Tocilizumab is effective in a familial <scp>M</scp>editerranean fever patient complicated with histologically proven recurrent fasciitis and myositis

Umeda, Masataka; Aramaki, Toshiyuki; Fujikawa, Keita; Iwamoto, Naoki; Ichinose, Kunihiro; Terada, Kaoru; Takeo, Gou; Yonemitsu, Nobuhisa; Ueki, Yukitaka; Migita, Kiyoshi; Kawakami, Atsushi

doi:10.1111/1756-185x.12776

Cited by 22 publications

(12 citation statements)

References 11 publications

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“…Other recent case reports have shown the efficacy of an IL-6 inhibitor in clinical practice for colchicine-resistant FMF or secondary amyloidosis in FMF patients. 19 – 22 Taken together, our data support the notion of IL-6 as a main inflammatory cytokine in FMF and, thus, as a promising target in this disease.…”

Section: Discussionsupporting

confidence: 82%

Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

Koga¹,

Migita

Sato

et al. 2016

Medicine

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The precise cytokine networks in the serum of individuals with familial Mediterranean fever (FMF) that are associated with its pathogenesis have been unknown. Here, we attempted to identify specific biomarkers to diagnose or assess disease activity in FMF patients.We measured serum levels of 45 cytokines in 75 FMF patients and 40 age-matched controls by multisuspension cytokine array. FMF in “attack” or “remission” was classified by Japan College of Rheumatology-certified rheumatologists according to the Tel Hashomer criteria. Cytokines were ranked by their importance by a multivariate classification algorithm. We performed a logistic regression analysis to determine specific biomarkers for discriminating FMF patients in attack. To identify specific molecular networks, we performed a cluster analysis of each cytokine.Twenty-nine of the 45 cytokines were available for further analyses. Eight cytokines’ serum levels were significantly elevated in the FMF attack versus healthy control group. Nine cytokines were increased in FMF attack compared to FMF remission. Multivariate classification algorithms followed by a logistic regression analysis revealed that the combined measurement of IL-6, IL-18, and IL-17 distinguished FMF patients in attack from the controls with the highest accuracy (sensitivity 89.2%, specificity 100%, and accuracy 95.5%). Among the FMF patients, the combined measurement of IL-6, G-CSF, IL-10, and IL-12p40 discriminated febrile attack periods from remission periods with the highest accuracy (sensitivity 75.0%, specificity 87.9%, and accuracy 84.0%).Our data identified combinational diagnostic biomarkers in FMF patients based on the measurement of multiple cytokines. These findings help to improve the diagnostic performance of FMF in daily practice and extend our understanding of the activation of the inflammasome leading to enhanced cytokine networks.

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Section: Discussionsupporting

confidence: 82%

Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

Koga¹,

Migita

Sato

et al. 2016

Medicine

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“…If the participants meet the inclusion criteria at this point, they will be randomized. In line with these observations, other case reports have shown the efficacy of an IL-6 inhibitor in clinical practice for colchicine-resistant FMF or secondary amyloidosis in patients with FMF [10–13]. Taken together, these findings enabled us to design the current phase III study to confirm the beneficial effects of tocilizumab (TCZ) in patients with FMF.…”

Section: Introductionsupporting

confidence: 63%

Comparison of the efficacy and safety of tocilizumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: study protocol for an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial

Koga

Sato

Miyamoto

et al. 2018

Trials

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BackgroundFamilial Mediterranean fever (FMF) is an inherited disorder caused by a number of mutations of the Mediterranean fever (MEFV) gene, coding a protein named pyrin that acts as a major regulatory component of the inflammasome. The first-line drug for FMF treatment is colchicine, but 10% of patients with FMF do not respond well to colchicine. Although the efficacy of tocilizumab (TCZ), which is a recombinant, humanized, antihuman interleukin 6 (IL-6) receptor monoclonal antibody, has been reported to prevent FMF attacks, the effects of TCZ on individuals with colchicine-resistant or colchicine-intolerant FMF have not been evaluated in a randomized clinical trial.Methods/designIn this phase III, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of TCZ will be compared with placebo in patients with colchicine-resistant or colchicine-intolerant FMF. The study will be conducted in nine centers in Japan. Participants (n = 24) will be randomly assigned to receive 162 mg of TCZ (n = 12) or placebo (n = 12) administered subcutaneously once weekly for 24 weeks. Rescue treatment will be allowed if rescue criteria are met. A primary endpoint is the number of fever attacks until 24 weeks. Secondary endpoints include the number of occurrences of accompanying symptoms during attacks; the time until a fever attack occurs; the duration of fever attacks; serum C-reactive protein and serum amyloid A; 36-item Short Form Health Survey; general evaluation by a physician (100-mm visual analogue scale); body temperature; the percentage of subjects who achieve FMF 50 at 12 weeks and 24 weeks; and pharmacodynamic assessment, including the measurement of serum TCZ level and soluble IL-6 receptor.DiscussionThe study is expected to produce evidence regarding the efficacy of a potential new therapeutic agent, TCZ, in improving the clinical course and outcome for patients with colchicine-resistant or colchicine-intolerant FMF.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry, UMIN000028010. Registered on 7 July 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3105-6) contains supplementary material, which is available to authorized users.

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“…TCZ has also shown promise in several other indications, including amyloidosis [97][98][99][100], FMF [101][102][103], Schnitzler's syndrome [104,105], and polychondritis [106][107][108][109]. Results of the doubleblind, randomized, placebo-controlled, phase 3 TAKT trial in 36 patients with Takayasu arteritis demonstrated a trend toward relapse suppression in favor of TCZ-SC over placebo [110].…”

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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Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis

Cited by 22 publications

References 11 publications

Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

Comparison of the efficacy and safety of tocilizumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: study protocol for an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial

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

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