Scleroderma Best Practice

Best Practice & Research Clinical Rheumatology 35 (2021) 101707
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
12
A comprehensive framework for navigating

patient care in systemic sclerosis: A global
response to the need for improving the practice
of diagnostic and preventive strategies in SSc*
Lesley Ann Saketkoo a, b, c, d, *, Tracy Frech e, Cecília Varjú f,
Robyn Domsic g, Jessica Farrell h, i, Jessica K. Gordon j,
Carina Mihai k, l, Nora Sandorfi m, Lee Shapiro i, n, Janet Poole o,
Elizabeth R. Volkmann p, Monika Lammi q, Kendra McAnally r,
Helene Alexanderson s, t, Henrik Pettersson s, t, Faye Hant u,
Masataka Kuwana v, Ami A. Shah w, Vanessa Smith x,
Vivien Hsu y, Otylia Kowal-Bielecka z, Shervin Assassi aa,
Maurizio Cutolo ab, Cristiane Kayser ac,
Victoria K. Shanmugam ad, Madelon C. Vonk ae,
Kim Fligelstone af, ag, Nancy Baldwin ah, Kerri Connolly ai,
Anneliese Ronnow aj, ak, al, Beata Toth aj, ak, al,
Maureen Suave am, Sue Farrington af, aj, ak, al,
Elana J. Bernstein an, Leslie J. Crofford e, La
!szlo ! k f,
! Czirja
b, ao
Kelly Jensen , Monique Hinchclif , Marie Hudson aq,
ap
Matthew R. Lammi a, c, d, Jennifer Mansour b,

Nadia D. Morgan w, Fabian Mendoza ar, Mandana Nikpour as,
John Pauling at, Gabriela Riemekasten au, av,
Anne-Marie Russell aw, Mary Beth Scholand ax, Elise Seigart ay,
*
This effort is inspired by the grace, couarage and brilliance that people living with SSc have demonstrated in their lives and
by helping others through education, research and advocacy despite the ongoing challenges of this devastating disease.
We also dedicate this collaborative work to Dr. Nadia Morgan a young, energetic, meticulous, creative and heartful SSc
clinical scientist; her loss resounds in the SSc research community.
This work is endorsed by: Federation of European Scleroderma Associations (FESCA), Scleroderma Australia, Scleroderma
Canada, Scleroderma & Raynaud's UK (SRUK), and Scleroderma Foundation USA.
* Corresponding author. New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center; University Medical
Center e Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs; Louisiana State Uni-
versity School of Medicine, Section of Pulmonary Medicine; Tulane University School of Medicine, New Orleans, LA, 70112, USA.
E-mail address: lsaketk@tulane.edu (L.A. Saketkoo).
https://doi.org/10.1016/j.berh.2021.101707
1521-6942/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: L.A. Saketkoo, T. Frech, C. Varjú et al., A comprehensive framework for navi-
gating patient care in systemic sclerosis: A global response to the need for improving the practice of...,
Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2021.101707
L.A. Saketkoo, T. Frech, C. Varjú et al. Best Practice & Research Clinical Rheumatology 35 (2021) 101707
ax
University of Utah, Division of Pulmonary Medicine, Pulmonary Fibrosis Center, Salt Lake City, UT, USA
ay
Department of Rheumatology and Clinical Immunology Charit! e - Universita
€tsmedizin Berlin and Berlin
Institute of Health, Berlin, Germany
az
Instituto Nacional de Ciencias M!edicas y Nutricio
!n Salvador Zubira
!n, Mexico City, Mexico
ba
Dept. of Rheumatology, Basel University Hospital, Basel, Switzerland
bb
Division of Rheumatology, Department of Medicine, Georgetown University, Washington, DC, USA
a b s t r a c t
Keywords:
Interstitial lung disease Systemic sclerosis (SSc), the most lethal of rheumatologic condi-
Pulmonary fibrosis tions, is the cause of death in >50% of SSc cases, led by pulmonary
Renal crisis fibrosis followed by pulmonary hypertension and then sclero-
Pulmonary hypertension derma renal crisis (SRC). Multiple other preventable and treatable
Disability SSc-related vascular, cardiac, gastrointestinal, nutritional and
Scleroderma
musculoskeletal complications can lead to disability and death.
Systemic sclerosis
Symptom burden
Vascular injury with subsequent inflammation transforming to
Quality of life irreversible fibrosis and permanent damage characterizes SSc.
Organ involvement is often present early in the disease course of
SSc, but requires careful history-taking and vigilance in screening
to detect. Inflammation is potentially reversible provided that
treatment intensity quells inflammation and other immune
mechanisms. In any SSc phenotype, opportunities for early treat-
ment are prone to be under-utilized, especially in slowly pro-
gressive phenotypes that, in contrast to severe progressive ILD,
indolently accrue irreversible organ damage resulting in later-
stage life-limiting complications such as pulmonary hyperten-
sion, cardiac involvement, and malnutrition.
A single SSc patient visit often requires much more physician and
staff time, organization, vigilance, and direct management for
multiple organ systems compared to other rheumatic or pulmo-
nary diseases. Efficiency and efficacy of comprehensive SSc care
enlists trending of symptoms and bio-data. Financial sustainability
of SSc care benefits from understanding insurance reimbursement
and health system allocation policies for complex patients. Sharing
care between recognised SSc centers and local cardiology/pulmo-
nary/rheumatology/gastroenterology colleagues may prevent
complications and poor outcomes, while providing support to local
specialists.
As scleroderma specialists, we offer a practical framework with
tools to facilitate an optimal, comprehensive and sustainable
approach to SSc care. Improved health outcomes in SSc relies upon
recogntion, management and, to the extent possible, prevention of
SSc and treatment-related complications.
© 2021 Elsevier Ltd. All rights reserved.
Introduction
Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the direct cause of death in
>50% of SSc cases, followed by pulmonary fibrosis, pulmonary hypertension, and scleroderma renal
crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal,
nutritional, and musculoskeletal complications also lead to disability and death.
SSc is characterized by vascular injury and disrepair that incites systemic progressive inflammatory
transformation to fibrosis at widely variable rates and intensities. Inflammation is a reversible
3
phenomenon provided the intensity of treatment matches that of the inflammation. End-stage fibrosis
is permanent and irreversible. Organ involvement is present early in the SSc disease course, requiring
ongoing screening and careful patient questioning to detect. Reduction of disability and mortality
hinges on the prevention of vascular and fibrotic damage, which is directly dependent upon early
recognition of active disease, even in the indolent disease phenotypes, with initiation of appropriate
