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 John Varga
Christopher P. Denton
Fredrick M. Wigley
Yannick Allanore
Masataka Kuwana
Editors

Scleroderma
From Pathogenesis
to Comprehensive
Management
Second Edition

123
Scleroderma

Second Edition
John Varga • Christopher P. Denton
Fredrick M. Wigley • Yannick Allanore
Masataka Kuwana
Editors

Scleroderma
From Pathogenesis to Comprehensive
Management

Second Edition
Editors
John Varga Yannick Allanore
Feinberg School of Medicine Service de Rhumatologie A, INSERMU1016
Northwestern University Universit. Paris Descartes, Hôpital Cochin
Chicago, Illinois Paris
USA France

Christopher P. Denton Masataka Kuwana

Division of Medicine Department of Allergy and Rheumatology
Department of Inflammation Nippon Medical School, Graduate School
Centre for Rheumatology and Connective Tissue of Medicine
Diseases Tokyo
UCL Division of Medicine, Royal Free Hospital Japan
London
UK

Fredrick M. Wigley
Johns Hopkins University
Baltimore, Maryland
USA

ISBN 978-3-319-31405-1 ISBN 978-3-319-31407-5 (eBook)

DOI 10.1007/978-3-319-31407-5

Library of Congress Control Number: 2016955861

© Springer Science+Business Media New York 2017

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
express or implied, with respect to the material contained herein or for any errors or omissions that may have been
made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature

The registered company is Springer International Publishing AG Switzerland
The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland
I gratefully acknowledge Julie, Peter, and Andrew Varga for their unfailing
support, patience, and love; my parents who served as my role models; and
my patients who teach and inspire me every day.
-John Varga
I am indebted to the ongoing support of my family and the encouragement
and guidance from my mentors in rheumatology, especially Dame Carol
Black and the late Dr. Barbara Ansell.
-Christopher P. Denton
I am deeply grateful and indebted to Carol, my wife, and my children – Joy
and Julie, and family; the entire staff of the Johns Hopkins Scleroderma
Center; my colleagues in the Division of Rheumatology and my patients and
supporters
-Fredrick M. Wigley
I really appreciate the support and dedication of my family and colleagues at
Keio University and Nippon Medical School.
-Masataka Kuwana
I am grateful to all the colleagues and to all the patients who have taught me
about systemic sclerosis over the years. I thank all the collaborators with
whom we shared basic or clinical research projects, who were always source
of inspiration, with special thanks to the EUSTAR network members.
-Yannick Allanore
Foreword

Scleroderma, or systemic sclerosis, is a true multisystem disease that requires integrated mul-
tidisciplinary management including rheumatology, cardiology, renal and thoracic medicine
and gastroenterology as well as other medical specialties and healthcare professionals. It also
has a peculiarly cruel impact on quality of life and the potential to take a dreadful toll on
affected patients and their families. No one who has come across the disease in a severe form
will ever underestimate its importance or clinical impact. However, it is uncommon and there
is a great need for high-quality resources to educate and inform about the disease. I learnt dur-
ing a medical career dedicated to improving understanding and treatment of scleroderma the
tremendous importance of integrated management including all of these disciplines and also
that to really advance understanding of scleroderma it was critical to align clinical practice and
fundamental clinical and laboratory research.
As a young junior doctor in my first clinical post, I came across scleroderma when a young
woman was admitted under my care with scleroderma renal crisis. I was disturbed to learn from
the professor of medicine that there was no effective treatment and that she would be dead within
3 months. This was the case, and this incident sowed in my mind the seeds of curiosity about this
potentially devastating disease and determination to seek ways to do more. There have been
enormous strides in managing scleroderma over the past four decades, and a patient presenting
with the same clinical problem to a modern scleroderma unit could expect to survive and have a
much better outcome. However, it remains one of the most challenging of the rheumatic diseases
and one that still has to reveal much about the underlying cause and mechanism.
I have personally witnessed progress in understanding and managing scleroderma in its
diverse forms and would have relished access to this textbook earlier in my career as I estab-
lished one of the first units in the UK that specializes in scleroderma and later was involved in
developing the pulmonary hypertension service in our hospital that has made a major contribu-
tion to treatment and improving outcome for patients developing this important complication.
In my professional life, I have taken on new challenges over recent years and moved into other
areas of academic, medical, and government endeavor. This has focused on the tremendous
impact that health issues have on ability to work and participate in society and brings the indi-
vidual impact of a disease such as scleroderma into sharp focus.
The first edition of this textbook was a masterful integration of basic science and clinical
practice, and the second edition builds upon this model but includes new sections, including
clinical case summaries, that bridge the gap between the pathology and biological basis of
disease and clinical impact. It provides a very clear demonstration of progress in managing
major and life-threatening aspects of this disease and highlights the important links between
scleroderma and other medical conditions. I am delighted to write this foreword for the second
edition of what has emerged as the most comprehensive and up-to-date book on this disease,
spanning pathogenesis to clinical management of scleroderma. It more than lives up to expec-
tation and I am sure that it will help prepare and stimulate more healthcare professionals and
scientists to work on the disease and further improve treatments and outcome.
Professor Dame Carol Black
Principal of Newnham College, Cambridge, UK
Emeritus Professor of Rheumatology, UCL Division of Medicine, London, UK

vii
Foreword from Bob Saget

I am so honored to have been asked by the Editors to write a foreword for what will shortly
become the premier book on scleroderma now in existence …written for doctors, scientists and
patients.
Scleroderma is a disease that is very close to my heart, having lost my sister, Gay, to it in
1994 at only 47 years old. She was initially misdiagnosed and treated without full knowledge
of the latest clinical trials and forward thinking that can try to help patients stricken with this
complex disease.
I have had the pleasure over the years to shoot two short documentaries that were used to
raise awareness and to raise much needed funds to support research around the country.
The authors of this book are the forerunners in scleroderma research and clinical trials. The
doctors who have written this second new and revised edition are making a significant contri-
bution. One that I trust rheumatologists and doctors who come across scleroderma, no matter
their discipline, will take note of and read cover to cover.
I would like to acknowledge all the contributors and thank the editors of this book—the
very smartest and passionate Doctors—Dr. John Varga, Dr. Chris Denton, Dr. Yannick Allanore,
Dr. Masataka Kuwana, and Dr. Fredrick Wigley.
I became familiar with scleroderma several years before my sister Gay came down with it.
Twenty-five years ago I met a woman who was to become one of the dearest friends of my life,
Sharon Monsky. She was the founder and then CEO of the Scleroderma Research Foundation.
A great woman, mother of three, who’d been stricken with the disease as a young mom.
Sharon cold-called me to perform standup at a benefit in Santa Monica, which she had
titled, “Cool Comedy Hot Cuisine.” I had never met her before. I knew nothing about sclero-
derma. She explained the word scleroderma meant “hard skin.” She told me that it affects
mostly women in the prime of their lives. That it was a difficult disease to pinpoint—some
called it “auto-immune,” some used the word “vascular,” and she also said it occasionally
struck people living in the same area and in some rare cases, people in the same family.
The only way to raise money for research was to do what most people do in this situation—
have benefits and try to raise the much needed money to fund cutting edge research that goes
to helping find a cure, or at the very best, ways to put the disease into some kind of remission
in its victims.
Soon as she explained to me what the benefit was, I said “yes” over the phone and since
have been involved in her foundation’s signature event: a night of comedians and amazing food
by chefs and friends—with the idea that the best way to deal with this difficult disease was to
try and raise money for research through humor.
The beautiful Robin Williams was the first performer to give of himself to perform for this
cause I had yet to have strike my family directly. After I started doing the benefit as a comedian
and then its host for twenty-four years, Robin had come to do the event seven times and Top
Chefs Susan Feniger and Mary Sue Milliken have been amazing. The first year I performed,
Ellen DeGeneres and Rosie O’Donnell were performing as well. It was such a moving night
for me personally and I have since hosted it over thirty times to this day. I am also a proud
board member of the Scleroderma Research Foundation and these events called “Cool Comedy
Hot Cuisine” are the main fundraisers we have to raise money for research.

ix
x Foreword from Bob Saget

Just a couple years forward from that first night I did the benefit from that cold-call, my
sister Gay had to move back to LA from Bucks County, PA… To move back in with our par-
ents, as a forty-four-year-old woman, so they could help her try and get better medical care
than she’d been receiving. She had finally been diagnosed with this disease I had connected
with seemingly out of nowhere.
So just three years after I even found out what “scleroderma” was, my sister was sitting in
the audience at the benefit, now actually diagnosed as having this orphan disease. One year
later, she lost her life to it. I couldn’t believe that this happened. It snuck up on her and a year
later she was on a decline that ended just two years later. It’s how many of us get involved with
a cause that cuts us deep to the bone.
I wanted to do something about it. Share our family’s story with others and let them know
that they aren’t alone in this battle that—like any disease, makes you feel completely alone. So,
in 1996, I directed a television movie for ABC called, “For Hope,” a story “loosely based” on
events that “directly” affected my family. The writer was my friend Susan Rice, the producer,
the dear Karen Moore. And the cast was extraordinary: Dana Delany, Henry Czerny, Polly
Bergen, and Harold Gould basically playing my parents, and Chris Demetral representing my
nephew, Adam. And my dear friend, Sharon Monsky, playing “herself.” It was a very emo-
tional and fulfilling project, a poignant moment in my life, one that I will always treasure. And
through my work with helping to fund research for this disease—coming into contact with so
many people who have it –I believe that TV movie helped put scleroderma on the map for
some. Still, it’s such a long road for the hundreds of thousands of people who have scleroderma
in its many incarnations.
Once Sharon passed away thirteen years ago, I knew then I would be working the rest of my
life to do whatever I could to help those affected with scleroderma.
Thanks to research, new drugs, and new therapies have since been developed, helping thou-
sands of those struggling with this sometimes fatal disease that there still is no known cure for.
Pharmaceutical companies have developed several drugs to deal specifically with the symp-
toms of scleroderma, mainly the biggest killer of its patients, pulmonary arterial hypertension
(PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the
need for transplantation. So real progress has been made since I started trying to help decades
ago.
After the loss of my sister, I have had the good fortune of meeting hundreds, maybe a thou-
sand scleroderma patients—who I feel connected to on a deep level. As though it’s some sort
of horrific rite of passage to be in “this club.” I cannot bear to think of what people go through
when their loved ones are hit with this disease that still needs so much attention and funding.
We have all been touched beyond words by all of the comedians who have given their time
to perform to get money to support research.
So many dear friends who have been there for me and helped many with scleroderma
through the support given to research: Robin Williams, Whoopi Goldberg, Dana Carvey,
Jimmy Kimmel, Seth Meyers, John Oliver, Jeff Garlin, Jeff Ross, John Mayer, Jim Gaffigan,
Michael Che, Jimmy Fallon, Rodney Dangerfield, Sarah Silverman, Jerry Seinfeld, Conan
O’Brien, Craig Ferguson, Jon Stewart, Lily Tomlin, Pat Monahan and Train, The Goo Goo
Dolls, Adam Duritz and Counting Crows, and most recently, Andy Cohen, Michael Che and
Louie C.K.
No one should have to suffer as my sister Gay did, who lost her life at 47. My heart goes out
to the patients and families of those afflicted by this terrible disease—they always say “terrible
disease,” yet as we all know, there are no “good” ones.
I will spend the rest of my life dedicated to helping support the best medical minds in sci-
ence as we try to fund what will one day be a day that we all would love to see happen in our
lifetime: to find a cure.
Foreword from Bob Saget xi

