Two Cases of Adult-onset Still's Disease Treated with Tocilizumab that Achieved Tocilizumab-free Remission

Kobayashi, Daisuke; Ito, Satoshi; Murasawa, Akira; Narita, Ichiei; Nakazono, Kiyoshi

doi:10.2169/internalmedicine.54.4935

Cited by 12 publications

(9 citation statements)

References 37 publications

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“…We reviewed the literature for reports on the treatment of AOSD-associated MAS with biologics [ 22 – 27 ] ( Table 1 ). We searched for literature in English and Japanese languages published up until December 2015 in PubMed database for eligible articles that simultaneously met with Medical Subject Headings terms of AOSD and MAS/HPS.…”

Section: Discussionmentioning

confidence: 99%

“…IL-18 acts upstream of IL-6 in the inflammatory cytokine cascade [ 14 , 31 ]. Therefore, TCZ monotherapy might be ineffective, as it is unable to fully inhibit the inflammatory cytokines downstream of IL-18 [ 27 ]. The inhibition of a single cytokine pathway may cause an unfavorable imbalance in the cytokine network involved in AOSD-associated MAS [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease: A Case-Based Review

Watanabe

Sugawara

Yamashita

et al. 2016

Case Reports in Medicine

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We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease: A Case-Based Review

Watanabe

Sugawara

Yamashita

et al. 2016

Case Reports in Medicine

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“…No published prospective clinical trials evaluating TCZ in AOSD are available, but promising efficacy results have been observed in several case reports and retrospective analyses [84][85][86][87]. Improvements in clinical (fever, rash, and myalgia) and laboratory (ESR and CRP) manifestations were observed after treatment with TCZ in a review of 24 cases of AOSD in Korean patients [88].…”

Section: Other Diseasesmentioning

confidence: 99%

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

et al. 2018

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Tocilizumab (TCZ) is the first humanized antiinterleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the longterm efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although longterm data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents. Keywords: Interleukin-6; Rheumatoid arthritis; Tocilizumab TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTOR-NEUTRALIZING BIOLOGICInterleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in both acute and chronic inflammatory responses. Consequently, the dysregulated or persistent production of IL-6 can lead to the development of inflammatory disorders [1]. Elevated levels of IL-6 in serum, synovial fluid, and various tissues have been correlated with disease activity in patients with rheumatoid arthritis (RA) [2], juvenile idiopathic arthritis (JIA) [3,4], Castleman's disease [5,6], systemic sclerosis (SSc) [7], giant cell arteritis (GCA) [8,9], adult-onset Still's disease (AOSD) [10], familial Mediterranean fever (FMF) [11,12], Schnitzler's syndrome [13,14], polychondritis [15], and amyloidosis [1]. These associations suggest a pathogenetic role for IL-6 in multiple inflammatory conditions and form the basis of the rationale for the development of anti-IL-6 therapies.Tocilizumab (TCZ) is the first humanized monoclonal antibody targeting the IL-6 receptor subunit alpha (IL-6Ra) [16], and its mechanism of action has been described in detail in previous reviews [17,18]. Briefly, TCZ targets both membrane-bound and soluble IL-6Ra, which prevents t...

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“…[1,27] Indeed, tocilizumab has been shown to be effective for refractory AOSD around the world. [25,28–33] However, it remains unknown whether tocilizumab would be effective for SIRS complicating AOSD. Although SIRS complicating AOSD is extremely rare and mild cases are responsive to high-dose steroids, [8,34] it can also be fatal.…”

Section: Discussionmentioning

confidence: 99%

Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease

Masui-Ito

Okamoto²,

Ikejiri³

et al. 2017

Medicine

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Rationale:Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, fever spikes, arthralgia, and lymphadenopathy. AOSD usually has a good prognosis, but it can sometimes be fatal, especially when it is complicated by systemic inflammatory response syndrome (SIRS) and multiple organ failure.Patient concerns:A previously healthy 26-year-old woman was referred to our hospital for persistent high fever and mild systemic edema. Five days later, the patient presented with dyspnea, hypotension, and anuria. Anasarca developed with massive pleural effusion, ascites, and systemic edema, resulting in an increase of 47 kg in body weight.Diagnoses:The patient was diagnosed as AOSD after infection, malignancy, hematologic disorders, and other autoimmune diseases were excluded.Interventions:We administered tocilizumab, an IL-6 receptor inhibitor, intravenously in addition to cyclosporine, prednisolone, plasma exchange, and continuous hemodiafiltration.Outcomes:The patient's systemic condition improved. After stabilization by all medications, the patient was managed and responded to tocilizumab alone. To the best of our knowledge, this was the first case of severe SIRS complicating AOSD that was successfully treated with an anti- IL-6 receptor antibody.Lessons:SIRS should not be overlooked in a patient with steroid-resistant AOSD and edema. Inhibitors of the IL-6 receptor can be used safely and effectively to control AOSD complicated with severe SIRS.

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Two Cases of Adult-onset Still's Disease Treated with Tocilizumab that Achieved Tocilizumab-free Remission

Cited by 12 publications

References 37 publications

Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease: A Case-Based Review

Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease: A Case-Based Review

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease

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