Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial

被引：172

作者：

Khanna, Dinesh ^{[1
]}

Spino, Cathie ^{[1
]}

Johnson, Sindhu ^{[2
,3
]}

Chung, Lorinda ^{[4
]}

Whitfield, Michael L. ^{[5
]}

Denton, Christopher P. ^{[6
]}

Berrocal, Veronica ^{[1
]}

Franks, Jennifer ^{[5
]}

Mehta, Bhavan ^{[5
]}

Molitor, Jerry ^{[7
]}

Steen, Virginia D. ^{[8
]}

Lafyatis, Robert ^{[9
]}

Simms, Robert W. ^{[10
]}

Gill, Anna ^{[6
]}

Kafaja, Suzanne ^{[11
]}

Frech, Tracy M. ^{[12
]}

Hsu, Vivien ^{[13
]}

Domsic, Robyn T. ^{[14
]}

Pope, Janet E. ^{[15
]}

Gordon, Jessica K. ^{[16
]}

Mayes, Maureen D. ^{[17
]}

Schiopu, Elena ^{[1
]}

Young, Amber ^{[1
]}

Sandorfi, Nora ^{[18
]}

Park, Jane ^{[19
]}

Hant, Faye N. ^{[20
]}

Bernstein, Elana J. ^{[21
]}

Chatterjee, Soumya ^{[22
]}

Castelino, Flavia, V ^{[23
]}

Ajam, Ali ^{[24
]}

Wang, Yue ^{[5
]}

Wood, Tammara ^{[5
]}

Allanore, Yannick ^{[25
]}

Matucci-Cerinic, Marco ^{[26
]}

Distler, Oliver ^{[27
]}

Singer, Ora ^{[1
]}

Bush, Erica ^{[1
]}

Fox, David A. ^{[1
]}

Furst, Daniel E. ^{[28
]}

机构：

[1] Univ Michigan, Ann Arbor, MI 48109 USA

[2] Mt Sinai Hosp, Toronto, ON, Canada

[3] Univ Hlth Network, Toronto, ON, Canada

[4] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA

[5] Geisel Sch Med Dartmouth, Hanover, NH USA

[6] Royal Free Campus, London, England

[7] Univ Minnesota, Minneapolis, MN USA

[8] MedStar Georgetown Univ Hosp, Washington, DC USA

[9] Pittsburgh Univ, Med Ctr, Pittsburgh, PA USA

[10] Boston Univ, Sch Med, Boston, MA 02118 USA

[11] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[12] Univ Utah, Salt Lake City, UT USA

[13] Robert Wood Johnson Univ, New Brunswick, NJ USA

[14] Univ Pittsburgh, Pittsburgh, PA USA

[15] Univ Western Ontario, London, ON, Canada

[16] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA

[17] Univ Texas McGovern Med Sch, Houston, TX USA

[18] Univ Penn, Perelman Sch Med, Pittsburgh, PA USA

[19] Seattle Rheumatol Associates, Washington, DC USA

[20] Med Univ South Carolina, Charleston, SC 29425 USA

[21] Columbia Univ, New York, NY USA

[22] Cleveland Clin, Cleveland, OH 44106 USA

[23] Harvard Med Sch, Boston, MA 02115 USA

[24] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA

[25] Hop Cochin, Paris, France

[26] Univ Florence, Florence, Italy

[27] Univ Hosp Zurich, Zurich, Switzerland

[28] Univ Calif Los Angeles, Los Angeles, CA USA

来源：

ARTHRITIS & RHEUMATOLOGY | 2020年 / 72卷 / 01期

关键词：

SKIN THICKNESS SCORE; CLINICAL-TRIALS; AMERICAN-COLLEGE; GENE-EXPRESSION; SCLERODERMA; DISEASE; EFFICACY; SAFETY; CLASSIFICATION; INVOLVEMENT;

D O I：

10.1002/art.41055

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Results Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. Conclusion In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

引用

页码：125 / 136

页数：12

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