I am deeply indebted to all of the doctors, both contributing writers as well as the brilliant
editors, all working so diligently in sharing their research and advanced knowledge of a dis-
ease that can take so many lives. And thanks to the hard work of these exceptional doctors who
have created this book, more lives can be saved, and more progress will be made.
I just want all other doctors around the world to read it, so they are up to date with where
we are now, not where we were ten years ago in treating a scleroderma patient. I do believe my
sister may have been alive today if the regime of medicine that was cast upon her had the
knowledge that is within these pages.
My good fortune is I get to be a small part of this big picture– this book. It is a monumental
and defining work and I am so proud to have been asked to write this foreword. And now,
enough from me, enjoy reading this, created by the people who are truly making a difference
that will change the lives of so many.
Bob Saget
Preface to the First Edition

Scleroderma remains the most enigmatic and challenging of all rheumatic diseases and the one
associated with the greatest burden of morbidity and mortality. Despite decades of intense
clinical and basic research, and dozens of clinical trials, the causes and pathophysiology of the
disease had remained, until recently, largely beyond our grasp, and effective disease modifying
therapies are still lacking. The reasons for slow progress in scleroderma are many. They include
the remarkable heterogeneity of the disease, its protean and multisystemic manifestations, its
low prevalence and orphan disease status, the lack of animal models, low level of public aware-
ness, and so on. Moreover, government investment in scleroderma research has, until recently,
lagged behind other comparable diseases; likewise, the pharmaceutical industry has histori-
cally viewed scleroderma as a limited market. In the absence of dramatic research advances
and faced with disappointing results from clinical trials, a nihilistic attitude toward sclero-
derma took hold in some circles. Upon receiving a diagnosis of scleroderma, patients were not
infrequently informed that “there is no treatment for scleroderma” and denied access to poten-
tially effective interventions or the opportunity to participate in clinical trials.
Fortunately, the scleroderma landscape is now changing rapidly. Indeed, readers of this
book will be convinced that the future for scleroderma research and for affected patients has
never been brighter. The book highlights the concurrent advances on many fronts that explain
this sea-change. Discoveries from the laboratory have led, during the past decade, to the iden-
tification and characterization of a plethora of new molecules, pathways, and cell types as criti-
cal players in the diverse manifestations of scleroderma. This line of research has been
energized by the recent application of “omics” such as genomics and proteomics that allow
large-scale, hypothesis-free examination of tens of thousands of molecular components, each
representing a potential target for therapy. Increasingly powerful genetic association studies
are shedding light on the genetic factors associated with scleroderma, including the identifica-
tion of specific genes and alleles, and in the near future, of epigenetic changes reflecting the
interplay of environment with the genome. Genetic engineering is making it possible to gener-
ate complex mouse strains to model particular scleroderma traits such as fibrosis, inflamma-
tion, autoimmunity, and vasculopathy. Meticulous evaluation of novel transgenic mice is likely
to yield fresh insights into pathogenesis, including the mechanistic bases of distinct disease
manifestations. Moreover, innovative animal models provide appealing experimental plat-
forms for preclinical testing of novel anti-inflammatory, vasoprotective, and antifibrotic drugs.
The vital bench-to-bedside research continuum is alive, and basic discoveries are translated
into clinical trials at an increasingly rapid pace.
Enormously powerful analytic platforms, such as microchip DNA arrays to examine genetic
polymorphisms or genome-wide changes at the tissue level, now allow investigators to probe
disease heterogeneity at the molecular level. These studies, as elegantly illustrated in this book,
reveal a surprising and unsuspected level of complexity and heterogeneity in scleroderma.
While new insights often challenge existing paradigms, they open the door for vital progress
in disease subclassification and phenotyping that in turn enhances our ability to target specific
interventions to predefined patient subsets. They also make it possible to identify and validate
novel biomarkers, and to develop novel treatment strategies, including drug repurposing.
Integration of laboratory-based reductionist research with hypothesis-free omics surveys on

xiii
xiv Preface to the First Edition

the one hand and patient phenotyping with meticulous clinical, laboratory, serologic, and path-
ological data collection on the other hand will be vital. Optimal research integration will
require real-time coordination among clinical centers and research laboratories and is vitally
dependent on shared access to robust registries, databanks, and linked biorepositories. We
must be realistic in appreciating the challenges, including the cost, of developing and main-
taining requisite infrastructures. These efforts can only succeed with long-term commitment.
Steady advances reflect the enthusiasm and dedication of the community of scleroderma
researchers, clinicians, advocates, and patients working in tandem with governmental agen-
cies, and, increasingly, the pharmaceutical and biotechnology sectors.
Although truly effective disease-modifying interventions are lacking and a single “magic
bullet” for scleroderma is unlikely, disease management is improving, as reflected in better
quality of life and survival for patients with scleroderma. The need for comprehensive care to
address the totality of the disease is increasingly appreciated. Optimal management should
include a holistic approach encompassing nutrition, psychological aspects, exercise, physical
and occupational therapy, and sleep optimization to reduce suffering and disability. This book
showcases these advances and highlights evidence-based contemporary clinical recommenda-
tions, practice guidelines, diagnostic and screening strategies, and innovative approaches to
patient care. Each of the chapters is informed by the need to integrate emerging understanding
of pathophysiology with the latest advances in clinical practice.
The contributors to this book represent an exceptionally broad spectrum of expertise and
come from many countries. Together, the 52 chapters reflect a contemporary global perspec-
tive and provide a comprehensive view of scleroderma: where we are and where we are headed.
We believe that, having perused this book, the reader will be as impressed as the editors are
that we are at the threshold of an era of unprecedented progress in scleroderma.
Finally, a word about the name for the disease that is the subject of this book. Originally
called scleroderma, the disease came to be called “progressive systemic sclerosis” and more
recently “systemic sclerosis” to illustrate the important role of fibrosis as a hallmark feature
and to emphasize the striking systemic nature of the disease. We however use the term “sclero-
derma” throughout. There are several reasons for this. In conversations with physicians, scien-
tists, and health-care providers around the world, “scleroderma” seems to resonate most of all
the alternate terms. Advocacy and patient support groups prefer this term, as do most patients
with the diagnosis. Finally, let’s face it, “systemic sclerosis” is a mouthful, whereas “sclero-
derma” is succinct and carries a certain austere elegance. So, while in full recognition that
scleroderma is a systemic disease and is not to be confused with localized scleroderma, we
have chosen to stick with this name.

Chicago, IL, USA John Varga, MD

London, UK Christopher P. Denton, PhD, FRCP
Baltimore, MD, USA Fredrick M. Wigley, MD
Preface to the Second Edition

We are witnessing significant advances in scleroderma. Perhaps the most challenging to

understand and manage of all rheumatic diseases, scleroderma is no longer viewed with
bewilderment and a sense of helplessness. Indeed, in the years since the first edition of
Scleroderma: From Pathogenesis to Comprehensive Management was published, much
that we understand about scleroderma has changed. Progress in the science and practice of
medicine is occurring rapidly, and new information about scleroderma is accruing at an
unprecedented pace. The number of investigators, investigative teams, and research con-
sortia focusing on scleroderma around the globe; the size of the study cohorts; the variety
of experimental disease models; and the power and depth of high throughput technologies
for data acquisition have all grown exponentially during this time. While this explosion of
new information is truly good news for people living with scleroderma as well as students
of the disease, it is posing formidable new challenges for anyone seeking to achieve
a deeper understanding. The second edition of Scleroderma: From Pathogenesis to
Comprehensive Management seeks to address these challenges. Our goal is to communi-
cate progress in the field in an up-to-date, authoritative, comprehensive, and accessible
manner.
Building on the approach established in the first edition, we present a systematic and
critical survey of current knowledge about the epidemiology, genetic basis, pathogenesis,
classification, clinical manifestations, evaluation, and management of all aspects of sclero-
derma. We seek to integrate, to the fullest degree possible, contemporary concepts of patho-
physiology and physiology with clinical aspects for each major feature of scleroderma. The
book is written with a broad and global readership in mind. We aim to provide a uniquely
valuable reference for anyone interested in scleroderma, be they clinicians, investigators,
students, or other health professionals. Each chapter is written by distinguished experts in
the field, typically representing more than one continent, in order to assure a truly balanced
and global perspective. Up-to-date analysis of genetic risk, a very rapidly evolving area, is
provided in the context of its impact on understanding pathophysiology, informing disease
classification, and identification of innovative therapeutic approaches. Additional chapters
discuss the significance and utility of novel and evolving biomarker discovery efforts and
how these efforts might yield biomarkers that will have real-life utility in the clinic. The
rationale for the use of novel treatments is presented, along with data regarding their effi-
cacy, safety, and appropriate role in patient management. Throughout, each chapter high-
lights growing awareness of disease heterogeneity and its impact on the practice of
individualized “precision” medicine in scleroderma. Finally, for this edition we introduce a
series of short clinically oriented chapters that highlight current approaches to common and
important disease manifestations. In this way, both clinicians and nonclinician readers can
gain a better understanding of the complex challenges of scleroderma and how these chal-
lenges are addressed by experts in the field. It is the editors’ hope that the second edition of
Scleroderma: From Pathogenesis to Comprehensive Management will inform and inspire
and catalyze new ideas, collaborations, and discoveries that bring us closer to the prevention
and cure of scleroderma.

xv
xvi Preface to the Second Edition

We wish to express our gratitude for the editorial assistance provided by Pam Hill
(Baltimore), Elise Paxson (Philadelphia), and Margaret Moore (New York). Without their ded-
ication, hard work, and unfailing patience, this book would not have come to fruition.

Chicago, IL, USA John Varga

Baltimore, MD, USA Fred Wigley
London, UK Christopher Denton
Tokyo, Japan Masa Kuwana
Paris, France Yannick Allanore
Abbreviations

6-MP 6-mercaptopurine
6MWT 6-minute walk test
α-SMA α-smooth muscle actin
ACA Anticentromere antibodies
ACR American College of Rheumatology
ACT Acceptance and commitment therapy
ACTD Autoimmune connective tissue diseases
ACVR1B Activin A receptor, type IB
ADAM Adamalysines
ADHD Attention deficit hyperactivity disorder
ADM Antroduodenal manometry
AE Adverse events
AECA Antiendothelial cell antibodies
AECG American-European Conesus Group
AFA Antifibrillarin antibodies
AGE Glycation/lipoperoxidation end product
AGTRL2 Angiotensin receptor-like 2
AHA Antihistone antibodies
AIF1 Allograft inflammatory factor 1
AIH Autoimmune hepatitis
AKI Acute kidney injury
ALK Anti-liver-kidney microsome
AMA Antimitochondrial antibody
ANA Antinuclear antibody
ANS Autonomic nervous system
anti-Scl70 antitopoisomerase 1 antibodies
APC Antigen-presenting cell or argon plasma coagulation
APRIL A proliferation-inducing ligand
APS Antiphospholipid antibody syndrome
ARB Angiotensin receptor blocker
ARHB Ras homolog gene family, member B
ASCT Autologous stem cell transplantation
aSSC Adult onset systemic sclerosis
AST Aspartate aminotransferase
ASTIS Autologous Stem Cell Transplantation International Scleroderma
ATG5 Autophagy-related 5
AUC Area under the curve
autoAb Autoantibodies
AV Atrioventricular
AVNRT Atrioventricular reentry tachycardia
BAFF B-cell activating factor
BAL Bronchoalveolar lavage

