Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial

Khanna, Dinesh; Lin, Celia J F; Fürst, Daniel E.; Goldin, Jonathan G.; Kim, Grace; Kuwana, Masataka; Allanore, Yannick; Matucci‐Cerinic, Marco; Distler, Oliver; Shima, Yoshihito; Laar, Jacob M van; Spotswood, Helen; Wagner, Bridget K.; Siegel, Jeffrey; Jahreis, Angelika; Denton, Christopher P.; Lucero, Eleonora; Pons-Éstel, Bernardo A; Rivero, Mariano; Tate, Guillermo; Smith, Vanessa; Langhe, Ellen De; Rashkov, Rasho; Batalov, Anastas; Goranov, I; Стоилов, Румен; Dunne, James V.; Johnson, Sindhu R.; Pope, Janet; Kaliterna, Dušanka Martinović; Mogensen, Mette; Olesen, Anne Braae; Henes, Joerg; Müller‐Ladner, Ulf; Riemekasten, Gabriela; Skapenko, Alla; Vlachoyiannopoulos, Panayiotis G.; Kiss, Emese; Minier, Tünde; Beretta, Lorenzo; Gremese, Elisa; Valentini, Gabriele; Asano, Yoshihide; Atsumi, Tatsuya; Ihn, Hironobu; Ishii, Tomonori; Ishikawa, Osamu; Takahashi, Hiroki; Takehara, Kazuhiko; Tanaka, Yoshiya; Yamasaki, Yoshioki; Bukauskienė, Loreta; Butrimienė, İrena; Ramírez, Gabriel Medrano; Ramos-Remus, César; Reyna, Tatiana Sofía Rodríguez; Vries‐Bouwstra, Jeska de; Batko, Bogdan; Jeka, Sławomir; Kucharz, Eugeniusz J.; Majdan, Maria; Olesińska, Marzena; Smoleńska, Żaneta; Alves, José Delgado; Santos, María José; Mihai, Carmen Marina; Rednic, Simona; Barranco, Ivan Castellví; Longo, Francisco; Aznar, Carmen Simeon; Carreira, Patrícia; Walker, Ulrich A.; Derrett-Smith, Emma; Griffiths, Bridget; McKay, Neil; Aelion, Jacob; Borofsky, Michael; Fleischmann, Roy; Forstot, Joseph Z.; Kafaja, Suzanne; Khan, Mohammad Faisal; Kohen, Michael David; Martin, Richard W.; Mendoza-Ballesteros, Fabian; Nami, Alireza; Pang, Shirley; Ríos, Grissel; Simms, Robert W.; Sullivan, Keith M.; Steen, Virginia D.

doi:10.1016/s2213-2600(20)30318-0

Cited by 460 publications

(287 citation statements)

References 30 publications

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“…In this view, the phase 3 double-blind randomized placebo-controlled study (FocuSSced) of TCZ enrolled 210 early dcSSc patients. Similarly, a reduced FVC decline was seen in the TCZ group (difference between groups 4.2 (95% CI 2.0-6.4) favoring TCZ; p = 0.0002), with a trend for a lower rate of patients requiring rescue immunosuppressive therapy for ILD indication (p = 0.08) [49].…”

Section: Tocilizumabmentioning

confidence: 79%

“…The first two studies on TCZ, an anti-IL-6 soluble receptor monoclonal antibody, reported inconclusive results [48,49]. TCZ was administered in a phase 2 study (FaSScinate), and the data suggested this drug played a role in the IL-6 pathway in SSc-ILD and treatment of early SSc with elevated C-Reactive protein (CRP) and that it led to the stabilization of the FVC% in the tocilizumab group vs. a clinically meaningful decline in the placebo group over 48 weeks [48].…”

Section: Tocilizumabmentioning

confidence: 99%

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The Treatment of Lung Involvement in Systemic Sclerosis

et al. 2021

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Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.

