings were well controlled with tocilizumab and prednisolone, the dosage of which was steadily tapered to 7.5 mg/day. Tocilizumab did not induce any side effects, including infusion reactions, except for an episode of enterocolitis due to viral infection. Antibodies against tocilizumab were measured approximately every 6 weeks but could not be detected at any time during the long-term treatment (⬎5 years). DISCUSSION Tocilizumab treatment improved the inflammatory manifestations and laboratory findings of TA in our patient, indicating that IL-6 plays a major role in the pathogenetic mechanisms of this chronic inflammatory disease. Episodes of syncope disappeared after the start of tocilizumab treatment, and arterial pulses became easily palpable, indicating that ischemia also improved. This observation suggests that the impairments were still reversible, even after a disease duration of ⬃5 years, and that this reversal could be achieved with IL-6R inhibition. However, it is generally preferable that treatment be introduced before pathologic changes such as granuloma formation are established. An additional clinical benefit of treatment with tocilizumab was the corticosteroid- and immunosuppressant-sparing effect without a disease flare. UC activity was suppressed using tocilizumab, although it returned at a low degree of severity upon further reduction of the corticosteroid dosage to ⬍7.5 mg/day prednisolone. Consistent with the results of a study showing that tocilizumab was beneficial in treating Crohn’s disease (10), our results suggest that tocilizumab may also be effective in treating UC. The association of inflammatory bowel disease with granulomatous vasculitides has rarely been reported. HLA analysis has shown that HLA–A24, B52, Dw12, and DR2 are associated with TA in Japanese patients and that HLA–B52 and DR2 are associated with UC in Japanese patients; therefore, HLA–B52 and DR2 are common
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genetic factors that predispose to TA and UC (11). Indeed, this patient was positive for HLA–A24, B52, and DR2. We analyzed the serum cytokine profiles during tocilizumab treatment. In this patient, elevated serum TNF levels during inhibition of IL-6 signaling did not affect the improvement in disease activity, suggesting that IL-6 may act as an effector in the pathogenesis of TA. Considering that anti-TNF therapy is effective in TA (5) and that TNF is positioned upstream of IL-6 in the cytokine cascade, the mechanism by which anti-TNF therapy reduces disease activity in TA might be exerted indirectly by the suppression of IL-6 production. Because IL-1 was not detectable before and during tocilizumab treatment in this patient, no conclusions can be made about its role in TA. Long-term treatment with tocilizumab reduced serum IL-6 levels, suggesting that IL-6R inhibition indirectly suppresses IL-6 production, the original cause of vascular inflammation associated with TA. Recently, Th17 cells, which mediate autoimmunity and allergy, were reported to be induced by IL-6 and transforming growth factor  (TGF) (12,13). Th17 cells produce cytokines with proinflammatory properties, such as TNF and IL-6. However, TGF alone induces regulatory T cells, which suppress autoimmunity and allergy. Blockade of IL-6 signaling by tocilizumab may inhibit the development of Th17 cells and simultaneously induce regulatory T cells, resulting in a reduction of serum IL-6 levels. Therefore, tocilizumab treatment may interrupt the vicious circle. Because serum IL-6 levels are reported to correlate with disease activity in TA (6), the reduction of IL-6 levels by tocilizumab treatment might allow for an extended treatment interval or discontinuation of tocilizumab treatment without flare. Although further studies would be required to elucidate the exact mechanism, IL-6R inhibition with tocilizumab might be a therapeutic option for TA. ACKNOWLEDGMENTS We would like to thank Dr. Karsten Kissel, Dr. Tadamitsu Kishimoto, Dr. Ichiro Kawase, and Dr. Yoshihito Shima for valuable discussions, and Miss Tami Nanga for secretarial support.
AUTHOR CONTRIBUTIONS Dr. Nishimoto 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 design. Nishimoto. Acquisition of data. Nishimoto, Nakahara, Yoshio-Hoshino. Analysis and interpretation of data. Nishimoto, Mima. Manuscript preparation. Nishimoto, Nakahara, Yoshio-Hoshino, Mima. Patient care. Nishimoto, Nakahara, Yoshio-Hoshino, Mima.
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