xvii
xviii Abbreviations

BALF Expanded oligoclonal T cell subsets in affected skin or lungs

BANK1 B cell-specific scaffold protein with ankyrin
BAS Balloon atrial septostomy
BCR B cell receptor
BLK B lymphocyte kinase
BMI Body mass index
BMPRII Bone morphogenic protein receptor II
BNP Brain natriuretic peptide
BP Blood pressure
BPPV Benign paroxysmal positional vertigo
BUILD The Bosentan Use in Interstitial Lung Disease (study)
CACS Coronary artery calcium score
CAV1 Caveolin 1
CBAA Calcium-binding amino acid
CBC Complete blood count
CBT Cognitive-behavioral therapy
CCP Cyclic citrullinated peptide
CCP/ACPA Anticyclic citrullinated peptides
CCR6 Chemokine receptor 6
CDSMP Chronic Disease Self-Management Program
CES-D Center for Epidemiologic Studies Depression Scale
cGMP Cyclic guanosine monophosphate
cGVHD Chronic graft-versus host disease
CHFS Cochin hand function scale
CI Confidence interval or cardiac index
CIDI Composite International Diagnostic Interview
CIHR Canadian Institutes of Health Research
CIP Chronic intestinal pseudo-obstruction
CM Circumscribed morphea
CMR Cardiac magnetic resonance
CMV Cytomegalovirus
CNS Central nervous system
CO Carbon monoxide
COL1A2 Alpha 2 chain of collagen I
COL8A1 Alpha 1 chain of collagen VIII
COMP Cartilage oligomeric protein 1
CPET Cardiopulmonary exercise test
CPK Creatine phosphokinase
CREST Calcinosis, Raynaud’s, esophagitis, sclerodactyly, and telangiectasia
CRISS Combined response index for systemic sclerosis
CRP C-reactive protein
CSK c-Src tyrosine kinase
CSR Cumulative survival rates
CSRG Canadian scleroderma research group
CT Computed tomography
CTA Clinical Trial Application
CTD Connective tissue disease
CTD-PAH Connective tissue disease–pulmonary arterial hypertension
CTEPH Chronic thromboembolic PH
CTGF Connective tissue growth factor
CTL Cytotoxic T lymphocyte
CTLA-4 Cytotoxic lymphocyte antigen 4
CVD Collagen vascular disease
Abbreviations xix

CVD-PAH Collagen vascular disease–associated pulmonary arterial

hypertension
CYC Cyclophosphamide
DAMP Damage-associated molecular patterns
DAS Disease activity score
DASH Disabilities of the arm, shoulder, and hand
DC Dendritic cells
DCA Dichloroacetate
dcSSc Diffuse cutaneous SSc
DECT Dual-energy computed tomography
DHFR Dihydrofolate reductase
DID Double immunodiffusion
DIP Distal interphalangeal
DLCO Diffusion capacity of the lung for carbon monoxide
DM Dermatomyositis or diabetes mellitus
DMARD Disease-modifying antirheumatic drug
DNASEIL3 Deoxyribonuclease I-like 3
DNMT DNA methyltransferase
DNSS Deutsches Netzwerk für Systemische Sklerodermie
dsDNA Double stranded DNA
DSG2 Desmoglein-2
DU Digital ulcer
DZ Dizygotic
EBV Epstein Barr virus
EC Endothelial cell
ECDS En coup de sabre
ECG Electrocardiogram
ECM Extracellular matrix
ECV Extracellular volume
ED Erectile dysfunction
EF Eosinophilic fasciitis
EGD Esophagogastroduodenoscopy
EGF Epidermal growth factor
EGG Electrogastrography
EIA Enzyme immunoassay
ELAR European League Against Rheumatism
ELISA Enzyme-linked immunosorbent assay
ELR Enzyme-linked receptor
EMG Electromyogram
EMS Eosinophilia-myalgia syndrome
ENA Extractable nuclear antigen
EndoMT Endothelial-mesenchymal transition
eNOS Endothelial nitric oxide synthase
eNPV Estimated net present value
ENT Ear, nose, and throat
EPC Endothelial progenitor cell
EPOSS Outcome measures in pulmonary arterial hypertension related to sys-
temic sclerosis
ERA Endothelin receptor antagonist
ERK Extracellular signal-regulated kinase
EScSG European Scleroderma Study Group
ESR Erythrocyte sedimentation rate
ESSGAI European Scleroderma Study Group Activity Index
xx Abbreviations

ESWL Extracorporeal shock wave lithotripsy

ET-1 Endothelin-1
ETA Endothelin receptor type A
ETB Endothelin receptor type B
EULAR European League Against Rheumatism
EUSTAR EULAR Scleroderma Trials and Research
FBN1 Fibrillin 1
FC Functional capacity
FDAAA Food and Drug Administration Amendments Act of 2007
FDG PET Fluorodeoxyglucose positron emission tomography
FEV1 Forced expiratory volume in 1 s
FGF Fibroblast growth factor
FHL2 Four and a half LIM domains 2
FIH First in human
Fli1 Friend leukemia integration 1
FN Flattening ratio
FNEDA Fibronectin extracellular domain A
FRQS Fonds de recherche du Québec
FVC Forced vital capacity
GAVE Gastric antral vascular ectasia
GBCS Gadolinium-based contrast agents
GCGA Gamma-carboxyglutamic acid
GCP Good clinical practice
GENISOS Genetics versus Environment in Scleroderma Outcome study
GERD Gastroesophageal reflux
GI Gastrointestinal
GIT Gastrointestinal tract
GLS Global longitudinal strain
GLUT Glucose transporter molecule
GM Generalized morphea
GMA Gastric myoelectrical activity
GR Glucocorticoid receptor
GrB Granzyme B
GRB10 Growth factor receptor-bound protein 10
GVHD Graft-versus-host disease
GWAS Genome-wide association studies
H2O2 Hydrogen peroxide
HA Hyaluronan
HADa Hospital anxiety depression (anxiety)
HADd Hospital anxiety depression (depression)
HAMIS Hand mobility in scleroderma
HAQ-DI Health assessment questionnaire disability index
HAX-1 HS1-associated protein-1
HDAC Histone deacetylase
HFI Hand functional index
HFpEF Heart failure with preserved ejection fraction
HIF-1α Hypoxia inducible factor
HLA Histocompatibility locus antigen or human leukocyte antigen
hPAH Heritable pulmonary arterial hypertension
HPN Home parenteral nutrition
HRCT High-resolution computed tomography
HRM High-resolution esophageal manometry
HRQOL or HRQL Health-related quality of life
Abbreviations xxi

HSC Hematopoietic stem cell

hUBF Human upstream binding factor
ICAM Intercellular adhesion molecule
ICC Intraclass correlation coefficient
ICD-9 International Classification of Diseases Version 9
icIL-1RA IL-1 receptor antagonist
IDDM Insulin-dependent diabetes mellitus
IDL Ischemic digital loss
IFN Interferon
IFN-γ Interferon-γ
IgG Immunoglobulin G
IIF Indirect immunofluorescence
IIP Idiopathic interstitial pneumonia
IL Interleukin
ILC Innate lymphoid cell
ILD Interstitial lung disease
IMP Integrated multispecies prediction
IMPRESS International Multicentric Study on PRegnancy in Systemic Sclerosis
IND Investigational new drug
iNOS Inducible nitric oxide synthase
IP Immunoprecipitation
IPAH Idiopathic pulmonary arterial hypertension
IPF Idiopathic pulmonary fibrosis
iPH Idiopathic-associated pulmonary arterial hypertension
IPSP Inhibitory postsynaptic potential
IRAK Interleukin 1 receptor associated kinase-1
IRB Institutional Review Board
IRF Interferon regulatory factor or interferon-releasing factor
IRF-7 Interferon regulatory factor 7
iTreg inducible Treg
IV Intravenous or intraventricular
IVIG Intravenous immunoglobulin
jSSc Juvenile systemic sclerosis
Kco Diffusion coefficient
KCS Keratoconjunctivitis sicca
KFT Keitel functional test
KL6 Krebs von den Lungen-6
KLF5 Krüppel-like factor 5
LBT Lactulose hydrogen breath test
Lc Limited cutaneous
lcSSc Limited cutaneous SSc
LD Linkage disequilibrium
LES Lower esophageal sphincter
LKM-1 Liver-kidney-microsomal
LOH Loss of heterozygosity
LOX Lysyl oxidase
LPS Lipopolysaccharide
LV Left ventricular
LVEDP Left ventricular end diastolic pressure
LVEF Left ventricular ejection fraction
M3R Muscarinic-3 receptor
MAC Morphea in adults and children (cohort)
MACTAR McMaster Toronto Arthritis patient preference questionnaire
xxii Abbreviations

MCP Metacarpophalangeal
MCTD Mixed connective tissue disease
MDC Macrophage-derived chemokine
mDC Myeloid DC
MDCT Multidetector computed tomography
MDD Major depressive disorder
MDRD Modification of diet in renal disease
MECP2 Methyl-CpG-binding protein 2
MEF2 Myocyte enhancing factor 2
MHC Major histocompatibility complex
MHISS Mouth handicap in systemic sclerosis scale
MINI Mini-international neuropsychiatric interview
MIP Macrophage inflammatory protein
mLoSSI Modified localized scleroderma skin severity index
MMC Myoelectric complexes
MMF Mycophenolate mofetil
MMP-1 Matrix metalloproteinase-1
MOA Mechanism of action
mPAP Mean pulmonary artery pressure
MPP Methylprednisolone
MRA Magnetic resonance angiography
MREc Magnetic resonance enteroclysis
MREg Magnetic resonance enterography
MRI Magnetic resonance imaging
MRSA Methionine sulfoxide reductase A
MRSB Methionine sulfoxide reductase B
mRss Modified Rodnan skin score
MSC Mesenchymal stem cell
MTX Methotrexate
MUST Malnutrition universal screening tool
MVEC Microvascular endothelial cell
MZ Monozygotic
NASH Nonalcoholic steatohepatitis
NBUVB Narrowband UVB treatment
NCI National Cancer Institute
NCS Nerve conduction studies
Nd:YAG Neodymium-yttrium aluminum garnet
NDA New drug application
NFD Nephrogenic fibrosing dermopathy
NFS Nephrogenic systemic fibrosis
NIH National Institutes of Health
NIH PROMIS National Institute of Health Patient-Reported Outcomes Measurement
System
NK Natural killer
NLR NOD-like receptors
NME New medical entity
NOS Nitric oxide synthase
NPWT Negative pressure wound therapy
NRH Nodular regenerative hyperplasia
NSAID Nonsteroidal anti-inflammatory drug
NSF Nephrogenic systemic fibrosis
NSIP Nonspecific interstitial pneumonia
NTproBNP N-terminal brain natriuretic peptide
Abbreviations xxiii

nTreg Natural Tregs

NYHA New York Heart Association
O2− Superoxide anion
OMERACT Outcome measure in rheumatologic clinical trials
OR Odds ratio
P1GF Placenta growth factor
P1NP Amino-terminal procollagen I
PA Plasminogen activator
PACK PBC, ACA, CREST, Keratoconjunctivitis sicca
PAH Pulmonary arterial hypertension
PAMPs Pathogen-associated molecular pattern molecules
PAP Pulmonary arterial pressure
PARC Pulmonary and activation-regulated chemokine
PBC Primary biliary cirrhosis
PBMC Peripheral blood mononuclear cells
PCP Primary care provider
PCWP Pulmonary capillary wedge pressure
PD Pharmacodynamics
pDC Plasmacytoid dendritic cell
PDGFR Platelet-derived growth factor receptor
PDH Pyruvate dehydrogenase
PE Pulmonary embolism
PF Pulmonary fibrosis
PFT Pulmonary function test
PH Pulmonary hypertension
PHA Progressive hemifacial atrophy
PHAROS Pulmonary Hypertension Assessment and Recognition of Outcomes
in Scleroderma
PHC Proangiogenic hematopoietic cell
PHQ-9 9-item Patient Health Questionnaire
PICP Carboxy terminal telopeptide of type I collagen
PIIINP Amino-terminal III procollagen
PIP Proximal interphalangeal
PK Pharmacokinetics
PM Polymyositis
PN Parenteral nutrition
PoC Proof of Concept
POEMS Polyneuropathy, organomegaly, endocrinopathy, monoclonal gam-
mopathy, and skin changes
PoPH Portopulmonary hypertension
PPI Proton pump inhibitors
PreS or PRES Pediatric Rheumatology European Society
PRS Parry-Romberg syndrome
PSC Primary sclerosing cholangitis
PTPN22 Protein tyrosine phosphatase, nonreceptor type 22 (lymphoid)
PTX3 Pentraxin 3
PUVA Psoralen with UVA
PVOD Pulmonary veno-occlusive disease
PVR Pulmonary vascular resistance
QST Quantitative sensory testing
RA Rheumatoid arthritis or right atrium
RAGE Glycation/lipoperoxidation end product receptor
RANTES Regulated upon activation, normal T-cell expressed and secreted
xxiv Abbreviations