treatment to prevent fibrotic transformation.
Delayed diagnosis is common in autoimmune diseases and disproportionately frequent in those of
African and Hispanic descent, for whom these diseases tend to be more severe and deadly [1e6].
Importantly, slowly progressive phenotypes indolently accruing irreversible structural changes and
organ damage are less prone to receive treatment, resulting in end-stage SSc complications such as
pulmonary hypertension, cardiac involvement, and malnutrition. Diagnostic delays, misdiagnoses, and
complication oversights are likely underpinned by preferential reliance on laboratory data and a
clinical setting that is hurried which impair authentic empathetic listening, careful history-taking, and
physical exam performance.
Efficiency and efficacy of SSc care that meets the health-related quality of life (HRQoL) and survival
needs of patients require trending of symptoms and over time; and also requires multiple streams of
management that are sustained by understanding visit reimbursement policies. A single SSc patient
visit commonly involves extensive chart review, investigation, coordination and direct management
for multiple organ systems, and exacting physician and staff time and effort beyond that of other
diseases. Sharing care between scleroderma centers and local specialists provides robust patient-
centered management and patient skill-building for self-management of this complex disorder.
As scleroderma specialists, we offer an abbreviated reference manual and practical framework, that
we hope supports clinicians and patients, with informational summaries on symptoms, manifesta-
tions, and complications with tools and templates for screening, assessment, documentation, risk
stratification, counselling, and anticipatory guidance, and discussions surrounding clinician
sustainability.
Pathologic drivers in SSc that impact treatment decisions
Inflammation-fibrosis axis: from preventable to irreversible damage
Beyond the widely heterogeneous nature of SSc presentation, progression and potential organ
involvement, a major challenge impeding SSc care is the ability to distinguish between states of active
progressive disease and its subsequent fibrotic damage. Inflammation-fibrosis transformation is a
progressive process with an advancing front of potentially reversible inflammatory assault. Inflam-
matory tissue left untreated is damaged with increasing expanses of fibrosis. Inflammation and fibrosis
are often coexistent, but increasing fibrotic expanse leads to worsening irreversible disability and,
possibly, death over time. Though currently difficult to distinguish with certainty, even in the absence of
ESR or CRP elevation and regardless of coexistent fibrosis or the rate of progression, the concern for any
degree of inflammation, i.e., progression, should prompt consideration to initiate systemic immuno-
modulatory therapy.
Symptoms and impairment burden dynamically relate to the extent of either inflammation, fibrosis,
or a combination thereof (Fig. 1). Symptoms worsen with extent of involvement; but potential
symptom reduction or reversal with systemic treatment requires some degree of active tissue
inflammation to be present. For example, progressive ILD, can manifest by dropping forced vital ca-
pacity (FVC), dry inspiratory cough, and breathlessness that improves after systemic treatment [7e10].
Whereas, residual inactive fibrotic damage resulting from prior inflammation is now unresponsive to
immunosuppression.
Circulation and mechanisms of disease
Vasculopathy, vascular injury with tissue hypoxia, and pathologic circulation interplay with and are
drivers of inflammation and fibrosis. The earliest hallmark of SSc disease is vascular injury, dysfunction
4
Fig. 1. SSc involved tissue, of which the lung is one example, experiences transition from healthy tissue to fibrosis as inflammation is
incited and progressively extends within resident organs. Vascular injury with tissue hypoxia is an important factor to the devel-
opment of tissue fibrosis. Symptoms and disability can be transient in active inflammation with systemic treatment. Over time
untreated inflammation irreparably injures effected tissue, resulting in scarring and fibrosis. Fibrosis is irreversible and results in
permanent organ-related disability. (Courtesy of LA Saketkoo, rights reserved).
and disrepair, without overt evidence of inflammatory infiltration i.e. not vasculitis [11,12]. Vascular
dysfunction and Raynaud's phenomenon (RP) symptoms predominantly predate non-RP symptoms by
several years. In the genetically predisposed host, vascular injury may incite immune system activation
through upregulation of adhesion cells and perivascular migration of immune cells, including mac-
rophages, which may have a direct role in fibroblast stimulation.
The presence of abnormal capillaroscopy predicts the development of connective tissue disease
(CTD) in patients with RP, and ANA positivity heightens that predictive power [13]. SSc nailfold
capillaroscopy patterns are well described reflecting the vasculature struggling against the pathologic
progression of the disease [14].(Fig. 2). The presence of abnormal nailfold capillaries contributes >20%
toward SSc classification criteria [15] and predicts [16] the development of a CTD [17] and SSc
[13,16,18,19]; making capillaroscopy, with at least a handheld device, an essential assessment tool in
rheumatologic care (Fig. 3).
A normal nailfold bed demonstrates long thin hairpin loops resembling the abundance of wheat
fields. In the “early” and “active” SSc patterns, the capillaries dilate and giant loops occur, as well as
microhemorrhages, ballooning above the injured vessels. Later in the course of SSc, capillaries “drop-
out” leading to a rarefaction of the capillary network. Edematous “puffy fingers” or diffuse infiltrative
fibrosis sometimes make nailfold capillaries difficult to visualize [19e25]. The “late” pattern is char-
acterized by marked rarefaction and often reflects the vasculature's struggles to repair itself, albeit
ineffectively despite high levels of circulating pro-angiogenic factors, creating a network of thin,
matted vessels inefficient for supporting healthy tissue. This can be seen also in GI and skin, i.e., GAVE
and telangiectasias.
Lethal vascular complications such as PH and cardiac involvement correlate with other circulatory
phenomena, e.g., digital ulcers (DU), telangiectasias [20,21], osseous vascular complications, e.g.,
radiographic calcinosis, and acro-osteolysis [22], and with inflammation-predominant complications,
5
L.A. Saketkoo, T. Frech, C. Varjú et al.
6

