Introduction

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology and is characterized by remittent fever, evanescent salmon pink rash, and polyarthralgia frequently accompanied by neutrophilic leukocytosis [1, 2]. AOSD treatment comprises non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive drugs such as methotrexate (MTX) [3]. Corticosteroids, in particular, still provide mainstay AOSD therapy despite various adverse effects [3].

Recently, numerous studies have revealed that proinflammatory cytokines such as IL-1, IL-6, IL-18, tumor necrosis factor (TNF), and interferon-gamma are involved in AOSD’s pathogenesis [4, 5]. In fact, AOSD patients have been successfully treated with anti-cytokine therapies such as with TNF-α blocking agents [6, 7], an IL-1 receptor antagonist (anakinra) [8, 9], and an anti-IL-6 receptor monoclonal antibody (tocilizumab, TCZ) [10–23]. Most of the cases are refractory to conventional therapies including high-dose corticosteroids and immunosuppressive drugs (cyclosporin and methotrexate, etc.) [11, 14, 16–18, 20, 22]. Among these case reports, TCZ seems to be highly effective for treating patients refractory to TNF antagonists [16, 17, 20] and anakinra [11, 14, 18, 22].

Here, we describe two patients with AOSD who were treated with TCZ monotherapy without corticosteroids. Table 1 summarizes the patients’ characteristics.

Table 1 Characteristics of patients
Full size table

Case reports

Case 1

A 32-year-old woman was admitted to our hospital in January 2009 with fever, polyarthralgia, sore throat, and skin eruptions. Two years earlier, she experienced self-limiting high fever and cervical lymphadenopathy. Eight months prior to admission, she developed eruptions on her back, both arms and legs, which were improved by olopatadine hydrochloride and clobetasol propionate ointment treatment. Two weeks prior to admission, she developed a sore throat followed by skin eruptions, fever and polyarthralgia, which did not respond to cefcapene pivoxil hydrochloride hydrate and NSAIDs.

Laboratory test results on admission were as follows: leukocyte count 13,000/μl (neutrophils, 10,900/μl), hemoglobin 13.4 g/dl, platelet count 198,000/μl, erythrocyte sedimentation rate (ESR) 110 mm/hr, C-reactive protein (CRP) 33.8 mg/dl, aspartate aminotransferase (AST) 29 IU/l, alanine aminotransferase (ALT) 22 IU/l, lactate dehydrogenase (LDH) 285 IU/l, creatinine 0.55 mg/dl, ferritin 1,679 ng/ml, and normal urine values. Serological tests were negative for rheumatoid factor (RF) and antinuclear antibodies (ANA). The serum IL-6, TNF-α and soluble IL-2 receptor levels were 398 pg/ml (normal range <4.0 pg/ml), 3.2 pg/ml (normal range 0.6–2.8 pg/ml) and 1,090 U/ml (normal range 220–530 U/ml), respectively. Computed tomography revealed cervical lymphadenopathy and mild splenomegaly. Laboratory evaluations ruled out infections and malignancies, and she was therefore given a diagnosis of AOSD based on Yamaguchi’s classification criteria [2].

Because the patient refused to take corticosteroids, we tried etanercept (50 mg/week) first, since there are some case reports on anti-TNF agents’ efficacy for treating AOSD [6, 7]. However, there was no improvement in patient’s clinical symptoms (Fig. 1).

Fig. 1
figure 1

Clinical course in case 1.Improvement in symptoms, WBC, CRP and ferritin levels in a patient with AOSD treated with TCZ monotherapy. Note that fever, skin rash, arthralgia and CRP levels rapidly normalized. ETN Etanercept

Full size image

Therefore, we administered 8 mg/kg of TCZ, which rapidly mitigated symptoms and lowered inflammatory marker levels. Although the third infusion was planned at week 6, CRP and leukocyte count slightly increased and her symptoms such as low grade fever and polyarthralgia appeared at week 4 (Fig. 1). Therefore, the third infusion was administered at week 5 soon after. After the infusions at weeks 5, 8, and 11, all the symptoms and signs of AOSD disappeared, and the patient received TCZ subsequently every 4 weeks to remain in complete remission, which has lasted for more than 2 years. Serum IL-6 level also decreased to 5.4 pg/ml and ferritin level was normal. Corticosteroids were never administered throughout her disease course.