RAS Renin-angiotensin system

RCT Randomized controlled trial
REMS Risk evaluation and mitigation strategies
RF Rheumatoid factor
RFA Radiofrequency ablation
RHC Right heart catheterization
RLR RIG-I-like receptors
RNApol3 RNA polymerase III
RNP Ribonucleoprotein
rNPV Risk-adjusted net present value
RONS Reactive oxygen and nitrogen species
ROS Reactive oxygen species
RP Raynaud’s phenomenon
RT Rituximab
RV Right ventricular or residual volume
RVDEV Right ventricular end-diastolic volume
RVEF Right ventricular ejection fraction
SAE Serious adverse events
SaO2 Arterial oxygen saturation
Schisto-PAH Schistosomiasis-induced pulmonary arterial hypertension
SCID Severe combined immunodeficiency
SD Standard deviation
SDF Stromal cell-derived factor
SE Standard error
SERAPHIN Study with an Endothelin Receptor Antagonist in Pulmonary Arterial
Hypertension to Improve Clinical Outcome
SERT Serotonin transporter
SF-36 Short form-36
SF-6D Short form-6D
sFlt-1 Soluble fms-like tyrosine kinase-1
SGRQ Saint George’s Respiratory Questionnaire
sHAQ Scleroderma Health Assessment Questionnaire
SIBO Small intestine bacterial overgrowth
SIR Standardized incidence ratio
SLE Systemic lupus erythematosus
SLS Scleroderma Lung Study
SLS-II Second Scleroderma Lung Study
SMA Smooth muscle antigen
SNHL Sensorineural hearing loss
SNP Single nucleotide polymorphism
SOD2 Superoxide dismutase 2
SOX5 SRY (sex determining region Y)-box 5
sPAP Systemic pulmonary arterial pressure
sPAP Systolic pulmonary artery pressure
SPARC Secreted protein acidic and rich in cysteine
SP-B Surfactant protein B
SPECT Single-photon emission computed tomography
SPIN Scleroderma Patient-centered Intervention Network
SRC Scleroderma renal crisis
SS Sjögren’s syndrome
SSc Systemic sclerosis
SSc-ILD Systemic sclerosis–associated interstitial lung disease
SSc-PAH Systemic sclerosis–associated pulmonary arterial hypertension
SSRI Selective serotonin reuptake inhibitor
Abbreviations xxv

SSS Stiff skin syndrome

STAT3 Transducer and activator of transcription-3
STAT4 Transcription factor signal transducer and activator of transcription 4
STPR Skin thickness progression rate
SWAP Satisfaction with Appearance Scale
99m
Tc-DTPA Technetium-labelled diethylene triamine pentacetate
TAPSE Tricuspid annular plane systolic excursion
TARC Thymus and activation regulated chemokine
TCR T-cell receptor
TdT Transmission disequilibrium test
TFR Tendon friction rubs
TGF-beta Transforming growth factor beta
THY1 Thy-1 cell surface antigen
TIMP Tissue inhibitor of matrix metalloproteinases
TIN Tubule-interstitial nephritis
TK Tyrosine kinase
TLC Total lung capacity
TLR Toll-like receptor
TNFAIP3 Tumor necrosis factor, alpha-induced protein 3
TNFSF4 Tumor necrosis factor ligand superfamily, member 4
TNIP1 TNFAIP3 interacting protein 1
TOS Toxic oil syndrome
TPMT Thiopurine methyltransferase
TPN Total parenteral nutrition
TPO Thyroid peroxidase
TPP Target product profile
Treg T regulatory cell
TRIM-21 Tripartite motif family of protein 21
TRJ Tricuspid regurgitant jet
TSH Thyroid-stimulating hormone
Tsk-1 Tight skin-1
TSLP Thymic stromal lymphopoietin
TSP-1 Thrombospondin-1
TSS Total skin score
UCD University of California at Davis
UCLA SCTC GIT 2.0 University of California-Scleroderma Clinical Trial Consortium
Gastrointestinal Instrument
UDCA Ursodeoxycholic acid
UIP Usual interstitial pneumonia
UKFS UK Functional Score
uPA Urokinase plasminogen activator
uPAR Urokinase plasminogen activator receptor
US Ultrasonography
VA Volume of ventilated lung
VAS Visual analogue scale
VCAM Vascular cell adhesion molecule
VEDOSS Very early diagnosis of SSc
VEGF Vascular endothelial cell growth factor
VQ Ventilation-perfusion
VSM Vascular smooth muscle
vWF Von Willebrand factor
WHO World Health Organization
WML White matter lesions
Contents

Part I Introduction

1 Historical Perspective of Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Christopher P. Denton and Marco Matucci-Cerinic

Part II Epidemiology, Genetics and Classification

2 Epidemiology, Environmental, and Infectious Risk Factors . . . . . . . . . . . . . . . . 11

Jammie K. Barnes, Luc Mouthon, and Maureen D. Mayes
3 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Shervin Assassi and Yannick Allanore
4 Disease Subsets in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Robyn T. Domsic and Thomas A. Medsger Jr.
5 Evolving Concepts of Diagnosis and Classification . . . . . . . . . . . . . . . . . . . . . . . . 49
Sindhu R. Johnson, Lorinda Chung, Jaap Fransen,
and Frank H.J. Van den Hoogen
6 Overlap Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Pia Moinzadeh and Christopher P. Denton
7 Juvenile Localized and Systemic Scleroderma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Lauren V. Graham, Amy S. Paller, and Ivan Foeldvari
8 Morphea (Localized Scleroderma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Noelle M. Teske and Heidi T. Jacobe
9 Scleroderma Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Laura K. Hummers and Alan Tyndall
10 Systems Biology Approaches to Understanding the
Pathogenesis of Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
J. Matthew Mahoney, Jaclyn N. Taroni, and Michael L. Whitfield

Part III The Biological Basis of Systemic Sclerosis

11 Introduction: The Etiopathogenesis of Systemic Sclerosis –

An Integrated Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Carol Feghali-Bostwick and John Varga
12 Pathology of Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Lisa M. Rooper and Frederic B. Askin
13 Inflammation and Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Francesco Boin and Carlo Chizzolini

xxvii
xxviii Contents

14 Autoantibodies as Markers and Possible Mediators

of Scleroderma Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Kimberly Doering Maurer and Antony Rosen
15 The Clinical Aspects of Autoantibodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Masataka Kuwana and Thomas A. Medsger Jr.
16 Mechanisms of Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Mirko Manetti and Bashar Kahaleh
17 Biomarkers in Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Robert Lafyatis and Sergio A. Jimenez
18 Pathophysiology of Fibrosis in Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 261
Maria Trojanowska and John Varga
19 Overview of Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Yoshihide Asano and Jörg H.W. Distler

Part IV Cardiovascular Manifestations and Management

20 Raynaud’s Phenomenon, Digital Ulcers and Nailfold Capillaroscopy. . . . . . . . . 297

Ariane L. Herrick, Fredrick M. Wigley, and Marco Matucci-Cerinic
21 Renal Crisis and Other Renal Manifestations of Scleroderma. . . . . . . . . . . . . . . 317
Christopher P. Denton and Marie Hudson
22 Cardiac Involvement: Evaluation and Management. . . . . . . . . . . . . . . . . . . . . . . 331
Sanjiv J. Shah, Ahmad Mahmood, and J. Gerry Coghlan

Part V Pulmonary Manifestations and Management

23 Overview of Lung Involvement: Diagnosis, Differential Diagnosis

and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Christopher P. Denton
24 Clinical Assessment of Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Gregory J. Keir, Richard M. Silver, and Athol U. Wells
25 Treatment of Interstitial Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Kevin K. Brown and Vincent Cottin
26 Pathogenesis of Pulmonary Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . 385
Rubin M. Tuder, Markella Ponticos, and Alan Holmes
27 Clinical Assessment of Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . 403
Harrison W. Farber and Marc Humbert
28 The Management of Pulmonary Arterial Hypertension in the Setting
of Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Stephen C. Mathai and N. Nazzareno Galié

Part VI Gastrointestinal Manifestations and Management

29 Overview of Gastrointestinal Tract Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Christopher P. Denton
30 Upper Gastrointestinal Tract: Manifestations of Systemic Sclerosis . . . . . . . . . . 427
John O. Clarke and John E. Pandolfino
31 Small and Large Intestinal Involvement and Nutritional Issues . . . . . . . . . . . . . 443
Elizabeth Harrison, Charles Murray, and Simon Lal
Contents xxix

Part VII Skin, Musculoskeletal and Other Complications

32 Calcinosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Antonia Valenzuela and Lorinda Chung
33 Evaluation and Management of Skin Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Noëlle S. Sherber and Fredrick M. Wigley
34 Assessment and Management of Progressive Skin Involvement
in Diffuse Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Robert W. Simms
35 Skeletal Muscle Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Andrew L. Mammen
36 Tendons, Joints, and Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Jérôme Avouac, Maya H. Buch, and Yannick Allanore
37 Cancer in Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Ami A. Shah and Masataka Kuwana
38 Overlooked Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Edward V. Lally, Ami A. Shah, and Fredrick M. Wigley
39 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Eliza F. Chakravarty and Virginia Steen

Part VIII Management and Outcome Assessment

40 Introduction to Section VIII: Management and Outcome Assessment . . . . . . . . 565

John Varga, Fredrick M. Wigley, and Christopher P. Denton
41 Immunomodulatory, Immunoablative, and Biologic Therapies. . . . . . . . . . . . . . 567
Jacob M. van Laar and Robert W. Simms
42 Investigative Approaches to Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Voon H. Ong and Christopher P. Denton
43 Drug Development and Regulatory Considerations for SSc Therapies. . . . . . . . 595
Timothy M. Wright
44 Physical and Occupational Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Luc Mouthon and Janet L. Poole
45 Psychosocial Issues and Care for Patients with Systemic Sclerosis . . . . . . . . . . . 615
Lisa R. Jewett, Linda Kwakkenbos, Vanessa C. Delisle, Brooke Levis,
and Brett D. Thombs
46 Clinical Trial Design in Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
Yossra A. Suliman, Harsh Agrawal, and Daniel E. Furst
47 Measuring Disease Activity and Outcomes in Clinical Trials . . . . . . . . . . . . . . . . 637
Dinesh Khanna and Sindhu R. Johnson
48 Innovative Approaches to Clinical Trials in Systemic Sclerosis . . . . . . . . . . . . . . 649
Rucsandra Dobrota, Ulf Müller-Ladner, and Oliver Distler
49 Molecular Stratification by Gene Expression as a Paradigm
for Precision Medicine in Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Monique Hinchcliff and Michael L. Whitfield
xxx Contents