Fig. 2. Demonstration of ‘normal’ and various SSc patterns on nail fold video capillaroscopy. (Images courtesy of Vanessa Smith; University of Ghent, Belgium.)
7

Fig. 3. Capillaroscopy is an essential rheumatologic service. An abnormal capillaroscopy satisfies >20% of SSc criteria and confers 96% predictive power for development of CTD, making it an
essential part of the rheumatologic exam. With any method, capillaries become increasingly easier to visualize with practice over time. (Courtesy of T Frech & LA Saketkoo, rights reserved). 1The
ophthalmoscope has lowest magnification but easily found in doctors’ offices. 2The dermatoscope is affordable, convenient and portable. 3The smartphone dermatoscope is affordable and easy to
use. 4. The stereomicroscope is costly, and cumbersome for transport. Images are comparable quality to that of dermatoscope. 5. The video capillaroscope is costly but produces high-quality
digital images enabling fine measurements. The camera attaches to a laptop or other computer.
e.g., arthritis and muscle involvement. These associations suggest a deep-rooted interplay between
systemic inflammation, autoimmunity, fibrosis, and vasculopathy.
Systemic autoimmune, inflammatory drivers influencing SSc vascular complications is a major
current consideration in research and patient care [23e27]. SSc-specific autoantibodies help predict
the potential clinical course and phenotypes in SSc patients. However, only functional antibodies not
specific to SSc, such as the anti-endothelial cell antibody, demonstrate a direct pathogenic role,
although reports are conflicting [28,29]. Healing of non-friction DUs upon initiation of systemic
treatment, e.g., mycophenolate mofetil (MMF), and subsequent DU re-emergence upon immunosup-
pression discontinuation are anecdotally noted by SSc experts. Potential influence of immunosup-
pressants on improved outcomes in SSc-PH are increasingly being investigated [23e27].
Considerations that drive management in SSc
Goals of SSc management
Preventing death and permanent disability in SSc is accomplished with early and appropriate treatment.
SSc is an extensively complex disease often with delayed diagnosis. By the time patients receive expert
management, most will have permanently lost some degree of physical function and have diminished
well-being, eroding one's ability to sustain the crucial life areas and personal satisfactions of family,
intimate and social interactions including financial solvency. Recent data suggest initiating early
treatment may prevent development or progression of complications such as ILD [30].
SSc is associated with significant unemployment, worker absenteeism, and decreased worker
productivity [31]. Preventable SSc-related work impairment results in substantial economic burden
and diminished HRQoL [32] with loss of work, lost income, and loss of health insurance and healthcare.
Working closely with patients and their employers to attain appropriate modifications to their work
environment and situation may improve functioning and improve productivity [31e36].
Goals of SSc care are rooted in prevention and reversal of disease progression (including indolent
progression) and restoration of function and HRQoL due to diverse symptom burdens and therefore
include:
! Early recognition of probable SSc and initiation of early appropriate systemic treatment for SSc
! Early recognition, treatment and responsive observation of each SSc manifestation over time
! Early recognition and prevention of complications related to SSc-manifestations and treatment
! Engaging patients in preventive strategies via ongoing education and shared decision making
! Early introduction of key specialists that preserve and augment function, health and HRQoL,
e.g. physiotherapists, occupational or respiratory therapists, dietician, cardiologist, gastroenterol-
ogist, pulmonologist, etc.
! Tight communication in care planning with key specialists and local care teams
! As much as is possible, restoration of baseline functioning for each manifestation
! As much as is possible, reduction of symptom burden for each manifestation
Risk awareness in SSc
The risk for and the actual rate of disease progression guide the level of systemic treatment
intended to quell inflammation and prevent further organ damage. They also identify patients with
rapidly progressive disease potentially benefitting from more aggressive therapy such as hematopoi-
etic stem cell transplantation (HSCT) before end-organ damage occurs. While there is no formal SSc
risk stratification tool, certain factors put patients with SSc at even greater risk of death, disability and
rapidly progressive disease (Tables 1 and 2). Sensitizing clinicians to these risk factors heightens vig-
ilance for treatable lethal and/or permanently disabling disease.
It should be clarified that both limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc)
carry an increased risk of death. The terms diffuse and limited cutaneous are descriptors of skin
8
Table 1
Risk factors for death, disability and rapidly progressive disease.
Risk Factor Clinical measures Indication of Rapidly Progressive SSc or Severe Disease
Diffuse skin involvement Modified Rodnan total Skin Increasing diffuse skin thickness, mRSS > 29
thickness Score (mRSS)
Tendon Friction Rub Palpable presence on exam Palpable presence on exam
Anti-topoisomerase I See measures for ILD, dcSSc,
renal crisis, and cardiac fibrosis
Interstitial lung disease PFT: spirometry FVC<70%
PFT: DLCO DLCO<70%
HRCT: Extent of ground-glass >20% extent of disease on HRCT
opacity and honeycombing
fibrosis
Pulmonary arterial Echocardiography Estimated sPAP >40 mmHg
hypertension (PAH) Right atrial or ventricular enlargement
Septal flattening
Right heart catheterization mPAP>20 mmHg
PVR " 3 Wood units
WHO/NYHA Classification Class III/IV
Cardiac Involvement ECG ECG arrhythmia, heart block, valve disease,
Echocardiography Diastolic dysfunction > grade 2
Cardiac MRI Left ventricular ejection fraction <45%
Digital ulcers, gangrene Nailfold capillaroscopy Severe capillary loss, with fibrotic infiltration
Scleroderma renal crisis Hypertension Abnormal or an unusually elevated value for patient
Normotensive possible if on prednisone, vasodilators or
anti-hypertensives
Serum biomarkers Rising serum creatinine
Anti-RNA polymerase III
GAVE Gastric bleeding Frank blood on inspection
Anemia Hb < 9.6 g/dL
Severe malabsorption Weight loss
Muscle atrophy
Stool frequency
Electrolytes
Albumin/Pre-albumin
Polyarthritis HAQ-DI HAQ-DI >2.00
DAS-28
General health status Weight loss/BMI Weight loss > 10%
Serum biomarkers Low albumin, Low Hb
Comorbidities Presence of: COPD, malignancy, Anti-polymerase III in relation to malignancy
diabetes mellitus
GAVE: gastric antral vascular ectasia, ILD: Interstitial lung disease; PAS: estimated pulmonary artery systolic pressure by Doppler
echo; HAQ-DI: Health Assessment Questionnaire-Disability Index.
thickness distribution only and provide crude sub-typing of an extremely complex disease. However,
limited sub-type may carry a higher risk of PAH, dcSSc carries higher risk for progressive ILD; and
early dcSSc with rapid increases in skin thickening is associated with new internal organ involve-
ment [37,38], [19,39e49]. Both subtypes can develop ILD and PH, and malnutrition from severe GI
involvement.
Autoantibodies can be helpful for predicting outcome, particularly anti-centromere predicting PAH,
Scl-70 predicting ILD and RNA polymerase III predicting renal crisis (Fig. 4). Race and ethnicity are also
associated with increased risk of severe disease. Black race, compared to whites, independently pre-
dicts more rapid progression and higher mortality, more severe disease at a younger age of onset, and
with higher risk of early and concomitant ILD and PH. These racial differences may be associated with
distinct antibody and genetic profiles supporting that early aggressive intervention in Blacks with ILD
may offset mortality [5,32]. Hispanic and Asian ancestry also portends higher severity than whites
[50e52]. Male sex, early diffuse cutaneous disease or presence of tendon friction rubs also confer
increased risk of mortality.
9
Table 2
Risk factors for the development of severe organ manifestations of systemic sclerosis [19,39e44].
Risk factors with Associated Findings

Organ manifestation
Heart Diffuse cutaneous SSc

Elevated ultra-sensitive CRP
Myocardial fibrosis on CMR
Anti-topoisomerase 1 antibody
Male gender
Pericarditis
Arrhythmia
Right bundle branch block (RBBB)
Left ventricular dysfunction
Myopathy
Tendon friction rubs
Kidney, (renal crisis) Diffuse cutaneous SSc
Rapid skin progression in the first year of the onset
Presence of anti-RNA polymerase III autoantibodies
Medium or high dose glucocorticoid therapy, i.e. >10 mg prednisone daily
Significant cardiac manifestation
Joint contractures
Tendon friction rubs
Interstitial lung disease (ILD) African ancestry
Male gender
High mRSS
Diffuse cutaneous SSc
Anti-topoisomerase I antibody (Scl-70)
Anti-Th/To antibody
Anti-U11/U12 (RNPC) antibody
Increased ESR or CRP
FVC<70%, DLCO<70%
Progressive ILD Active polyarthritis
Increased ESR or CRP
Disease onset over 55 years
High mRSS
Reflux (GERD)
NYHA III-IV heart disease
Decreased SpO2 during 6 MWT
Progressive drop in %FVC corroborated by HRCT and symptoms
Advanced ILD (traction bronchiectasis, honeycombing) within 5 years of disease
onset
Pulmonary arterial Disease onset over 55 years
hypertension Long disease duration
African ancestry for early onset
Skin telangiectasia (increased number and size)
Isolated DLCO decrease
FVC/DLCO ratio > 1.6
Severe Raynaud's
Severe digital ulcers
Decreased capillary density by nail fold capillaroscopy
Increased serum uric acid
Presence of anti-nucleolar (anti-Th/To, and anti-U3 RNP) autoantibodies
Gastrointestinal Disease duration
Anti-U3-RNP
Dysbiosis (microbiome composition)
End-stage vasculopathy features such as DU, calcinosis
Dysphagia
Frequent food regurgitation
Small Intestinal Bacterial Overgrowth (SIBO) and related chronic diarrhea
Chronic intestinal pseudo-obstruction
Fecal soiling
Weight loss
Low albumin/pre-albumin
10
Table 2 (continued )
Risk factors with Associated Findings

Organ manifestation
Digital ulcers Diffuse cutaneous SSc

High mRSS
Male gender
Polyarthritis
Early non-Raynaud's first symptom
Increased capillary loss by capillary-microscopy
Arthritis, contractures, tendon Early manifestation in diffuse cutaneous SSc
friction rubs DAS-28
Presence of overlap SSc
Presence of anti-RNA Polymerase III and anti-Scl-70 (anti-Topoisomerase I)
autoantibodies
6MWT: 6-min walk test, CMR: Cardiac MRI, CRP: C-reactive protein, DAS-28: Disease Activity Score-28, DLCO: diffusion capacity
of the lung for carbon monoxide, ESR: erythrocyte sedimentation rate, FVC: forced vital capacity, GERD: gastroesophageal reflux
disorder, mRSS: modified Rodnan Skin Score, NYHA: New York Heart Association; SpO2: blood oxygen saturation; WHO: World
Health Organization.
Fig. 4. Clinical-Serologic Classification and Internal Organ Associations (Courtesy of RT Domsic, rights reserved). ILD ¼ interstitial
lung disease; DU ¼ digital ulcers; SRC ¼ scleroderma renal crisis; PH ¼ pulmonary hypertension.
Tracking symptoms and metrics for recognition, monitoring and intervention
Any type of organized framework containing SSc domains and sub-domains that tracks changes in
clinical features, symptomatology, complications and bio-data of multiple manifestations over time,
facilitates a comprehensive and efficient care continuum. This also enables communication of
important details across specialties. Such documentation captures SSc manifestations as they newly
emerge, improve, resolve, stabilize or worsen, and creates an overview that depicts treatment
responsiveness, potentially sparking consideration for new, additive or change in treatment approach.
Tables 3e6 and the resource list provide example tools.
11
Table 3
Domain Organization for Clinical Assessment and Documentation in SSc. Each sub-domain is often characterized by onset,
coincident intervention, and changes over time.
Domains Sub-Domains Assessment Considerations
Background Biological sex

