Still’s disease, first described by G. Still in children in 1896, is an inflammatory disorder of unknown etiology characterized by arthritis, rash, and fever . An adult-onset form of the disease, adult-onset Still’s disease (AOSD), was subsequently reported by E. Bywaters in 1971 . The estimated prevalence of AOSD varies from 0.16 cases per 100,000 in France to 3.7 cases per 100,000 in Japan [3,4]. There is no specific diagnostic test for AOSD. It is most commonly diagnosed by using the Yamaguchi criteria (see Table 1), after excluding a wide range of disorders such as infection, malignancy, and other autoimmune conditions . Recent studies have showed that interleukin (IL)-1, IL-6, IL-18, interferon gamma, and tumor necrosis factors play important roles in the pathogenesis of AOSD. Inhibiting these cytokines by biological agents is a useful therapeutic strategy .
The Yamaguchi criteria for the classification of adult-onset Still’s disease
Macrophage-activation syndrome (MAS), an acute overwhelming inflammation caused by a “cytokine storm,” is one of the most serious complications of AOSD. The prevalence of MAS in AOSD is 7.7–16%, and the mortality ranges between 9.5% and 22% . AOSD closely resembles systemic juvenile idiopathic arthritis (sJIA). American College of Rheumatology (ACR) endorsed the new classification criteria for MAS complicating sJIA in 2016 (see Table 2). These include hyperferritinemia (>684 ng/mL) and any two of the following: thrombocytopenia (≤181 × 109/L), a high aspartate aminotransferase (AST) level (>48 units/L), hypertriglyceridemia (>156 mg/dL), and a low fibrinogen level (≤360 mg/dL) .
2016 American College of Rheumatology classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
|A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met:|
|Plus any two of the following:|
Tocilizumab (TCZ) is a humanized anti-IL-6 receptor monoclonal antibody. It blocks specifically the IL-6-mediated inflammatory pathways. A randomized placebocontrolled trial demonstrated the efficacy and safety of TCZ in sJIA . The use of TCZ for the treatment of refractory AOSD has also been recommended . Moreover, TCZ was found to be effective for AOSD complicated with MAS . However, intriguingly, MAS has been observedas a complication of TCZ treatment .
Here, we describe the case of a patient with AOSD complicated by MAS who required repeated courses of high-dose intravenous glucocorticoid and was subsequently well controlled by TCZ therapy. We also propose a strategy of blocking the specific pathogenic cytokine pathway with TCZ after adequate non-selective immunosuppression in treating AOSD-associated MAS.
2 Case Report
A 50-year-old Chinese woman with AOSD diagnosed in 2013, presented with unremitting fever and generalized lymphadenopathy, was admitted to our medical unit for fever. She has been put on prednisolone and methotrexate since the diagnosis of AOSD. Methotrexate was changed to azathioprine since 2014 because of disease flare. Three months before the current admission, she was managed in another medical unit for fever with pancytopenia while on prednisolone 10 mg daily and azathioprine 100 mg daily. Bone marrow examination showed hemophagocytosis. The diagnosis was AOSD flare with MAS and she was given methylprednisolone 100mg daily intravenously for 5 days with positive therapeutic response. She was discharged with tapering dose of prednisolone and azathioprine 50 mg daily. Azathioprine was later stopped because of an infected back sebaceous cyst that was treated uneventfully by incision and drainage.
The patient’s course in our hospital is shown in Figure 1. On admission to our unit, she was on prednisolone 12.5 mg daily. She complained of fever for 3 days with generalized arthralgia and myalgia. She also complained of sore throat. She had no rash or other focal symptoms. Physical examination revealed bilateral knees and ankles mild arthritis. There was also a sub-centimeter right axillary lymph node, which was non-tender. Initial blood tests were as follows: white cell count (WCC) is 8.1 × 109/L; hemoglobin (Hb), 9.4 g/dL; platelet (Plt), 189 × 109/L; C-reactive protein (CRP), 38.2 mg/L, AST, 18 units/L; and ferritin, 3,239 ng/mL. Synovial fluid tapped from the joints grew no microorganisms. Other septic work-ups were negative and the fever did not respond to antibiotics. Prednisolone was stepped up to 20 mg daily for the flare of AOSD. On hospital day 20, the patient was noted to have cytopenia with WCC 3 × 109/L and Plt 103 × 1099/L. Serum ferritin level was 5,893 ng/mL, AST 82 units/L, and triglycerides 280 mg/dL. A diagnosis of MAS complicating AOSD was made according to the new ACR classification criteria. Intravenous hydrocortisone 100 mg every 8 h was given with normalization of the cell counts. She was once put on cyclosporin A but she refused to take the medication further because of gastrointestinal upset. However, fever and pancytopenia recurred when the systemic steroid was tapered to prednisolone 20 mg daily. She was given methylprednisolone 250 mg daily intravenously on hospital day 33. On day 37, after the fever has subsided and the cell counts normalized, she was given TCZ 560 mg intravenously. She remained asymptomatic and afebrile with normal CRP. She was discharged on day 41. Subsequently, she completed a six-month course of TCZ and was maintained on prednisolone 7.5 mg daily only, as she refused additional immunosuppressive therapy. At the end of the course, she was asymptomatic with normal cell counts, liver function test, CRP, and a ferritin level of 318 ng/mL.