Part IX Case Studies: Approach to Complex Clinical Problems

50 Managing the Ischemic Finger in Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . 673

Fredrick M. Wigley
51 Scleroderma Renal Crisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
Edward P. Stern and Christopher P. Denton
52 Rapid Diffuse Skin Disease with Progressive Joint Contractures . . . . . . . . . . . . 683
Faye N. Hant and Richard M. Silver
53 Management of the Scleroderma Patient with Pulmonary
Arterial Hypertension Failing Initial Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Christopher J. Mullin and Stephen C. Mathai
54 Pseudo-obstruction with Malabsorption and Malnutrition . . . . . . . . . . . . . . . . . 701
John O. Clarke
55 Progressive Interstitial Lung Disease Nonresponse
to Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Katherine C. Silver, Kristin B. Highland, and Richard M. Silver
56 Coping with the Disfigurement of Scleroderma: Facial, Skin,
and Hand Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
Shadi Gholizadeh, Rina S. Fox, Sarah D. Mills,
Lisa R. Jewett, Brett D. Thombs, and Vanessa L. Malcarne
57 Managing Complicated Digital Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Robert J. Spence
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Contributors

Harsh Agrawal, MD, FACP Department of Internal Medicine, Division of Cardiology,

Paul. L. Foster School of Medicine Texas Tech University, El Paso, Texas, USA
Yannick Allanore, MD Service de Rhumatologie A, Université Paris Descartes, Hôpital
Cochin, Paris, France
Yoshihide Asano, MD, PhD Department of Dermatology, University of Tokyo Graduate
School of Medicine, Tokyo, Japan
Frederic B. Askin, MD Department of Pathology, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Shervin Assassi, MD, MS Division of Rheumatology, University of Texas Health Science
Center at Houston, Houston, TX, USA
Jérôme Avouac, MD Rheumatology A Department, Cochin Hospital, Paris Descartes
University, Sorbonne Paris Cité, Paris, France
Jammie K. Barnes, MD Department of Internal Medicine – Rheumatology, University
of Texas at Houston, Houston, TX, USA
Dame Carol Black Division of Medicine, UCL, London, UK
Francesco Boin, MD Division of Rheumatology, Department of Medicine, University
of California San Francisco, San Francisco, CA, USA
Kevin K. Brown, MD Department of Medicine, National Jewish Health, Denver, CO, USA
Maya H. Buch, MBChB, FRCP, PhD Leeds Institute of Rheumatic & Musculoskeletal
Medicine, Chapel Allerton Hospital, Leeds, UK
Eliza F. Chakravarty, MD, MS Department of Arthritis and Clinical Immunology,
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Carlo Chizzolini, MD Immunology and Allergy, Department of Medical Specialties,
Geneva University Hospital and School of Medicine, Geneva, Switzerland
Lorinda Chung, MD, MS Department of Medicine and Dermatology (Immunology
and Rheumatology Division), Stanford University School of Medicine, Stanford, USA
Palo Alto VA Hospital, Palo Alto, CA, USA
John O. Clarke, MD Division of Gastroenterology & Hepatology, Johns Hopkins
University, Baltimore, MD, USA
J. Gerry Coghlan, MD Department of Pulmonary Hypertension, Royal Free Hospital,
London, UK
Vincent Cottin, MD, PhD Department of Pulmonology, Reference Center for Rare
Pulmonary Diseases, Louis Pradel Hospital, Lyon, France

xxxi
xxxii Contributors

Vanessa C. Delisle, MSc Lady Davis Institute for Medical Research, McGill University
and Jewish General Hospital, Montreal, QC, Canada
Christopher P. Denton, PhD, FRCP Division of Medicine, Department of Inflammation,
Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, Royal
Free Hospital, London, UK
Jörg H.W. Distler, MD Department of Internal Medicine, University of Erlangen-
Nuremberg, Erlangen-Nuremberg, Germany
Oliver Distler, MD Division of Rheumatology, University Hospital Zurich, Zurich,
Switzerland
Rucsandra Dobrota, MD Division of Rheumatology, University Hospital Zurich, Zurich,
Switzerland
Department of Internal Medicine and Rheumatology, Carol Davila University of Medicine
and Pharmacy, Cantacuzino Hospital, Bucharest, Romania
Robyn T. Domsic, MD, MPH Department of Medicine/Rheumatology and Clinical
Immunology, University of Pittsburgh, Pittsburgh, PA, USA
Harrison W. Farber, MD Pulmonary Hypertension Center, Boston University Medical
Center, Boston, MA, USA
Carol Feghali-Bostwick, PhD Department of Medicine, Medical University of South
Carolina, Charleston, SC, USA
Ivan Foeldvari, MD Hamburg Centre for Pediatric Rheumatology, Head of the Juvenile
Scleroderma Working Group (JSScWG), Hamburger Zentrum Für Kinder- und
Jugendrheumatologie, Hamburg, Germany
Rina S. Fox, MS, MPH SDSU/UC San Diego Joint Doctoral Program in Clinical
Psychology, San Diego, CA, USA
Jaap Fransen, PhD Departments of Rheumatology, Radboud University Nijmegen Medical
Center and Sint Maartenskliniek, Nijmegen, The Netherlands
Daniel E. Furst, MD Department of Rheumatology, University of California, Los Angeles,
Los Angeles, CA, USA
N. Nazzareno Galié, MD Department of Experimental, Diagnostic and Specialty
Medicine-DIMES, University of Bologna, Bologna, Italy
Shadi Gholizadeh, MS, MSc SDSU/UC San Diego Joint Doctoral Program in Clinical
Psychology, San Diego, CA, USA
Lauren V. Graham, MD, PhD Department of Dermatology, Northwestern University,
McGraw Medical Center, Chicago, IL, USA
Faye N. Hant, DO, MSCR Division of Rheumatology and Immunology, Medical
University of South Carolina, Charleston, SC, USA
Elizabeth Harrison, MB, ChB Institute of Inflammation and Repair, University
of Manchester, Manchester, UK
Ariane L. Herrick, MD, FRCP Centre for Musculoskeletal Research,
Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre,
The University of Manchester, Manchester, UK
Kristin B. Highland, MD, MSCR Department of Pulmonary and Critical Care Medicine,
Cleveland Clinic Foundation, Cleveland, OH, USA
Contributors xxxiii

Monique Hinchcliff, MD, MS Department of Medicine, Northwestern University, Feinberg

School of Medicine, Chicago, IL, USA
Alan Holmes, PhD Drug Discovery Group, Translational Research Office, School
of Pharmacy, University College London, London, UK
Marie Hudson, MD, MPH Division of Rheumatology and Lady Davis Institute for Medical
Research, Jewish General Hospital, Montréal, QC, Canada
Faculty of Medicine, McGill University, Montréal, QC, Canada
Marc Humbert, MD, PhD Department of Respiratory Medicine, Hôpital Bicêtre, Paris, France
Laura K. Hummers, MD, ScM Department of Medicine and Rheumatology, Johns
Hopkins University, Baltimore, MD, USA
Heidi T. Jacobe, MD, MSCS Department of Dermatology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Lisa R. Jewett, MSc Lady Davis Institute for Medical Research, McGill University
and Jewish General Hospital, Montreal, QC, Canada
Sergio A. Jimenez, MD Department of Dermatology and Cutaneous Biology, Jefferson
Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
Sindhu R. Johnson, MD, PhD, FRCPC Toronto Scleroderma Program, Mount Sinai
Hospital, Toronto Western Hospital, Toronto, ON, Canada
Bashar Kahaleh, MD Division of Rheumatology and Immunology, University of Toledo
Medical Center, Toledo, OH, USA
Gregory J. Keir, MBBS, FRACP Department of Respiratory Medicine, Princess Alexandra
Hospital, Brisbane, QLD, Australia
Dinesh Khanna, MD, MSc Division of Rheumatology, Department of Internal Medicine,
University of Michigan, Ann Arbor, MI, USA
Masataka Kuwana, MD, PhD Department of Allergy and Rheumatology, Nippon Medical
School Graduate School of Medicine, Tokyo, Japan
Linda Kwakkenbos, PhD Lady Davis Institute for Medical Research, McGill University
and Jewish General Hospital, Montreal, QC, Canada
Robert Lafyatis, MD University of Pittsburgh School of Medicine, Pittsburgh, USA
Simon Lal, PhD, FRCP Intestinal Failure Unit, Salford Royal NHS Foundation Trust,
Salford, UK
Edward V. Lally, MD Division of Rheumatology, Rhode Island Hospital, Providence, RI, USA
Brooke Levis, MSc Lady Davis Institute for Medical Research, McGill University
and Jewish General Hospital, Montreal, QC, Canada
Ahmad Mahmood, MD Department of Pulmonary Hypertension, Royal Free Hospital,
London, UK
J. Mathew Mahoney, PhD Department of Neurological Sciences, University of Vermont,
Burlington, VT, USA
Vanessa L. Malcarne, PhD SDSU/UC San Diego Joint Doctoral Program in Clinical
Psychology, San Diego, CA, USA
Andrew L. Mammen, MD, PhD National Institutes of Health, National Institutes
of Arthritis and Skin and Musculoskeletal Diseases, Bethesda, MD, USA
Another random document with
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to act for him. Throughout, Osterman saw to it that he personally did
not appear.
Of course Greasadick, when he discovered what the plot was,
roared and charged like a bull. Indeed before he was eventually
defeated he became very threatening and dangerous, attempting
once even to kill Drewberry. Yet he was finally vanquished and his
holdings swept away. With no money to make a new start and
seeing others prosper where he had failed for want of a little capital,
he fell into a heavy gloom and finally died there in Larston in the bar
that had been erected after the K. B. & B. spur had been completed.
Through all of this Mr. Osterman appears to have been utterly
indifferent to the fate of the man he was undermining. He cared so
little what became of him afterwards that he actually admitted, or
remarked to Whitley, who remained one of his slaves to the end, that
one could scarcely hope to build a large fortune without indulging in
a few such tricks.
3. Lastly, there was the matter of the C. C. and Q. L. Railroad, the
major portion of the stock of which he and Frank O. Parm, of the
Parm-Baggott chain of stores, had managed to get hold of by the
simple process of buying a few shares and then bringing
stockholders’ suits under one and another name in order to
embarrass President Doremus and his directors, and frighten
investors so they would let go of the stock. And this stock, of course,
was picked up by Osterman and Parm, until at last these two
became the real power behind the road and caused it to be thrown
into the hands of a receiver and then sold to themselves. That was
two years before ever Michael Doremus, the first president of the
road, resigned. When he did he issued a statement saying that he
was being hounded by malign financial influences and that the road
was as sound as ever it had been, which was true. Only it could not
fight all of these suits and the persistent rumors of mismanagement
that were afoot. As a matter of fact, Mr. Doremus died only a year
after resigning, declaring at that time that a just God ruled and that
time would justify himself. But Mr. Osterman and Mr. Parm secured
the road, and finally incorporated it with the P. B. & C. as is well
known.
 III

Some data taken from the biographic study of the late J. H.