Ethnicity and race
Environmental exposure history e.g. chemicals via occupation or proximity
Cardiovascular history Especially noting hypertension
Disease Duration Raynaud's phenomenon onset (month/
year)
What was 1st non-Raynaud's
phenomenon symptom
Onset of 1st non-Raynaud symptom
(month/year)
Physician diagnosis of SSc (month/year)
Skin Thickening Onset month/year
Distribution (mRSS)
Pruritus
Pigmentation disturbances e.g. hypo-, hyer- or poikiloderma
Telangiectasia and Calcinosis Recorded here or under the vascular domain
Vascular Manifestations Please see and incorporate components of Table 7 for document template
HEENT Facial Changes Oral aperture
Eyes Dry Eyes
Oral Tooth loosening, Chewing difficulty
Oral pain
Dry mouth
Dental caries
Naso-pharyngeal Post Nasal Drip (lung irritant)
Hoarseness of voice (vocal cord fibrosis or acid
injury)
Cardiopulmonary History of symptoms 1st noticed symptoms to now
Dyspnea/Cough/Exercise Intolerance Tables 9 and 10 for contextualizing history-
taking
NYHA Symptom Category Although a categorical variable that limits
utility, a worsening NYHA classification marks
significant clinical worsening
Cardiac symptoms including lower Arrhythmias/conduction disturbances, heart
extremity edema, orthopnea failure
Gastrointestinal Swallowing difficulty Proximal
Consider following SCTC-GIT or Distal
Geissen tools for overall GI Choking, coughing
impact Acid related Heartburn
Hoarseness
Cough, timing e.g. morning
Gastric History of GAVE
Early satiety
Regurgitation of food
Emesis of food
Bloating/distension/pain
Biliary History of primary biliary cholangitis
Itching, jaundice, pruritus, but may be
asymptomatic
Bilirubin and transaminase profiles, possible
anti-mitochondrial antibody presence
Small bowel Diarrhea, pain, weight loss, malabsorption
Cramping
Bloating
Large bowel Constipation
Fecal soiling
Muscular Atrophy, MMT-8
Muscle strength, TST/30-sec CST^
Muscle endurance, FI-2/FI-3^
Aerobic capacity (submaximal test) Ebbeling treadmill test*
Hand grip and pinch strength Astrand cycle test*
12
Domains Sub-Domains Assessment Considerations
6 MWT*
Jamar or Grippit dynamometer*
Pinch meter*
Joint AROM upper extremity, FSA*
AROM/PROM hands/fingers Goniometer*
HAMIS*
Cochin Hand Function Scale*
DAS-28
6MWT: 6 min walk test for distance, CST: Chair-Stands Test, DAS-28: Disease Activity Scale-28, FI-2: Functional Index 2, FI-3:
Functional Index 3, FSA: Function Shoulder Assessment, HAMIS: Hand Mobility in Scleroderma, mRSS: modified Rodnan Skin
Score, NYHA: New York Heart Association, *implemented routinely by OT, PT,împlemented by PT, OT but can be performed in
clinic by physician or staff.
Table 4
Snapshot diagram of common diagnostic testing in SSc.
Âs indicated by history or clinical findings, SIBO: small intestine bacterial overgrowth.
Multifactorial symptomatology
This section addresses common SSc symptoms that have multiple or combined causes, approaches
to distinguishing cause(s), and where applicable, therapeutic intervention. SSc being a disease of
inciting vascular injury, special attention is given to RP in this section, though not a multifactorial
symptom, as it is pervasive and often not straightforward to diagnosis.
A. Cold in SSc, and Raynaud's Phenomenon specifically, is the most common symptom and
highest ranked SSc-specific symptom diminishing HRQoL. Without preventive and palliative
13
Table 5
Common laboratory abnormalities in SSc. Courtesy of JK Gordon & LA Saketkoo, rights reserved.
Category Specific Lab Common Implications
Antibody Presence
ANA, bAnti-nucleolar pattern of Positive in 90e95% of cases. Perform by immunofluorescence. If negative,
any titer consider other fibrosing illnesses.
a
Anti-Scl-70 (Anti- 70% diffuse SSc, 30% limited SSc, higher risk ILD and higher risk severe ILD
topoisomerase I)
a
Anti-RNA Polymerase III Higher risk diffuse SSc, rapidly progressive skin, musculoskeletal involvement,
higher risk SRC, GAVE, concomitant malignancy; Raynaud may present later in
disease course
a
Anti-centromere Limited SSc, PAH
b
Anti-Fibrillarin (U3-RNP) Severe ILD, PAH, cardiomyopathy, severe GI involvement, diffuse SSc,
b
Anti-Th/To Limited skin involvement, PAH, ILD
b
Anti-PM-Scl Myositis, overlap
Anti-U11/U12 RNP Limited skin, ILD
Anti-U1-RNP Myositis, MCTD/Overlap, ILD, PAH, arthritis
Anti-Ku Myositis, Overlap
Anti-NOR 90 Anecdotally associated with SSc, and other CTDs with RP; forgotten antibody
Anti-Ro52 ILD, overlap
HEMATOLOGIC
Hemoglobin/Hematocrit GI loss, Medication effect, active inflammation
Schistocytes Concern for SRC
Platelets Elevated: Active inflammation,
Low: SRC, medication effect
Erythrocyte Sedimentation Rate Active inflammation, infection, malignancy
Serum Protein Electrophoresis Hypergammaglobulinemia
Associated with active disease, severe lung involvement, SSA antibody;
More prevalent in African ancestry
Chemistry
Creatinine SRC related renal injury
Transaminases (ALT/SGOT, AST/ Medications, myopathy,
SGPT)
Creatine Kinase Myopathy, myocardial infarction
Albumin If low: Active inflammation, low nutrition status, malabsorption
Troponin Myocarditis
C-Reactive Protein Active inflammation, infection
Prognostic indicator
Aldolase Myopathy
Uric Acid Pulmonary hypertension predictor, cardiovascular disease
Pro-NT-beta natriuretic Pulmonary hypertension, heart failure
protein/Beta-natriuretic
protein
Urine
Protein Prognostic indicator
SRC
Red cells SRC
a
Indicates criteria marker.
b
Indicates strong correlation with SSc diagnosis.
intervention, RP can lead to other vascular complications such as DUs, acro-osteolysis, and calcinosis
[20,53e56]. (Table 7) RP affects glabrous skin regions (fingers, toes, nipples, ears, and toes). Glabrous
skin's unique vascular structure contains large numbers of cutaneous arteriovenous connections. RP in
SSc, triggered by stress or cold has variable duration and severity, generally lasts <20 min upon trigger
removal, but can endure hours or days, or establish a new baseline severity upon which exacerbations
occur.
The classic tri-phasic episodes of RP, more noticeable in lesser pigmented populations demonstrates
discoloration with distinct demarcation lines of blanching (white), cyanosis (blue/purple) and then
erythematous (red) phase with rewarming, which can be the most painful phase. Not all individuals
14
Table 6
Key Physical Exam Assessments in SSc Courtesy of T Frech & LA Saketkoo, rights reserved.
Category Assessment Area Observed Finding Comment
CONSTITUTIONAL Nutrition Weight

