PMID- 33651671
OWN - NLM
STAT- MEDLINE
DCOM- 20210920
LR  - 20230331
IS  - 1535-4970 (Electronic)
IS  - 1073-449X (Print)
IS  - 1073-449X (Linking)
VI  - 204
IP  - 2
DP  - 2021 Jul 15
TI  - 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.
PG  - 209-221
LID - 10.1164/rccm.202009-3481OC [doi]
AB  - 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).
FAU - Zamanian, Roham T
AU  - Zamanian RT
AUID- ORCID: 0000-0002-0734-0994
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine and.
AD  - Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, California.
FAU - Badesch, David
AU  - Badesch D
AD  - Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado 
      Anschutz Medical Campus, Aurora, Colorado.
FAU - Chung, Lorinda
AU  - Chung L
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine and.
AD  - Division of Rheumatology and Immunology, Stanford University, Stanford University 
      School of Medicine, Stanford, California.
FAU - Domsic, Robyn T
AU  - Domsic RT
AD  - Division of Rheumatology and Clinical Immunology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania.
FAU - Medsger, Thomas
AU  - Medsger T
AD  - Division of Rheumatology and Clinical Immunology, University of Pittsburgh School 
      of Medicine, Pittsburgh, Pennsylvania.
FAU - Pinckney, Ashley
AU  - Pinckney A
AD  - Rho Federal Systems Division, Durham, North Carolina.
FAU - Keyes-Elstein, Lynette
AU  - Keyes-Elstein L
AD  - Rho Federal Systems Division, Durham, North Carolina.
FAU - D'Aveta, Carla
AU  - D'Aveta C
AD  - Rho Federal Systems Division, Durham, North Carolina.
FAU - Spychala, Meagan
AU  - Spychala M
AD  - Rho Federal Systems Division, Durham, North Carolina.
FAU - White, R James
AU  - White RJ
AUID- ORCID: 0000-0003-1399-5206
AD  - Division of Pulmonary and Critical Care Medicine, University of Rochester, 
      Rochester, New York.
FAU - Hassoun, Paul M
AU  - Hassoun PM
AD  - Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of 
      Medicine, Baltimore, Maryland.
FAU - Torres, Fernando
AU  - Torres F
AD  - Division of Pulmonary and Critical Care Medicine, University of Texas 
      Southwestern, Dallas, Texas.
FAU - Sweatt, Andrew J
AU  - Sweatt AJ
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine and.
AD  - Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, California.
FAU - Molitor, Jerry A
AU  - Molitor JA
AD  - Division of Rheumatic and Autoimmune Diseases, University of Minnesota, 
      Minneapolis, Minnesota.
FAU - Khanna, Dinesh
AU  - Khanna D
AD  - Division of Rheumatology, University of Michigan, Ann Arbor, Michigan.
FAU - Maecker, Holden
AU  - Maecker H
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine and.
FAU - Welch, Beverly
AU  - Welch B
AD  - National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and.
FAU - Goldmuntz, Ellen
AU  - Goldmuntz E
AD  - National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and.
FAU - Nicolls, Mark R
AU  - Nicolls MR
AUID- ORCID: 0000-0001-9473-7422
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine and.
AD  - Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, California.
AD  - Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
LA  - eng
SI  - ClinicalTrials.gov/NCT01086540
GR  - R01 HL095686/HL/NHLBI NIH HHS/United States
GR  - UM2 AI117870/AI/NIAID NIH HHS/United States
GR  - R01 HL141105/HL/NHLBI NIH HHS/United States
GR  - P01 HL108797/HL/NHLBI NIH HHS/United States
GR  - U01 HL107393/HL/NHLBI NIH HHS/United States
GR  - U19 AI046374/AI/NIAID NIH HHS/United States
GR  - K23 HL151892/HL/NHLBI NIH HHS/United States
GR  - R01 HL138473/HL/NHLBI NIH HHS/United States
GR  - UM1 AI110498/AI/NIAID NIH HHS/United States
GR  - U19 AI056363/AI/NIAID NIH HHS/United States
GR  - R01 HL082662/HL/NHLBI NIH HHS/United States
GR  - U19 AI110491/AI/NIAID NIH HHS/United States
GR  - P01 HL014985/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Crit Care Med
JT  - American journal of respiratory and critical care medicine
JID - 9421642
RN  - 0 (Biomarkers, Pharmacological)
RN  - 0 (Immunologic Factors)
RN  - 4F4X42SYQ6 (Rituximab)
SB  - IM
CIN - Am J Respir Crit Care Med. 2021 Jul 15;204(2):123-125. PMID: 33856964
CIN - Am J Respir Crit Care Med. 2021 Aug 1;204(3):377-378. PMID: 34107229
CIN - Am J Respir Crit Care Med. 2021 Aug 1;204(3):359. PMID: 34107236
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - B-Lymphocytes/*drug effects
MH  - Biomarkers, Pharmacological
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Immunologic Factors/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Pulmonary Arterial Hypertension/*drug therapy/*etiology
MH  - Rituximab/*therapeutic use
MH  - Scleroderma, Systemic/*complications
MH  - Young Adult
PMC - PMC8650794
OTO - NOTNLM
OT  - pulmonary hypertension
OT  - systemic sclerosis
OT  - treatment
EDAT- 2021/03/03 06:00
MHDA- 2021/09/21 06:00
PMCR- 2022/07/01
CRDT- 2021/03/02 17:07
PHST- 2021/03/03 06:00 [pubmed]
PHST- 2021/09/21 06:00 [medline]
PHST- 2021/03/02 17:07 [entrez]
PHST- 2022/07/01 00:00 [pmc-release]
AID - 10.1164/rccm.202009-3481OC [doi]
PST - ppublish
SO  - Am J Respir Crit Care Med. 2021 Jul 15;204(2):209-221. doi: 
      10.1164/rccm.202009-3481OC.