Osterman, multimillionaire and oil king, prepared for Lingley’s
Magazine and by it published in its issue for October, 1917.
In order to understand the late J. H. Osterman and his great
success and his peculiar faults one would first have to have known
and appreciated the hard and colorless life that had surrounded him
as a boy. His father, in so far as I have been able to ascertain, was a
crude, hard, narrow man who had been made harder and, if
anything, cruder by the many things which he had been compelled to
endure. He was not a kind or soft-spoken man to his children. He
died when John Osterman, the central figure of this picture, was
eleven. Osterman’s mother, so it is said, was a thin and narrow and
conventional woman, as much harried and put upon by her husband
as ever he was by life. Also there was one sister, unattractive and
rough-featured, an honest and narrow girl who, like her mother,
worked hard up to nineteen, when her mother died. After that, both
parents being dead, she and her brother attempted to manage the
farm, and did so fairly successfully for two years when the sister
decided to marry; and Osterman consenting, she took over the farm.
This falling in with his mood and plans, he ceased farming for good
and betook himself to the Texas oil fields, where he appears to have
mastered some of the details of oil prospecting and refining.
But before that, what miseries had he not endured! He was wont
to recount how, when grasshoppers and drought took all of their
crops for two years after his father’s death, he and his mother and
sister were reduced to want and he had actually been sent to beg a
little cornmeal and salt from the local store on the promise to pay,
possibly a year later. Taxes mounted up. There was no money to buy
seed or to plant or replace stock, which had had to be sold. The
family was without shoes or clothes. Osterman himself appeared to
be of the fixed opinion that the citizens and dealers of Reamer, from
near which point in Kansas he hailed, were a hard and grasping
crew. He was fond of telling how swift they were to point out that
there was no help for either himself or his mother or sister as farmers
and to deny them aid and encouragement on that score. He once
said that all he ever heard in the local branch of his mother’s church,
of which he was never a confessing communicant, was “an eye for
an eye, a tooth for a tooth”; also “with whatsoever measure ye mete
it shall be measured to you again.” Obviously such maxims taken
very much to heart by a boy of his acquisitive and determined nature
might bring about some of the shrewd financial tricks later accredited
to him. Yet he appears to have been a man of some consideration
and sympathy where boys were concerned, for it was said that he
made it a rule in all his adventures to select the poorest if most
determined youths of his organization for promotion and to have
developed all of his chief lieutenants from the ranks of farm or
orphan boy beginners whom he encouraged to work for him. How
true this is the writer is not able to state. However, of the forty or
more eminent men who have been connected with him in his
enterprises, all but four were farm or orphan boys who had entered
his enterprises as clerks or menials at the very bottom, and some
seven of the total were from his native State, Kansas.

IV

The private cogitations of the late John H. Osterman in his

mansion at 1046 Fifth Avenue, New York, and elsewhere during the
last five years of his life.

Oh, but those days when he had been working and scheming to
get up in the world and was thinking that money was the great thing
—the only thing! Those impossible wooden towns in the Northwest
and elsewhere in which he had lived and worked, and those worse
hotels and boarding-houses—always hunting, hunting for money or
the key to it. The greasy, stinking craft in which he had made his way
up weedy and muddy rivers in Honduras and elsewhere—looking for
what? Snakes, mosquitoes, alligators, tarantulas, horned toads and
lizards. In Honduras he had slept under chiqua trees on mats of
chiqua leaves, with only a fire to keep away snakes and other things.
And of a morning he had chased away noisy monkeys and
parroquets from nearby branches with rotten fruit so as to sleep a
little longer. Alone, he had tramped through fever swamps, pursued
by Pequi Indians, who wanted only the contents of his wretched
pack. And he had stared at huge coyal palms, a hundred feet high,
with the great feathery leaves fifteen feet long and their golden
flowers three feet high. Ah, well, that was over now. He had shot the
quetzal with its yellow tail feathers three feet long and had traded
them for food. Once he had all but died of fever in a halfbreed’s hut
back of Cayo. And the halfbreed had then stolen his gun and razor
and other goods and left him to make his way onward as best he
might. That was life for you, just like that. People were like that.
And it was during that time that he had come to realize that by no
honest way at his age was he likely to come to anything financially.
Roaming about the drowsy, sun-baked realm, he had encountered
Messner, an American and a fugitive, he guessed, and it was
Messner who had outlined to him the very scheme by which he had
been able, later, to amass his first quick fortune in New York. It was
Messner who had told him of Torbey and how he had come up to
London from Central Africa to offer shares in a bogus rubber
enterprise based on immense forests which he was supposed to
have found in the wilds of Africa yet which did not exist. And it was
the immense though inaccessible rubber forests in Honduras that
had inspired him to try the same thing in New York. Why not? A new
sucker was born every minute, and he had all to gain and nothing to
lose. Messner said that Torbey had advertised for a widow with some
money to push his enterprise, whereupon he had proceeded to tell
the London speculative public of his treasure and to sell two pound
shares for as low as ten shillings in order to show tremendous rises
in value—to issue two million pounds’ worth of absolutely worthless
stock.
By these methods and by having the stock listed on the London
curb he was able to induce certain curb or “dog” brokers to go short
of this stock without having any of it in their possession. Finally they
began to sell so freely and to pay so little attention to the amount that
was being sold that it was easy for Torbey to employ agents to buy
from all of them freely on margin. And then, as the law of the curb
and the state permitted, he had demanded (through them, of course)
the actual delivery of the shares, the full curb value of the stock
being offered. Of course the brokers had none, although they had
sold thousands; nor had any one else except Torbey, who had seen
to it that all outstanding stock had been recalled to his safe. That
meant that they must come to Torbey to buy or face a jail sentence,
and accordingly they had flocked to his office, only to be properly
mulcted for the total face value of the shares when they came.
Well, he had done that same thing in New York. Following the
example of the good Torbey, he had picked up a few unimportant
options in Honduras, far from any railroad, and had come to New
York to launch Calamita. Just as Torbey had done, he had looked for
a rich widow, a piano manufacturer’s wife in this case, and had
persuaded her that there were millions in it. From her he had gone
on to Wall Street and the curb and had done almost exactly as
Torbey had done.... Only that fellow De Malquit had killed himself,
and that was not so pleasant. He hadn’t anticipated that anything like
that would happen! That unfortunate wife of his. And those two
children made orphans. That was the darkest spot. He hadn’t known,
of course, that De Malquit himself was helping orphans—or—And
from there he had gone on to the forests of Washington and Oregon,
where he had bought immense tracts on which even yet he was
realizing, more and more. And from there it had been an easy step to
oil in southern California and Mexico—Ah, Greasadick, another sad
case!—And from there to mines and government concessions in
Peru and Ecuador, and the still greater ones in Argentina and Chile.
Money came fast to those who had it. At last, having accumulated a
fortune of at least nine millions, he had been able to interest Nadia,
and through her the clever and well-to-do fashionable set who had
backed his projects with their free capital. And by now his fortune
had swollen to almost forty millions.
But what of it? Could he say he was really content? What was he
getting out of it? Life was so deceptive; it used and then tossed one
aside. At first it had seemed wonderful to be able to go, do, act, buy
and sell as he chose, without considering anything save whether the
thing he was doing was agreeable and profitable. He had thought
that pleasure would never pall, but it had. There was this thing about
age, that it stole over one so unrelentingly, fattening one up or
thinning one down, hardening the arteries and weakening the
muscles and blood, until it was all but useless to go on. And what
was the import of his success, anyhow, especially to one who had no
children and no friends worthy of the name? There was no such
thing as true friendship in nature. It was each man for himself,
everywhere, and the devil take the hindmost. It was life that used
and tossed one aside, however great or powerful one might be.
There was no staying life or the drift of time.
Of course there had been the pleasure of building two great
houses for Nadia and living in them when he was not living in other
parts of the world. But all that had come too late; he had been too
old to enjoy them when they did come. She had been a great catch
no doubt, but much too attractive to be really interested in him at his
age. His wealth had been the point with her—any one could see that;
he knew it at the time and would not now try to deceive himself as to
that. At the time he had married her she had had social position
whereas he had none. And after she married him all her social
influence, to be sure, had been used to advance his cause. Still, that
scheme of hers to get him to leave his great fortune to those two
worthless sons of hers. Never! They were not worthy of it. Those
dancing, loafing wasters! He would see to it that his fortune was put
to some better use than that. He would leave it to orphans rather
than to them, for after all orphans in his employ had proved more
valuable to him than even they had, hadn’t they?—That curious
fellow, De Malquit!—So long ago. Besides wasn’t it Nadia’s two sons
who had influenced their mother to interest herself in D’Eyraud, the
architect who had built their two houses and had started Nadia off on
that gallery idea. And not a picture in it that would interest a sensible
person. And wasn’t it because of her that he had never troubled to
answer the letters of his sister Elvira asking him to educate her two
boys for her. He had fancied at the time that taking her two children
into his life would in some way affect his social relations with Nadia
and her set. And now Elvira was dead and he did not know where
the children were. He could charge that to her if he wanted to,
couldn’t he?
Well, life was like that. When he had built his two great houses he
had thought they would prove an immense satisfaction to him, as
they had for a time; but he would not be here much longer now to
enjoy them. He wasn’t nearly as active as he had been, and the sight
of the large companies of people that came to pose and say silly
things to each other was very wearying. They were always civil to
him, of course, but little more. They wanted the influence of his
name. And as long as he permitted it, his homes would be haunted
by those who wished to sell him things—stocks, bonds, enterprises,
tapestries, estates, horses. And those two boys of hers, along with
Nadia herself where her so-called art objects were concerned, so
busy encouraging them! Well, he was done with all that now. He
would not be bothered. Even youth and beauty of a venal character
had appeared on the scene and had attempted to set traps for him.
But his day was over. All these fripperies and pleasures were for
people younger than he. It required youth and energy to see beauty
and romance in such things, and he hadn’t a trace of either left. His
day was over and he might as well die, really, for all the good he
was, apart from his money, to any one.