Fit of clothes
Temporal muscle atrophy
Overall mobility Observation into room, seating,
reaching for coat, bag etc
Use of assist device for
ambulation
HEMATOLOGICAL Pallor Observation Anemia can occur from GAVE,
medication effect, SRC
Lymph nodes Palpation
HEENT
Facial appearance General facial structural Lip thinning Most facial changes are difficult to
features track
a
Telangiectasia See below May indicate increasing
vasculopathy
Eyes Dryness
Conjunctival pallor
Oropharyngeal Oral Cavity Dryness
Sublingual pallor
Dentition/crowding
Oral aperture Aperture diameter in mm
a
Telangiectasia See below Often the first location to appear
Naso-pharyngeal Signs of post-nasal drip (PND), PND and Reflux are micro-
i.e., erythema, “cobble-stoning” aspirated and irritate sensitive
lung tissue causing parenchymal
inflammation and possibly
worsening ILD.
VASCULAR
a
Circulation/RP - color
- coolness
- location
a
Capillaroscopy Positive morphology contributes
- morphology: to diagnosis.
Drop-out Ophthalmoscope or
Hemorrhage dermatoscope easily identify
Dilated (giant) morphologic changes. Nailfold
Tortuous video capillaroscope can mark
Disorganized detailed changes over time.
a
Digital ulcers - number
- location
- depth
- ‘true’ vs friction
- drainage
- infection^
a
Pitting - number
- location
- tenderness
Calcinosis - number Size, draining or not
- location
- consistency (solid v paste)
- tenderness
- infection^
(Acro)-Osteolysis Presence of distal to proximal:
- Digital shortening
- Nailbed tapering from sides
- Nailbed blunting from tip
a
Telangiectasias - count - used for diagnostic purposes
- location (inner lip, face, chest, - followed over time
palms)
- matted v non-matted
(continued on next page)
15
CARDIOPULMONARY
Cardiac Observation Jugular venous distension
Lower extremity edema
Positional chest pain Pericarditis
Auscultation Rhythm, presence of gallop, rub Pericarditis can occur in early
phase dcSSc
Aerobic capacity 6 MWT
Pulmonary Observation Respiratory rate
Depth of inhalation Patients with ILD/PF often ‘splint’
to protect from coughing
Cough with inhalation Possible ILD/PH
Auscultation From apices to bases, from If not hearing breath sounds,
beginning of inhalation to end of instruct patient during exam.
exhalation Splinting occurs commonly in ILD
Listening for crackles, absent to avoid inspiratory cough.
breath sounds Otherwise, consider pleural
effusion
Inspiratory cough
Oximetry SpO2%/Pulse oximetry, at rest and Preferably ear or forehead
exertione e.g. walk to exam oximetry
room. 6 MWT Finger may display results not
reflective of true SpO2
Aerobic capacity 6 MWT for distance Musculoskeletal involvement
may impact results, but overall
6 MWT can reliably tend exercise
tolerance
GASTROINTESTINAL Nutrition As above
Abdomen Observable, palpable distension
MUSCULOSKELETAL
Articular/Peri-articular Joint extension To 180$ PIPs, MCPs, wrists, elbows,
shoulders, knees, hips, ankle
joints
Joint flexion Fixed contracture (yes/no)
Finger-to-palm
Tenderness ± swollen Palpation especially PIPs, MCPs, Synovitis is even more difficult to
joints wrists appreciate in SSc than other CTDs
Tendon Friction Rubs Localization for documentation
Muscle Observation Mobility Muscle involvement is:

- common in SSc
- of variable and combined
pathology: atrophy,
inflammatory, necrotic, fibrotic
- associated with SSc cardiac
involvement
Atrophy
Strength/Endurance MMT 5 or 8y
Functional Index-2 (FI-2)^ Endurance is a more revealing
FI-3-2y^ assessment and more
problematic for SSc patients than
isometric strength. Usually
performed by physiotherapist.
Functional capacity TSTôr 30-sec CSTy^
SKIN General Appearance Pigmentation:
- Hyper-
- Hypo-
- Poikiloderma
Sheen:
- Across chest
16
Telangiectasias (here or detailed

in ‘vascular’ domain)
Breakdown Ulceration
- Digital
- Other areas
Pitting
a
Thickness: Extent and mRSSy Skin thickness may also impair
Degree ROM
Phase of Thickness - Edematous v Bound-down Edematous phase can cause
- Initial signs of edematous phase diffuse pain and itching and often
often include puffy fingers; before mistaken as fibromyalgia.
skin thickening occurs
Stretching may reduce
inflammation, edema,
contractures and skin tightness of
hands, fingers, shoulders, chest,
hamstrings and hips; as well as
increase ROM.
a
Indicates SSc classification criteria marker, Înfection ¼ assessing for redness and purulence, ^see corresponding photo/s
yplease see resource list for instructional contentîmplemented by PT, OT but can be performed in clinic by physician or staff z
experience tri-phasic attacks, but some degree of blanching which may be difficult to notice in highly
pigmented patients, supports a RP diagnosis.
While Primary RP may affect healthy individuals or be familial, SSc-RP vascular patterns are
uniquely associated with vascular injury and vasculopathy. As previously mentioned, ANA presence
with abnormal capillaroscopy predict CTD occurrence [13]. Similarly, puffy fingers, SSc-specific anti-
bodies, and abnormal capillaroscopy are highly predictive for the development of SSc [57].
The impact of RP events on vital organ vasculature or hastening PAH, is lesser known, but patients report
that episodes can result in systemic symptoms of whole-body heat loss, debilitating fatigue, headache in
addition to worsening pain of DUs and calcinosis [55,56,58]. Thus, RP worsens diffuse, diverse disability,
making recurrent preventive counselling imperative, with non-pharmacological therapy, e.g., electrical
heated gloves and treat-to-target pharmacological therapy often required [54,56,58e60].
B. Pain in SSc is often multifactorial requiring careful discernment to address coinciding diverse,
modifiable causes. SSc pain can be an overwhelming prospect for the clinician resulting in inaccurate
“fibromyalgia” diagnoses [61]. Careful characterization of each pain type the patient is experiencing is
critical towards determining the most appropriate treatment (Table 8). For example, inflammatory pain
can manifest as either diffuse subcutaneous edematous tenderness, or skin-tightening, often with
accompanying pruritus, neuropathic pain from small nerve fiber disruption, or as joint tenderness,
stiffness or aching, or even myalgias possibly requiring systemic treatment [56,62]. While fibrous
shoulder tendinopathy might require targeted physical therapy.
The presence of tendon friction rubs (TFRs), another source of pain from inflammation and tendon
sheath irritation, indicates active cutaneous or inflammatory disease that without appropriate treatment,
portends a poor prognosis including worsening skin and risk for SRC [38,62,63]. Thus, careful tendon
examination is necessary, and ultrasound can helpful to assess for active joint inflammation and risk for
disability [63].
Vascular complications such as ischemic RP, ischemic digital ulcers and calcinosis cause significant,
and sometimes constant, pain even at rest [55]. Increased intensity of pain and local tenderness may
also signal concomitant infection; however, calcinotic lesions are frequently painful in the absence of
infection depending on location. Large lesions can occasionally lead to nerve impingement resulting in
neuropathic pain symptoms.
Pain and discomfort related to the GI system in SSc is diverse. Dry mouth, oral thrush, odynophagia
from esophageal candidiasis, abdominal pain, and cramping from obstipation or distention are
17
Table 7
Vascular history, physical, counselling, therapeutic considerations. (Table courtesy of T Frech and LA Saketkoo, rights reserved).