Case 2

An 18-year-old man was admitted to our hospital in August 2010 because of fever, polyarthralgia, sore throat, and myalgia. He had been well until about 3 weeks earlier. Two weeks prior to admission, he had received antibiotics, including azithromycin hydrate, levofloxacin hydrate, and panipenem/betamipron, but had shown no response. Laboratory test results on admission were as follows: leukocyte count 30,400/μl (neutrophils 25,500/μl), hemoglobin 12.5 g/dl, platelet count 521,000/μl, ESR 53 mm/h, prothrombin time INR 1.26, activated partial thromboplastin time 30.0 seconds, fibrinogen 700 mg/dl, D-dimer 1.96 μg/ml, CRP 25.6 mg/dl, AST 15 IU/l, ALT 26 IU/l, LDH 245 IU/l, serum creatinine 0.81 mg/dl, and ferritin 2,756 ng/ml. The urine values were all normal. Serological tests were negative for both RF and ANA. The serum IL-6 and soluble IL-2 receptor levels were, respectively, 18.8 pg/ml and 1,050 U/ml. Abdominal ultrasonography showed mild splenomegaly. We excluded infections, malignancies, and other rheumatic diseases by radiological examinations, gastrointestinal and colon endoscopy, and laboratory examinations that included repetitive culture for microorganisms as well as assays for various autoantibodies. The patient got a diagnosis of AOSD, but he and his family did not consent to corticosteroid therapy. We decided to administer 8 mg/kg of TCZ at weeks 0, 2, 6, and subsequently every 4 weeks. One day after the first TCZ infusion, fever and polyarthralgia abated markedly and serum CRP level returned to normal within 1 week. The second TCZ was administered at week 3 because of patient’s affairs, and the patient was discharged 3 days later. TCZ has been continued every 4 weeks for 8 months and the patient is still in complete remission.

Discussion

This is the first case report, to our knowledge, demonstrating that TCZ monotherapy was effective for AOSD. Corticosteroids are usually required to improve clinical symptoms and laboratory abnormalities and are still a mainstay for inducing remission in AOSD. In fact, most (76%–95%) AOSD patients can be successfully treated with corticosteroids, and they respond dramatically [3]. However, consensus is lacking on a therapeutic corticosteroid tapering scheme after achieving clinical remission. Slow reduction is often necessary to maintain a good response and to avoid relapse. Corticosteroid dependence increases the risk for potentially serious mid- and long-term side effects caused by Cushing-like phenomena, diabetes, osteoporosis, and osteonecrosis. Anti-rheumatic drugs such as MTX are also reported to be effective [24, 25], but we are not aware of any randomized controlled trials.

The mechanisms underlying AOSD are not completely understood, but the role of proinflammatory cytokines may play a significant role in its pathogenesis because biological response modifiers targeted to these cytokines have been used successfully to treat AOSD. Promising results have been reported with TNF inhibitors such as etanercept and infliximab, but treatment failures and apparent loss of efficacy have also been described [6, 7]. A role for IL-1 has been also demonstrated by patient’s response to anakinra [8, 9, 26].

IL-6 is also believed to play a crucial role in pathogenesis, and its serum levels correlate well with the AOSD’s severity [4, 27]. There have been several other reports regarding TCZ’s efficacy (Table 2) [10–23]. Fitzgerald et al. [8] proposed that TNF-α induces IL-1 production, which stimulates IL-6 expression. Therefore, Matsumoto et al. [13] stated that directly inhibiting IL-6 activity, which is the most downstream cytokine in the AOSD inflammatory cascade, may be better than blocking IL-1. In fact, AOSD patients who responded poorly to anakinra responded well to TCZ [11, 14, 18, 22]. Moreover, concomitant corticosteroid treatment described in 13 cases was successfully tapered in 7 [13–16, 18, 21, 23] and discontinued in 6 cases [10–12, 19, 20] after achieving TCZ-induced remission, suggesting that TCZ monotherapy may serve as first-line remission induction therapy.

Table 2 Literature review: Tocilizumab treatment for AOSD
Full size table

In our present report, TCZ monotherapy rapidly improved each patient’s health, and the patients have remained in complete remission. However, case 1 appeared to relapse after the second TCZ infusions. Although other cytokines such as IL-18 [4, 28, 29] might have been more important targets, TCZ may have been effective if biweekly infusion had been continued as used to treat systemic type juvenile idiopathic arthritis (classical Still’s disease) [30]. Biweekly infusions of TCZ can be necessary for some AOSD patients to protect exacerbation completely.

TCZ was well tolerated by our patients. However, severe adverse events with macrophage activation syndrome (MAS) due to cytomegalovirus infection have been reported [11]. AOSD itself may cause MAS, and it may be difficult to distinguish TCZ’s adverse effects from treatment insufficiency noted in the other case [21]. However, both patients were able to resume TCZ and continued after the MAS abated. Another concern is exacerbation of AOSD or MAS due to a transient increase of serum levels of target cytokine right after the cytokine blockade [31]. However, no exacerbation was seen in our cases, and was not described in all the reported cases treated with TCZ except one case [22]. We should be watchful for this kind of adverse event when we treat AOSD patients with cytokine blockade, but it seems to be rare in TCZ therapy.

In conclusion, TCZ monotherapy may be effective in some patients with AOSD.