The reminiscences of Byington Briggs, Esq., of Skeff,

Briggs & Waterhouse, private legal advisers to the late J.
H. Osterman, as developed in a private conversation at
the Metropolitan Club in New York in December, 19—.
“You knew old Osterman, didn’t you? I was his confidential adviser
for the last eight years of his life, and a shrewder old hawk never
sailed the air. He was a curious combination of speculator, financier
and dreamer, with a high percentage of sharper thrown in for good
measure. You’d never imagine that he was charitably inclined, now
would you? It never occurred to me until about a year and a half
before his death. I have never been able to explain it except that as
a boy he had had a very hard time and in his old age resented
seeing his two stepsons, Kester and Rand Benda, getting ready to
make free use of his fortune once he was gone. And then I think he
had come to believe that his wife was merely using him to feather
her own nest. I wouldn’t want it mentioned to a soul as coming from
me, but three months before he died he had me draw up a will
leaving his entire estate of something like forty millions, not to her, as
the earlier will filed by her showed, but to the J. H. Osterman
Foundation, a corporation whose sole purpose was to administer his
fortune for the benefit of something like three hundred thousand
orphans incarcerated in institutions in America. And but for the
accident of his sudden death out there at Shell Cove two years ago,
he would have left it that way.
“According to the terms of the will that I drew up, Mrs. Osterman
and her two sons were to receive only the interest on certain bonds
that were to be placed in trust for them for their lifetime only; after
that the money was to revert to the fund. That would have netted
them between forty and fifty thousand a year among them—nothing
more. In the will I drew up he left $500,000 outright to that Gratiot
Home for Orphans up here at 68th Street, and he intended his big
country place at Shell Cove as the central unit in a chain of modern
local asylums for orphans that was to have belted America. The
income from the property managed by the foundation was to have
been devoted to this work exclusively, and the Gratiot institution was
to have been the New York branch of the system. His wife has
leased the Shell Cove place to the Gerbermanns this year, I see, and
a wonderful place it is too, solid marble throughout, a lake a mile
long, a big sunken garden, a wonderful glassed-in conservatory, and
as fine a view of the sea as you’ll find anywhere. Yet she never knew
until the very last hour of his life—the very last, for I was there—that
he planned to cut her off with only forty or fifty thousand a year. If we
weren’t all such close friends I wouldn’t think of mentioning it even
now, although I understand that Klippert, who was his agent in the
orphan project, has been telling the story. It was this way:
“You see, I was his lawyer, and had been ever since the K. B. & B.
control fight in 1906, and the old man liked me—I don’t know why
unless it was because I drew up the right sort of ‘waterproof
contracts,’ as he always called them. Anyway, I knew six or seven
years before he died that he wasn’t getting along so well with Mrs.
Osterman. She is still an attractive woman, with plenty of brain
power and taste, but I think he had concluded that she was using
him and that he wasn’t as happy as he thought he would be. For one
thing, as I gathered from one person and another, she was much too
devoted to those two boys by her first husband, and in the next place
I think he felt that she was letting that architect D’Eyraud lead her
about too much and spend too much of his money. You know it was
common rumor at the time that D’Eyraud and his friend Beseroe,
another man the old captain disliked, were behind her in all her
selections of pictures for the gallery she was bringing together up
there in the Fifth Avenue place. Osterman, of course, knowing
absolutely nothing about art, was completely out of it. He wouldn’t
have known a fine painting from a good lithograph, and I don’t think
he cared very much either. And yet it was a painting that was one of
the causes of some feeling between them, as I will show you. At that
time he looked mighty lonely and forlorn to me, as though he didn’t
have a friend in the world outside of those business associates and
employés of his. He stayed principally in that big town house, and
Mrs. Benda—I mean Mrs. Osterman—and her sons and their friends
found a good many excuses for staying out at Shell Cove. There
were always big doings out there. Still, she was clever enough to be
around him sometimes so as to make it appear, to him at least, that
she wasn’t neglecting him. As for him, he just pottered around up
there in that great house, showing his agents and employés, and the
fellows who buzzed about him to sell him things, the pictures she
was collecting—or, rather, D’Eyraud—and letting it appear that he
was having something to do with it. For he was a vain old soldier,
even if he did have one of the best business minds of his time. You’d
think largeness of vision in some things might break a man of that,
but it never does, apparently.
“Whenever I think of him I think of that big house, those heavily
carved and gilded rooms, the enormous eighty-thousand dollar
organ built into the reception-room, and those tall stained-glass
windows that gave the place the air of a church. Beseroe once told
me that if left to follow her own taste Mrs. Osterman would never
have built that type of house, but that Osterman wanted something
grand and had got his idea of grandeur from churches. So there was
nothing to do but build him a house with tall Gothic windows and a
pipe-organ, and trust to other features to make it homelike and
livable. But before they were through with it Mrs. Osterman and
D’Eyraud had decided that the best that could be done with it would
be to build something that later could be turned into an art gallery
and either sold or left as a memorial. But I think both D’Eyraud and
Mrs. Osterman were kidding the old man a little when they had that
self-playing attachment built in. It looked to me as though they
thought he was going to be alone a good part of the time and might
as well have something to amuse himself with. And he did amuse
himself with it, too. I recall going up there one day and finding him
alone, in so far as the family was concerned, but entirely surrounded
by twenty-five or more of those hard, slick and yet nervous (where
social form was concerned) western and southern business agents
and managers of his, present there to hold a conference. A luncheon
was about to be served in the grand dining-room adjoining the
reception-room, and there were all these fellows sitting about that big
room like a lot of blackbirds, and Osterman upon a raised dais at one
end of the room solemnly rendering The Bluebells of Scotland, one
of his favorites, from the self-player attachment! And when he
finished they all applauded!
“Well, what I wanted to tell you is this: One day while I was there,
some dealer dropped in with a small picture which for some reason
took his fancy. According to Beseroe, it wasn’t such a bad thing,
painted by a Swedish realist by the name of Dargson. It showed a
rather worn-out woman of about forty-three who had committed
suicide and was lying on a bed, one hand stretched out over the
edge and a glass or bottle from which she had taken the poison lying
on the floor beside her. Two young children and a man were
standing near, commiserating themselves on their loss, I presume. It
seemed to have a tremendous impression on Osterman for some
reason or other. I could never understand why—it was not so much
art as a comment on human suffering. Nevertheless, Osterman
wanted it, but I think he wanted Nadia to buy it for her collection and
so justify his opinion of it. But Nadia, according to Beseroe, was
interested only in certain pictures as illustrations of the different
schools and periods of art in different countries. And when the dealer
approached her with the thing, at Osterman’s suggestion, it was
immediately rejected by her. At once Osterman bought it for himself,
and to show that he was not very much concerned about her opinion
he hung it in his bedroom. Thereafter he began to be quarrelsome in
regard to the worthwhileness of the gallery idea as a whole and to
object to so much money being squandered in that direction. But to
this day no one seems to know just why he liked that particular
picture so much.
“What I personally know is that it was just about this time that
Osterman began to be interested in that fellow Klippert and his plan
for improving the condition of the orphan. He finally turned him over
to me with the request that I go into the idea thoroughly, not only in
regard to the work done by the Gratiot Home but by orphan asylums
in general in America. He told us that he wanted it all kept very quiet
until he was ready to act, that if anything was said he would refuse to
have anything further to do with it. That was a part of his plan to
outwit Mrs. Osterman, of course. He told us that he wanted some
scheme in connection with orphans that would be new and
progressive, better than anything now being done, something that
would do away with great barracks and crowd regulations and cheap
ugly uniforms and would introduce a system of education and home
life in cottages. I had no idea then that he was planning the immense
thing that was really in his mind, and neither did Klippert. He thought
he might be intending to furnish enough money to revive the Gratiot
Home as an experiment, and he urged me to use my influence to
this end if I had any. As it turned out, he wanted to establish an
interstate affair, as wide as the nation, of which the place at Shell
Cove was to be the centre or head—a kind of Eastern watering-
place or resort for orphans from all over America. It was a colossal
idea and would have taken all of his money and more.
“But since he wanted it I went into the idea thoroughly with this
fellow Klippert. He was very clever, that man, honest and thorough
and business-like and disinterested, in so far as I could see. I liked
him, and so did Osterman, only Osterman wanted him to keep out of
sight of his wife until he was ready to act. Klippert made a regular
business of his problem and went all over the United States studying
institutions of the kind. Finally he came back with figures on about
fifty or sixty and a plan which was the same as that outlined to me by
Osterman and which I incorporated in his will, and there it ended for
the time being. He didn’t want to sign it right away for some reason,
and there it lay in my safe until—well, let me tell you how it was.
One Saturday morning—it was a beautiful day and I was thinking
of going out to the club to play golf—I received a long distance call
from Osterman asking me to get hold of Klippert and another fellow
by the name of Moss and bring them out to Shell Cove, along with
the will for him to sign. He had made up his mind, he said, and I
have often wondered if he had a premonition of what was going to
happen.
“I remember so well how excited Klippert was when I got him on
the wire. He was just like a boy, that fellow, in his enthusiasm for the
scheme, and apparently not interested in anything except the welfare
of those orphans. We started for Shell Cove, and what do you think?
Just as we got there—I remember it all as though it had happened
yesterday. It was a bright, hot Saturday afternoon. There were some
big doings on the grounds, white-and-green and white-and-red
striped marque tents, and chairs and swings and tables everywhere.
Some of the smartest people were there, sitting or walking or
dancing on the balcony. And there was Osterman walking up and
down the south verandah near the main motor entrance, waiting for
us, I suppose. As we drove up he recognized us, for he waved his
hand, and then just as we were getting out and he was walking
towards us, I saw him reel and go down. It was just as though some
one had struck him with something. I realized that it must be
paralysis or a stroke of apoplexy and I chilled all over at the thought
of what it might mean. Klippert went up the steps four at a time, and
as we all ran down the verandah they carried him in and I
telephoned for a doctor. Klippert was very still and white. All we
could do was to stand around and wait and look at each other, for
Mrs. Osterman and her sons were there and were taking charge.
Finally word came out that Mr. Osterman was a little better and
wanted to see us, so up we went. He had been carried into an airy,
sunny room overlooking the sea and was lying in a big white
canopied bed looking as pale and weak as he would if he had been
ill for a month. He could scarcely speak and lay there and looked at
us for a time, his mouth open and a kind of tremor passing over his
lips from time to time. Then he seemed to gather a little strength and
whispered: ‘I want—I want—’ and then he stopped and rested,
unable to go on. The doctor arrived and gave him a little whisky, and
then he began again, trying so hard to speak and not quite making it.
At last he whispered: ‘I want—I want—that—that—paper.’ And then:
‘Klippert—and you—’ He stopped again, then added: ‘Get all these
others out of here—all but you three and the doctor.’
“The doctor urged Mrs. Osterman and her sons to leave, but I
could see that she didn’t like it. Even after she went out she kept
returning on one excuse and another, and she was there when he
died. When she was out of the room the first time I produced the will
and he nodded his approval. We called for a writing board, and they
brought one—a Ouija board, by the way. We lifted him up, but he
was too weak and fell back. When we finally got him up and spread
the will before him he tried to grasp the pen but he couldn’t close his
fingers. He shook his head and half whispered: The——the——boys
—th—the—boys.’ Klippert was all excited, but Osterman could do
nothing. Then his wife came into the room and asked: ‘What is it that
you are trying to make poor Johnnie sign? Don’t you think you had
better let it rest until he is stronger?’ She tried to pick up the paper
but I was too quick for her and lifted it to one side as though I hadn’t
noticed that she had reached for it. I could see that she was aware
that something was being done that neither we nor Osterman
wanted her to know about, and her eyes fairly snapped. Osterman
must have realized that things were becoming a little shaky for he
kept looking at first one and then another of us with a most unhappy
look. He motioned for the pen and will. Klippert put down the board
and I the paper, and he leaned forward and tried to grasp the pen.
When he found he couldn’t he actually groaned: ‘The—the—I—I—I
want to—to—do something—for—for—the—the—the—’ Then he fell
back, and the next moment was dead.
 “But I wish you could have seen Klippert. It wasn’t anything he
said or did, but just something that passed over his face, the shadow
of a great cause or idea dying, let us say. Something seemed to go
out from or die in him, just as old Osterman had died. He turned and
went out without a word. I would have gone too, only Mrs. Osterman
intercepted me.
“You might think that at such a moment she would have been too
wrought up to think of anything but her husband’s death, but she
wasn’t. Far from it. Instead, as her husband was lying there, and
right before the doctor, she came over to me and demanded to see
the paper. I was folding it up to put into my pocket when she flicked it
out of my hands. ‘I am sure you can have no objection to my seeing
this,’ she said icily, and when I protested she added: ‘I am sure that I
have a right to see my own husband’s will.’ I had only been
attempting to spare her feelings, but when I saw what her attitude
was I let it go at that and let her read it.
“I wish you could have seen her face! Her eyes narrowed and she
bent over the paper as though she were about to eat it. When she
fully comprehended what it was all about she fairly gasped and
shook—with rage, I think—though fear as to what might have
happened except for her husband’s weakness may have been a part
of it. She looked at him, at his dead body, the only glance he got
from her that day, I’m sure, then at me, and left the room. Since
there was nothing more to do, I went too.
“And that’s the reason Mrs. Osterman has never been friends with
me since, though she was genial enough before. But it was a close
shave for her, all the same, and don’t you think it wasn’t. Just an
ounce or two more of strength in that old codger’s system, and think
what would have been done with those millions. She wouldn’t have
got even a million of it all told. And those little ragamuffins would
have had it all. How’s that for a stroke of chance?”
 XIII
THE SHADOW