The pathophysiology of MAS in AOSD is believed to be an overproduction of proinflammatory cytokine resulting in uncontrolled accumulation of activated T-lymphocytes and macrophages in many organs . Treatment is directed against the underlying disease. In a Japanese cohort of 30 cases of AOSD-associated MAS, high-dose corticosteroid monotherapy was effective only in 46% of cases . Various other traditional immunosuppressants have been tried in corticosteroid-resistant cases with inconsistent results.
With better understanding of the pathogenesis (see Figure 2), recently, there has been a growing evidence in a more targeted approach using biologics for treatment of MAS related to AOSD. IL-1 and IL-6 have been suggested as the essential contributing cytokines . While anti-IL-1 anakinra and TCZ have been recommended for refractory systemic AOSD, they seem to be ideal to prevent the detrimental effects of the cytokine storm in AOSD-related MAS by targeting the respective cytokine signaling pathways. Marked improvement in response to anakinra or TCZ in sJIA and AOSD-associated MAS after suboptimal effect of corticosteroid and various other traditional immunosuppressants has been described in case reports . However, as neither IL-1 nor IL-6 is the only driver constituting the development of MAS in AOSD, it is unknown whether blockade of a single cytokine pathway in the setting of a cytokine storm is sufficient to suppress the overwhelming inflammatory condition. Furthermore, despite growing evidence that markedly elevated levels of serum IL-1 and IL-6 are seen in patients with MAS-complicating AOSD, which seemingly correlate with disease activity, casualty is not necessarily established .
Paradoxically, the use of biologics has also been associated with the emergence of MAS in AOSD. In a database of 627 patients with sJIA with 1,253 patient-years of exposure to TCZ, 22 events were considered as definite (n = 11) or potential (n = 11) MAS in 21 (3.3%) patients. It was hypothesized that the imbalanced and destabilized cytokine network created by the biologics will favor the occurrence of serious infections and in turn lead to MAS . In a post-marketing surveillance study conducted in 417 patients with sJIA on TCZ, MAS occurred in 5.8% of the patients, with infection and active sJIA being considered to be the main contributing factors to MAS development . Similarly, MAS occurring during anakinra treatment in some patients with sJIA was reported to be improved by dose escalation of anakinra . Thus, biologics do not appear to cause MAS directly; rather, the susceptibility to infection related to its usage might play a role.
We reported a case of MAS-complicating AOSD refractory to systemic corticosteroid successfully treated with TCZ. High-dose parenteral corticosteroids were used to achieve initial control. The addition of TCZ after pulse corticosteroid led to complete disease remission with successful weaning of corticosteroids. Similar cases were reported before. Interestingly, all 6 reported cases of AOSD-associated MAS that were successfully treated by TCZ received initial pulse methylprednisolone therapy or high-dose prednisolone plus methotrexate [7,19,20,21,22]. While in one case report of MAS emerging after TCZ for AOSD, only high-dose prednisolone was given . It was postulated that TCZ monotherapy might be inadequate to fully inhibit the inflammatory cytokines acting upstream, such as IL-18. Pulse methylprednisolone therapy or high-dose corticosteroid in combination with other immunosuppressants could achieve overall immunosuppression by inhibiting multiple immune system components. Thus, concomitant non-selective potent immunosuppressive therapy might enable effective and safe use of TCZ in AOSD-related MAS by preventing cytokine imbalance.
In conclusion, TCZ following initial adequate non-selective immunosuppression seems to be a promising therapeutic strategy for patients with AOSD complicated by MAS. However, it remains unclear at what time point and how long TCZ should be administered. Future studies will hopefully elucidate the clinical efficacy and safety of IL-6 blockade for these patients.
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