Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis–associated pulmonary arterial hypertension: A multicenter, double-blind, randomized, placebo-controlled trial

NIH ASC01 Study Group

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13 Scopus citations

Abstract

Rationale: Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. Objectives: We investigated the safety and efficacy of B-cell depletion for SSc-PAH. Methods: In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. Measurements and Main Results: We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P  = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo ( P  = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). Conclusions: B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT01086540).

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume204
Issue number2
DOIs
StatePublished - Jul 15 2021

Bibliographical note

Funding Information:
We conducted a proof-of-concept, prospective, double-blind, multicenter, phase 2 randomized clinical trial of patients with SSc-PAH (NCT 01086540). The study was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), and the study drug was provided by Genentech. Recruiting field centers included 26 academic pulmonary, rheumatology, and cardiology programs in the United States. The protocol development committee, in collaboration with the NIAID and the statistical and clinical coordinating center (Rho Federal Systems Division) designed the study protocol (see the online supplement), and institutional review boards at each center approved the protocol. Data were collected and analyzed according to aprespecified statistical analysis plan. An

Funding Information:
Supported by the National Institute of Allergy and Infectious Diseases and the Autoimmunity Centers of Excellence (ACE) collaborative (5U19AI056363), Stanford ACE (U19AI110491), University of California, San Francisco, ACE (UM1AI110498), and Colorado ACE (U19AI046374). M.R.N. is supported by grants R01HL095686, R01HL141105, R01HL138473, 5P01HL01495, and R01HL082662 from the NIH. R.T.Z. is supported by grants from the NIH (NHLBI-HV-10-05, 1U01HL107393-01, PAR-09-185, and N01-HV-00242) and the Vera Moulton Wall Center for Pulmonary Vascular Diseases. A.J.S. is supported by NIH grant 1K23HL151892.

Publisher Copyright:
Copyright © 2021 by the American Thoracic Society

Keywords

  • Pulmonary hypertension
  • Systemic sclerosis
  • Treatment
  • Double-Blind Method
  • B-Lymphocytes/drug effects
  • Humans
  • Middle Aged
  • Biomarkers, Pharmacological
  • Pulmonary Arterial Hypertension/drug therapy
  • Male
  • Young Adult
  • Adolescent
  • Adult
  • Female
  • Aged
  • Rituximab/therapeutic use
  • Immunologic Factors/therapeutic use
  • Scleroderma, Systemic/complications

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Multicenter Study

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