W HAT had given him his first hint that all might not be as well at
home as he imagined was the incident of the automobile. Up to
that time he had not had a troubled thought about her, not one. But
after—Well, it was a year and a half now and although suspicion still
lingered it was becoming weaker. But it had not been obliterated
even though he could not help being fond of Beryl, especially since
they had Tickles to look after between them. But anyhow, in spite of
all his dark thoughts and subtle efforts to put two and two together,
he had not been able to make anything of it. Perhaps he was being
unjust to her to go on brooding about it.... But how was it possible
that so many suspicious-looking things could happen in a given time,
and one never be able to get the straight of them?
The main thing that had hampered him was his work. He was
connected with the Tri-State Paper Company, at the City Order desk,
and as a faithful employé he was not supposed to leave during
working hours without permission, and it was not always easy to get
permission. It was easy to count the times he had been off—once to
go to the dentist, and two or three times to go home when Beryl was
ill. Yet it just happened that on that particular afternoon his superior,
Mr. Baggott, had suggested that he, in the place of Naigly who
always attended to such matters but was away at the time, should
run out to the Detts-Scanlon store and ask Mr. Pierce just what was
wrong with that last order that had been shipped. There was a mix-
up somewhere, and it had been impossible to get the thing straight
over the telephone.
Well, just as he was returning to the office, seated in one of those
comfortable cross seats of the Davenant Avenue line and looking at
the jumble of traffic out near Blakely Avenue, and just as the car was
nearing the entrance to Briscoe Park he saw a tan-and-chocolate-
colored automobile driven by a biggish man in a light tan overcoat
and cap swing into view, cross in front of the car, and enter the park.
It was all over in a flash. But just as the car swung near him who
should he see sitting beside the man but Beryl, or certainly a woman
who was enough like her to be her twin sister. He would have sworn
it was Beryl. And what was more, and worse, she was smiling up at
this man as though they were on the best of terms and had known
each other a long time! Of course he had only had a glimpse, and
might have been mistaken. Beryl had told him that morning that she
was going to spend the afternoon with her mother. She often did
that, sometimes leaving Tickles there while she did her mother’s
marketing. Or, she and her mother, or she and her sister Alice, if she
chanced to be there, would take the baby for a walk in the park. Of
course he might have been mistaken.
But that hat with the bunch of bright green grapes on the side....
And that green-and-white striped coat.... And that peculiar way in
which she always held her head when she was talking. Was it really
Beryl? If it wasn’t, why should he have had such a keen conviction
that it was?
Up to that time there never had been anything of a doubtful
character between them—that is, nothing except that business of the
Raskoffsky picture, which didn’t amount to much in itself. Anybody
might become interested in a great violinist and write him for his
photo, though even that couldn’t be proved against Beryl. It was
inscribed to Alice. But even if she had written him, that wasn’t a
patch compared to this last, her driving about in a car with a strange
man. Certainly that would justify him in any steps that he chose to
take, even to getting a divorce.
But what had he been able to prove so far? Nothing. He had tried
to find her that afternoon, first at their own house, then at her
mother’s, and then at Winton & Marko’s real estate office, where
Alice sometimes helped out, but he couldn’t find a trace of her. Still,
did that prove anything once and for all? She might have been to the
concert as she said, she and Alice. It must be dull to stay in the
house all day long, anyhow, and he couldn’t blame her for doing the
few things she did within their means. Often he tried to get in touch
with her of a morning or afternoon, and there was no answer, seeing
that she was over to her mother’s or out to market, as she said. And
up to the afternoon of the automobile it had never occurred to him
that there was anything queer about it. When he called up Beryl’s
mother she had said that Beryl and Alice had gone to a concert and
it wasn’t believable that Mrs. Dana would lie to him about anything.
Maybe the two of them were doing something they shouldn’t, or
maybe Alice was helping Beryl to do something she shouldn’t,
without their mother knowing anything about it. Alice was like that,
sly. It was quite certain that if there had been any correspondence
between Beryl and that man Raskoffsky, that time he had found the
picture inscribed to Alice, it had been Alice who had been the go-
between. Alice had probably allowed her name and address to be
used for Beryl’s pleasure—that is, if there was anything to it at all. It
wasn’t likely that Beryl would have attempted anything like that
without Alice’s help.
But just the same he had never been able to prove that they had
been in league, at that time or any other. If there was anything in it
they were too clever to let him catch them. The day he thought he
had seen her in the car he had first tried to get her by telephone and
then had gone to the office, since it was on his way, to get
permission to go home for a few minutes. But what had he gained by
it? By the time he got there, Beryl and her mother were already
there, having just walked over from Mrs. Dana’s home, according to
Beryl. And Beryl was not wearing the hat and coat he had seen in
the car, and that was what he wanted to find out. But between the
time he had called up her mother and the time he had managed to
get home she had had time enough to return and change her clothes
and go over to her mother’s if there was any reason why she should.
That was what had troubled him and caused him to doubt ever since.
She would have known by then that he had been trying to get her on
the telephone and would have had any answer ready for him. And
that may have been exactly what happened, assuming that she had
been in the car and gotten home ahead of him, and presuming her
mother had lied for her, which she would not do—not Mrs. Dana. For
when he had walked in, a little flushed and excited, Beryl had
exclaimed: “Whatever is the matter, Gil?” And then: “What a crazy
thing, to come hurrying home just to ask me about this! Of course I
haven’t been in any car. How ridiculous! Ask Mother. You wouldn’t
expect her to fib for me, would you?” And then to clinch the matter
she had added: “Alice and I left Tickles with her and went to the
concert after going into the park for a while. When we returned, Alice
stopped home so Mother could walk over here with me. What are
you so excited about.” And for the life of him, he had not been able
to say anything except that he had seen a woman going into Briscoe
Park in a tan-and-chocolate car, seated beside a big man who
looked like—well, he couldn’t say exactly whom he did look like. But
the woman beside him certainly looked like Beryl. And she had had
on a hat with green grapes on one side and a white-and-green
striped sports coat, just like the one she had. Taking all that into
consideration, what would any one think? But she had laughed it off,
and what was he to say? He certainly couldn’t accuse Mrs. Dana of
not knowing what she was talking about, or Beryl of lying, unless he
was sure of what he was saying. She was too strong-minded and too
strong-willed for that. She had only married him after a long period of
begging on his part; and she wasn’t any too anxious to live with him
now unless they could get along comfortably together.
Yet taken along with that Raskoffsky business of only a few
months before, and the incident of the Hotel Deming of only the day
before (but of which he had thought nothing until he had seen her in
the car), and the incident of the letters in the ashes, which followed
on the morning after he had dashed home that day, and then that
business of the closed car in Bergley Place, just three nights
afterwards—well, by George! when one put such things together—
It was very hard to put these things in the order of their effect on
him, though it was easy to put them in their actual order as to time.
The Hotel Deming incident had occurred only the day before the
automobile affair and taken alone, meant nothing, just a chance
encounter with her on the part of Naigly, who had chosen to speak of
it. But joined afterwards with the business of the partly burned letters
and after seeing her in that car or thinking he had—Well—After that,
naturally his mind had gone back to that Hotel Deming business, and
to the car, too. Naigly, who had been interested in Beryl before her
marriage (she had been Baggott’s stenographer), came into the
office about four—the day before he had seen Beryl, or thought he
had, in the car, and had said to him casually: “I saw your wife just
now, Stoddard.” “That so? Where?” “She was coming out of the
Deming ladies’ entrance as I passed just now.” Well, taken by itself,
there was nothing much in that, was there? There was an arcade of
shops which made the main entrance to the Deming, and it was easy
to go through that and come out of one of the other entrances. He
knew Beryl had done it before, so why should he have worried about
it then? Only, for some reason, when he came home that evening
Beryl didn’t mention that she had been downtown that day until he
asked her. “What were you doing about four to-day?” “Downtown,
shopping. Why? Did you see me? I went for Mother.” “Me? No. Who
do you know in the Deming?” “No one”—this without a trace of self-
consciousness, which was one of the things that made him doubt
whether there had been anything wrong. “Oh, yes; I remember now. I
walked through to look at the hats in Anna McCarty’s window, and
came out the ladies’ entrance. Why?” “Oh, nothing. Naigly said he
saw you, that’s all. You’re getting to be a regular gadabout these
days.” “Oh, what nonsense! Why shouldn’t I go through the Deming
Arcade? I would have stopped in to see you, only I know you don’t
like me to come bothering around there.”
And so he had dismissed it from his mind—until the incident of the
car.
And then the matter of the letters ... and Raskoffsky ...
Beryl was crazy about music, although she couldn’t play except a
little by ear. Her mother had been too poor to give her anything more
than a common school education, which was about all that he had
had. But she was crazy about the violin and anybody who could play
it, and when any of the great violinists came to town she always
managed to afford to go. Raskoffsky was a big blond Russian who
played wonderfully, so she said. She and Alice had gone to hear
him, and for weeks afterward they had raved about him. They had
even talked of writing to him, just to see if he would answer, but he
had frowned on such a proceeding because he didn’t want Beryl
writing to any man. What good would it do her? A man like that
wouldn’t bother about answering her letter, especially if all the
women were as crazy about him as the papers said. Yet later he had
found Raskoffsky’s picture in Beryl’s room, only it was inscribed to
Alice.... Still, Beryl might have put Alice up to it, might even have
sent her own picture under Alice’s name, just to see if he would
answer. They had talked of sending a picture. Besides, if Alice had
written and secured this picture, why wasn’t it in her rather than
Beryl’s possession. He had asked about that. Yet the one flaw in that
was that Alice wasn’t really good-looking enough to send her picture
and she knew it. Yet Beryl had sworn that she hadn’t written. And
Alice had insisted that it was she and not Beryl who had written. But
there was no way of proving that she hadn’t or that Beryl had.
Yet why all the secrecy? Neither of them had said anything more
about writing Raskoffsky after that first time. And it was only because
he had come across Raskoffsky’s picture in one of Beryl’s books that
he had come to know anything about it at all. “To my fair little
western admirer who likes my ‘Dance Macabre’ so much. The next
time I play in your city you must come and see me.” But Alice wasn’t
fair or good-looking. Beryl was. And it was Beryl and not Alice, who
had first raved over that dance; Alice didn’t care so much for music.
And wasn’t it Beryl, and not Alice, who had proposed writing him. Yet
it was Alice who had received the answer. How was that? Very likely
it was Beryl who had persuaded Alice to write for her, sending her
own instead of Alice’s picture, and getting Alice to receive
Raskoffsky’s picture for her when it came. Something in their manner
the day he had found the picture indicated as much. Alice had been
so quick to say: “Oh yes. I wrote him.” But Beryl had looked a little
queer when she caught him looking at her, had even flushed slightly,
although she had kept her indifferent manner. At that time the
incident of the car hadn’t occurred. But afterwards,—after he had
imagined he had seen Beryl in the car—it had occurred to him that
maybe it was Raskoffsky with whom she was with that day. He was
playing in Columbus, so the papers said, and he might have been
passing through the city. He was a large man too, as he now
recalled, by George! If only he could find a way to prove that!