Manifestation Initial History Current & Past Symptoms Physical Exam Counselling Considerations Therapeutic Considerations
Function/Self
Esteem
Raynaud (RP) - 1st RP recollection - Pain sensation quality and - Impact on - Acro-osteolysis - Stress management - See table below for medications
- Provoking factors intensity (numbness, social life - Warming measures
- Location tingling, burning stinging, - Impact on - Discontinue exacerbating
- Frequency pain) employment medications
- Pain - Location (ears, nose, - Avoid tobacco
- Duration of attack fingers, nipples, toes)
- Medication use - Frequency
- History of: - Color changes
Gangrene,
Surgical amputation,
Sympathectomy,
Botox injections
Digital Ulcers - Location* Severity of Pain Impact on - Number - Identifying - RP prevention
- Number - Infection social life - Location critical digital ischemia - OT
- Concurrent infection - Size - Impact on - Size - Wound care
or gangrene - Location employment - Infection - Salves
- Duration - Frequency - Gangrene - IV prostacyclin
- Duration - See table below for medications
18
*Ulcers can appear in other locations

Pitting - Location - Pain - Impact on - Number Protective measures
- Pain - Numbness social life - Size
- Location - Impact on
- Frequency employment
Calcinosis - Location - Pain – Impact on - Number - Measures to protect site - RP treatment
- Pain - Drainage social life - Size from trauma - RP prevention
- Drainage - Location - Impact on - Location - Surgical options - Trauma prevention
- Surgical needs employment - Attachment to - Surgical removal
- Impact on tendons, ligaments, - Possible IV prostacyclin
joint function muscle planes
or contractures
Telangiectasia - Location - Location - Impact on - Number Cosmetic - Laser beam therapies
- Change in number - Treatment social life - New lesions from last options
- Impact on exam
employment - Location
Erectile Impact on self- Aerobic exercise may help, Referral to ED specialist, aerobic exercise
Dysfunction esteem, attention to cold
(ED) intimate life prevention may help e.g.
core warmth
GAVE - See below
PH - See below
common pain sources that patients experience. Opioid analgesics require careful consideration for
worsening SSc-symptoms, e.g., sicca, GI motility, with initiation of preventive regimens being
important.
C. Fatigue in SSc, another potentially overwhelming clinical consideration, impacts all areas of daily
living, work, parenting, and social participation. There are many types of fatigue: mental/cognitive,
motivational, physical, muscular, general, etc. Although a nonspecific symptom, fatigue can be evi-
dence of several serious SSc complications such as GI bleeding, ILD, or PH. Fatigue may also reflect
worsening inflammatory disease, malnutrition, poor sleep quality, gastroesophageal reflux (GERD), or
the burden of decreased physical function. Further, dyspnea and cough episodes with longer recovery
times are exhausting symptoms with high calorie demand and psychological burden. An organized
approach to assessing and addressing fatigue can guide investigation.
Sleep disordered breathing risk is significantly elevated in SSc and beyond inducing fatigue likely
impacts cardiopulmonary health [64,65]. Epworth Sleepiness Scale and the STOP-BANG questionnaire
help identify those patients at risk for OSA and qualify for a sleep study. If warranted, CPAP use im-
proves fatigue and potentially prevents SSc cardiopulmonary and esophageal complications [66].
However, as with breathlessness, fatigue in SSc can result from commonplace co-morbidities requiring
investigation, such as hypothyroidism and coronary artery disease.
D. Breathlessness and Exercise Intolerance in SSc is often multifactorial and can be related to
myriad, sometimes severe, complications beyond cardiopulmonary involvement, and like fatigue re-
quires thorough investigation. Breathlessness is the most common symptom of ILD, PH, and myocardial
disease. However, its development is often quite subtle, and patients may not recognize or explicitly
complain of dyspnea. Careful questioning of patients' activity and changes in activity over time is
necessary to determine if there has been a significant change (Table 9). Careful historical probing may
reveal a history of decreased exercise tolerance, changes in the intensity and duration of daily activities
and an unconscious slowing of movement. Further these changes may be apparent to patients’ loved
ones when not overtly apparent to the patient themselves. Therefore, screening requires physicians
asking appropriate questions and patients recognizing changes to determine if dyspnea is present.
Dyspnea or coughing with deep inspiration or activities that engage deeper inspiration such as
laughing, sneezing walking-talking suggest a restrictive process like ILD [67e70]. ILD, PH, anemia,
heart involvement, physical deconditioning, and anxiety are common causes of dyspnea in SSc and are
not mutually exclusive (Table 10).
E. Cough in SSc, the second most common symptom of ILD, is associated with increased ILD severity
and worse HRQoL [7,8]. Cough, though, is often multi-factorial and requires careful historical assess-
ment to differentiate the causes, e.g., ILD, reflux, post-nasal drip (PND), or sinus problems. A dry,
inspiratory cough limiting inspiratory depth is often ILD-related and can trigger frightening, embar-
rassing, exhausting and inconvenient episodes dyspneic coughing that usually have prolonged re-
covery phases [67e70]. Patients often restrict inspiration to prevent this from happening [67e70]. The
quality of cough varies in patients with SSc-ILD with >50% of patients reporting a cough productive of
sputum [8,71].
Dysphagia and GERD with micro- or macro-aspiration may produce a wet, post-prandial, or early
morning cough that often clears or lessens during the day, but recurs at night. However, a dry cough
related to GERD can also occur from pulmonary irritation. SSc-ILD patients with GERD reported cough
significantly more frequently than SSc-ILD patients without GERD [8]. PND can also cause a wet or
throat-irritating cough. Cylindrical bronchiectasis, weakening of bronchiole walls creating mucous
stasis and sub-acute infection (as opposed to traction bronchiectasis, an extrinsic force causing bron-
chial distortion often seen on HRCT in ILD) is not uncommon in CTDs often occurring with productive
cough that comes and goes, and often improves with antibiotic therapy.
System-based symptomatology and management
A. Gastrointestinal System manifestations occur in virtually all SSc patients from the oral cavity
through the lower GI tract and anus (Fig. 5). Gastrointestinal symptoms are associated with higher
patient-perceived disease severity and lower HRQoL when compared with traditional SSc severity
measures (PH, ILD, renal and cardiac) [54,56]. Multiple and diffuse morphological and functional GI
19
Table 8
Modifiable causes and treatment of fatigue and pain in SSc. (Table courtesy of LA Saketkoo, rights reserved.)
Symptom System/Origin Potential Causes Team Involvement/Interventions
Fatigue Anemia GI loss, chronic inflammatory