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Section: Tocilizumabmentioning

confidence: 79%

Section: Tocilizumabmentioning

confidence: 99%

The Treatment of Lung Involvement in Systemic Sclerosis

et al. 2021

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“…In current clinical practice, treatment is often initiated after progression has occurred, and novel treatment concepts are needed in patients at risk of developing a progressive fibrosing phenotype that aim for the prevention of progression. In this regard, tocilizumab, an IL-6 receptor antibody, is a promising biological agent as exploratory analysis of the faSScinate phase 2 trial and the focuSSced phase 3 trial suggested that tocilizumab could preserve pulmonary function in very early SSc-ILD patients [40,41].…”

Section: Systemic Sclerosis-associated Ild (Ssc-ild)mentioning

confidence: 99%

Progression in the Management of Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Diseases, Where Are We Now and Where We Would Like to Be

Goos

Sadeleer

Yserbyt

et al. 2021

JCM

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A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness of idiopathic pulmonary fibrosis (IPF). Common pathophysiological mechanisms such as a shared genetic susceptibility and a common downstream pathway—self-sustaining fibroproliferation—support the concept of a progressive fibrosing phenotype, which is applicable to a broad range of non-IPF ILDs. While antifibrotic drugs became the standard of care in IPF, immunosuppressive agents are still the mainstay of treatment in non-IPF fibrosing ILD (F-ILD). However, recently, randomized placebo-controlled trials have demonstrated the efficacy and safety of antifibrotic treatment in systemic sclerosis-associated F-ILD and a broad range of F-ILDs with a progressive phenotype. This review summarizes the current pharmacological management and highlights the unmet needs in patients with non-IPF ILD.

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“…It was tried on 2 patients with diffuse SSc and based on success then expanded to a phase 2/3 trial (31-35), which showed a trend toward skin and lung improvement in 87 patients (5). A larger, multicenter trial (N=210) in SSc has been completed and did not meet their primary endpoints (36).…”

Section: Biological Therapies and Hematopoietic Stem Cell Transplantation (Hsct) In Sscmentioning

confidence: 99%

Systemic sclerosis (scleroderma): remaining challenges

Connolly

2021

Ann Transl Med

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Despite progress in treating internal organ involvement in systemic sclerosis (scleroderma) (SSc), such as pulmonary disease, effective treatments for the hallmark of the disease, cutaneous fibrosis, remain elusive. None of the disease-modifying antirheumatic drugs (DMARDS) have shown proven efficacy for SSc skin fibrosis, and there remain no FDA-approved medications, all of which are off-label, for cutaneous fibrosis in SSc. This review article will briefly summarize conventional therapies, biologics and hematopoietic stem cell transplants and select ongoing clinical trials in SSc. The gold standard for measuring skin fibrosis in SSc is the modified Rodnan skin score (MRSSS). This is a validated test that measures skin thickness ( 0to 3) at 17 locations for a total score of 51. Improvements in skin score over time are used in clinical trials to quantitate skin fibrosis. Although recording the Rodnan skin score is technically straightforward, requiring no special equipment, and noninvasive, the fluctuating natural history of the disease includes improvement over time without interventions, rendering meaningful trials difficult to assess. Understanding of the basic molecular mechanisms driving pathologic fibrosis in SSc remains lacking, and underpins the often empiric nature and likely the lack of efficacy of many therapeutics that have been tried. Although repeated skin biopsies might be a more precise way to follow disease progression and regression, this is necessarily invasive and requires special tools. Here, this review will look at conventional therapies, biologics, autologous hematopoietic stem cell transplantation, and catalog some of the ongoing clinical trials in SSc with a focus on cutaneous fibrosis.

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Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 460 publications

References 30 publications

The Treatment of Lung Involvement in Systemic Sclerosis

The Treatment of Lung Involvement in Systemic Sclerosis

Progression in the Management of Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Diseases, Where Are We Now and Where We Would Like to Be

Systemic sclerosis (scleroderma): remaining challenges

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