disease
Cardiac PH, diastolic HF, CAD, physical PT and PR teach adapted aerobic and
deconditioning muscular exercises, and breath pattern
training
OT teaches energy conservation
strategies such as pacing, prioritizing
and accommodating devices
Respiratory PH, ILD, OSA OT, PT, PR as for cardiac
Muscular Low muscle endurance, muscle MT, MMM, PR-PTr, PT for Aerobic
strength or reduced aerobic exercises, muscle strengthening and
capacity endurance exercises, education
Systemic inflammation Effects on hypothalamic axis, Immunosuppression, exercise
causing systemic malaise,
effects on muscle
Psychological Anxiety, depression, fear, MT, MMM, PR-PTr, PT, OT, Breath
impact of reduced self-esteem pattern training, Psychologist, Social
and self-image Worker
Neurological Pain: ischemic, edematous skin, Assess treatable causes, MT MMM, PR
articular, restless leg syndrome
Malnutrition Weight loss, malabsorption Dietary and nutritional counselling
Sleep-related OSA, nocturnal pain, pruritus, SH, RSS, MMM, MT
GI symptoms, depression,
anxiety, steroid or opioid use
Medication-Related Methotrexate, MMF, nintedanib
etc.
Pain/Dysesthesia Vascular Raynaud EC preventive strategies, MT,
vasodilators, PT for aerobic exercise to
improve blood flow
Sympathectomy for critical ischemia
Digital ulcers EC wound care, protective dressing,
anesthetics, OT for daily activities, MT,
PT as for RP
Calcinosis As above, UTPRM: soaking for relief
Infected digital ulcers/calcinosis EC red flags, Aerobic exercise to
improve circulation
Dermal Skin tightening PT, ST, OT for stretching and
manipulation
Subcutaneous edema and MT,ST, OT as above
pressure
Pruritus MT, SH, ST, opioid receptor blocker,
phototherapy
Musculoskeletal Myopathy/Myalgias MMM, OT, PT, PR-PTr, for strength,
endurance and anti-inflammatory
effects of exercise
Fibrous tendinopathy MMM, OT, PT, THE as above
Inflammatory arthropathy/ MMM, OT, PT, ST, local injections,
tendinopathy muscle strengthening, stretching,
targeted hand exercises
Secondary fibromyalgia MMM, PR-PTr, SH, education
Gastrointestinal Heartburn EC, RH, NH, anti-acid and PPI
Abdominal cramping See below
Abdominal bloating
Genitourinary Dyspareunia Pelvic floor therapies, sometimes
systemic treatment
Vaginal dryness Lubricants, topical estrogen
Erectile dysfunction Vasodilators, PT for aerobic exercise,
specialist referral
20
Abbreviations: AG ¼ anticipatory guidance, ATT ¼ assessment with targeted treatment, EC ¼ education /counselling,
DHS ¼ dental hygiene strategies, ILD ¼ interstitial lung disease, MMM ¼ mindful movement modalities (e.g. gentle yoga, tai chi
etc), MT ¼ mindfulness training strategies, OSA ¼ obstructive sleep apnea, OT ¼ occupational therapy, NH ¼ nutrition hygiene
(EC on attention to selection, volume, texture, preparation, combination strategies of foods), PAH ¼ pulmonary arterial hy-
pertension, PPI ¼ proton pump inhibitors, POS ¼ practical organizational strategies, PT ¼ physiotherapy, RH ¼ reflux hygiene
(including head of bed elevation), RHS ¼ refer to hand specialist, RME ¼ refer to motility expert, THE ¼ targeted home exercises,
PR ¼ pulmonary rehabilitationist, PR-EC ¼ pulmonary rehabilitation educational component, PR-PTr ¼ PR physical training
component, RSS ¼ refer to sleep specialist, SH ¼ sleep hygiene, SR ¼ specialist referral, ST ¼ systemic treatment,
UTPRM ¼ untested patient-reported management[10]
Table 9
Screening questions to help patients reflect on potential onset and changes in dyspnea and cough. Courtesy of LA Saketkoo,
rights reserved.
Dyspnea screening Cough screening for ILD
Do you notice being more short-winded now than one Have you been coughing? More in the past 3/6 months?
month ago, six months ago, last year while doing activates
(consider likely activities for the patient)?
Do you notice it takes you longer to vacuum, mop, make the Do you cough when taking a deep breath in?
bed, mowing the lawn?
Do you notice that you need to take more breaks when
vacuuming, mopping, etc.
Do you notice you are becoming more short of breath when Do you cough with laughing or sneezing?
vacuuming, making the bed, mowing the lawn?
Are you able to keep up with family members/peers when Do you cough while talking?
walking?
Do you feel they slow their pace for you?
Do you find it difficult to walk and talk at the same time?
Do you feel that bending over takes your breath away? Does coughing make you feel short-winded?
Table 10
Common causes of dyspnea and cough in SSc. Courtesy of LA Saketkoo & MB Scholand, rights reserved.
Dyspnea Cough
ILD ILD e dry inspiratory

Pulmonary Hypertension e any or any combination of the PND e possible drip sensation, often in morning, sore throat
following: Groups I, II, III, IV
Bronchiectasisa Bronchiectasisa
Cardiac dysfunction or arrhythmia Heart failure
Anemia GERD e can be ‘wet’ cough/gastroparesis
Physical deconditioning
Intrinsic or extrinsic myopathy e.g. restrictive truncal skin
involvement (carapace chest), accessory muscle
myopathy
General population considerations: CAD, COPD
Disordered breath patterns
a
Bronchiectasis can be either traction (extrinsic pulling and distortion of the bronchioles often seen in pulmonary fibrosis on
HRCT) or cylindrical (laxity of the bronchiole wall either due to infection or perhaps CTD itself, creating a stasis environment for
bacteria; cough is often productive).
abnormalities result in high degrees of symptom distress, life disruption and diminished HRQoL. These
destructive changes are hypothesized to result from progressive sub-/mucosal inflammatory-fibrotic
infiltration and vascular insufficiency, leading to neuronal dysfunction, and subsequently to dys-/
non-motility.
Oro-maxillary and pharyngeal structural changes with painful or difficult mastication and swal-
lowing; esophageal dysmotility with dysphagia; malnutrition from malabsorption or decreased intake;
21
22

Fig. 5. Depiction of the diffuse nature of gastrointestinal involvement in SSc. Courtesy of T Frech, rights reserved.
gastroparesis with bloating, nausea/emesis; colonic inertia with constipation; bacterial overgrowth
with bloating, abdominal distension and diarrhea; and loss of anal sphincter tone resulting in fecal
incontinence. Dysmorphic surface vessels, vulnerable to abrasion, such as arteriovenous malforma-
tions and gastric antral vascular ectasia (GAVE), may cause symptomatic anemia with dyspnea/fatigue
due to slow or rapid blood loss.
Patients express frustration that despite extent and severity of GI manifestations in SSc, rheuma-
tologists generally avoid GI-related discussion. Anecdotal clinical evidence and patient discussions
support that systemic treatment in early SSc disease e as with ILD - may prevent or reverse GI
symptom progression.
While esophageal involvement is the most common aspect of GI involvement, weight loss, diarrhea,
and fecal soilage can indicate the presence of small bacterial overgrowth requiring treatment [72].
Additionally, micronutrient deficiency and malnutrition is a concern in SSc and patients’ appetite and
dietary intake should be assessed [43]. Working closely with a dietician and gastroenterologist to help
guide diagnostic and therapeutic interventions can help with the management of SSc GI involvement
[73].
Gastroesophageal Reflux Disorder (GERD), a manifestation with far-reaching detrimental effects on
the esophagus and the lung, demands dedicated robust attention. The ongoing injury caused to the
esophageal mucosa puts patients with SSc at higher risk of pre-malignant and malignant injury, as well
as structural abnormalities such as webbing, scarring, and the development of strictures. The injury to
associated neuromuscular complexes results in dysphagia and poor acid clearance. The absence of
heartburn or regurgitation are often discordant with endoscopic findings of esophageal injury and pH
testing. Prior to proton pump inhibitor (PPI) introduction, inability to eat from severe esophageal
dysfunction, was a major cause of malnutrition and mortality. The advent of PPI use, effected a sig-
nificant decrease in esophageal strictures. Further, the extent of ILD and lung parenchymal inflam-
mation is associated with degree of GERD and uncontrolled GERD, and hypothetically PND poses a
similar concern. Chronic GERD or PND can cause hoarse voice or dysphonia. Guideline-based care
highlights the value of a multidisciplinary approach and the role for diagnostic testing [74].
Severe GERD may not be symptomatic, as early stages require significant neuronal recruitment and
in later stages nerves may be dysfunctional to pain perception e but ongoing injury will still occur. The
SSc specialist community is largely of the opinion that benefit of empiric PPI use in SSc-GERD out-
weighs the risks. Often, standard dosing of PPIs may require increased frequency and possibly addition
of other agents such as histamine-2-blockers (H2-blockers), e.g., famotidine, or coating agents such as
sucralfate. Use of these therapies may require attention to timing of administration to avoid drug-drug
interactions [75].
However, it is essential that anti-reflux measures are thoroughly explained and strictly practiced.
This includes: elevation of the head of the bed to 60 degrees by wedge pillow, mattress elevation,
bricked bed legs or automatic adjustable bed; and avoidance of right-side sleeping as gastric contents
will spill back toward esophagus. For patients using CPAPs, we underscore that adherence can help to
suppress reflux [66].
B. Cardiopulmonary involvement
Pulmonary involvement in SSc

ILD and PH are the leading causes of SSc-related death. Identifying these entities early and initiating
early appropriate treatment prolongs survival [2,9,10]. Initial screening in all SSc patients with pul-
monary function testing (PFTs) including diffusion capacity of lung for carbon monoxide (DLCO) and
high resolution CT scan (HRCT), as well as exercise tolerance are key to detecting important changes
that reflect developing cardiopulmonary involvement (Diagram 1).
It is essential in SSc care to recognize that 1. ILD behavior is variable across patients (e.g. stable,
slowly progressive, rapidly progressive), can change over time and requires an individualized and
vigilant approach, 2. ILD and PH often coexist, combined PH/ILD occurs much earlier in patients of
African descent, 3. Patients with SSc are vulnerable to developing: a) either PH WHO Group 1, 2, 3, or 4,
each requiring different therapeutic approaches b). Coexistent PH group types (e.g. combined WHO
Groups 1 PAH and 2 diastolic dysfunction, combined WHO Groups 1 PAH and 3 ILD), 4. Screening,
23
Diagram 1. Proposed Screening and Monitoring Algorithm for Clinically Significant SSc-ILD. Courtesy of LA Saketkoo, rights reserved.
detection, characterization of PH Group type, and initiation of appropriate treatment demand adher-
ence to clinical diagnostic algorithms and tracking of patient symptoms (Table 11).
Though, without formal consensus amongst SSc specialists, HRCT is the gold standard to screen for ILD
in SSc. Numerous studies demonstrate that PFTs are inadequate in detecting ILD in this population,
particularly in the early stages [71]. However, insurance constraints may limit the ability to obtain HRCT
in a limited cutaneous, asymptomatic patient with normal PFTs. Follow-up PFTs with careful trending are
crucial. Repeat HRCT is indicated for unexplained symptom changes (dyspnea, cough), PFT worsening
(drop "10% in FVC or 5e10% fall in FVC with "15% decrease in DLCO) to investigate co-existent infection
or malignancy versus progressive ILD. Bronchoscopy is reserved for co-existent concern of infection or
malignancy. Lung biopsy is not warranted for diagnosing SSc-ILD in patients with SSc with a typical HRCT
pattern i.e. usual or non-specific interstitial pneumonitis (UIP or NSIP).
Documenting serial PFT data along with temporally coincident medication dosing and any
contextual factors that might explain an aberrant PFT performance on that day (e.g., sinusitis or al-
lergies) is an essential investment in the care of SSc patients. Charting the trajectory beginning from the
first available PFTs affords insights into disease behavior, e.g., rapidly progressive vs. stable vs. slowly
progressing ILD [76]. Furthermore, it can prevent the clinician from overlooking progressing disease in
the context of normal range values, as a 5% decrease in FVC over 6 months (or 10% annually) despite
normal values warrants investigation and possible modifications or additions to treatment.
Though serial FVC is considered a reliable reflection of restrictive lung disease, DLCO can be a key
differentiator between parenchymal versus vascular lung disease, and provide an early detection
mechanism for pulmonary hypertension. While FVC reflects restriction related to parenchymal lung
disease, DLCO reflects the ability of gas to cross from airspace to bloodstream which requires gas to
diffuse across two barriers: the lung parenchyma and also the blood vessel wall (Fig. 6). If either or both
are resistant to permeable gas, as can occur in SSc-ILD or SSc-PH this will cause reduction in DLCO. In
parenchymal disease the FVC and DLCO commonly trend downward in parallel; while in vascular disease
the DLCO has a much steeper decline than FVC (Fig. 7). However, early in the course of SSc-ILD, the FVC
may be normal, while the DLCO is often decreased. Over the course of SSc, the FVC:DLCO ratio may help
distinguish pulmonary vascular disease from progression of SSc-ILD with a higher ratio suggesting a
predominant pulmonary vascular process [77,78]. Therefore, in addition to yearly screening echocar-
diogram (ideally at rest and with exercise), DLCO is an important indicator of pulmonary vascular
involvement.
24
Table 11
Screening and characterization of pulmonary hypertension in SSc. Courtesy of LA Saketkoo, rights reserved.
Cardiac Involvement in SSc

Cardiac Involvement in SSc may result from microvascular insufficiency, or inflammatory-fibrotic
infiltration of the myocardium, causing arrhythmias, diastolic or systolic dysfunction, pericarditis, or
myocarditis which are managed similarly to non-SSc cardiac complications. Cardiac involvement was
often found to be associated with SSc-myopathy in several studies [79e83]. SSc-specific treatment is
yet unclear and likely depends on suspected disease activity. Baseline/annual echocardiogram serves as
a comparison should cardiac problems or PH develop later. Non-contrast cardiovascular magnetic
resonance (CMR) demonstrates 45% prevalence of myocardial fibrosis unexplained by other causes and
often associated with diffuse skin involvement and elevated ultra-sensitive CRP; CMR may play a role
25
26

Fig. 6. Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) Measures the Ability of Gas to Transfer Across Two Pulmonary Barriers: Parenchyma and Vascular (illustrations courtesy of LA
Saketkoo, rights reserved.).
Fig. 7. DLCO behavior in ILD versus PH Predominance. The closer the ratio of FVC:DLCO is to 1 the more likely abnormal DLCO
changes are related to restrictive lung disease. (illustration courtesy of LA Saketkoo).
in early diagnosis [79,84e86]. Additional serum biomarkers that are commonly followed as predictors
of onset and worsening are NT-Pro-BNP and uric acid, of which NT-Pro-BNP has demonstrated reliable
properties.
Routine cardiovascular risk reduction with blood pressure monitoring and lipid screening is
encouraged in SSc patients.
When to consider transplantation

Despite prior misconceptions of worse outcomes for patients with SSc (for ILD, PH, or both)
compared to those with non-SSc lung disease, lung transplantation in SSc is safe, with similar survival
outcomes. Lung transplantation is reserved for patients whose lung disease progresses despite
maximal systemic therapy. (Table 12). Early referral for transplant evaluation permits time for patients
and caregivers to become familiar with the transplant process, make informed unhurried decisions,
and adjust to psychosocial and financial pressures related to transplant.
Most common barriers to lung transplant in patients with SSc can be overcome (Table 13). Physical
conditioning is an important factor in transplant selection and successful post-transplant recovery.
Early referral gives patients who are deconditioned an opportunity to engage in healthy lifestyle
changes and home fitness practices supported by pulmonary rehabilitation.
Table 12
When to consider referral for lung transplant.
Diagnosis Indications for Referral
Interstitial lung disease ! Radiographic or biopsy proven disease

! FVC % 80%
! Need for supplemental oxygen
Pulmonary hypertension ! Severe functional limitation with NYHA functional class III or IV
! Rapid decline in functional status
! Decreasing 6 MWT
! Increasing oxygen requirements
! Need for intravenous therapies
Myocardial disease ! RV failure without evidence of RV infarction (isolated RV failure related to pulmonary
hypertension [any WHO class] recovers after lung transplant)
! Irreversible LV involvement, heart-lung transplant evaluation may be warranted
Abbreviations: 6MWT, 6-min walk test; FVC, forced expiratory volume; LV, left ventricle; NYHA, New York Heart Association;
RV, right ventricular; WHO, World Health Organization
27
Table 13
Common challenges of lung transplant evaluation in patients with systemic sclerosis.
Challenge Considerations
Obesity ! BMI <35, preferably <30 and transplant center dependent

! Early counselling regarding healthy weight
Age ! Highly variable and transplant center dependent
Frailty/Deconditioning/Post-transplant ! Pulmonary rehab participation
rehabilitation potential ! Frailty Assessment Score
! Chronic pain/Advanced osteoporosis
Active substance abuse/dependence ! 6 months sobriety with only rare exceptions
! Participation in counselling
Esophageal dysmotility ! Full evaluation of esophagus
! GJ tube for full nutritional support may be recommended, assessment for
willingness and compliance
History of malignancy ! Time free from malignancy is multifactorial and transplant center dependent
Social support ! Identify 24-hour caregiver for at least 3 months
! Some transplant centers also require a committed back-up caregiver
! Caregivers will be evaluated for appropriateness
Finances ! Financial counselling to establish ability to afford transplant
! Fundraising may be required/recommended
! Insurance clearance required before evaluation is initiated
Abbreviations: BMI, body mass index; GJ, gastrostomy-jejunostomy
Table 14
Common Therapeutic and Surgical Referrals Resourced in SSc Care. Cultivating referral relationships with colleagues who
are interested in SSc may have best outcomes for people living with SSc.
Therapeutic/Surgical Indications
Occupational Therapy For hand, face and oral health

Joint and skin mobility
Self-management, breath pattern training
Home and work adaptations
Hand Surgery Early referral (to establish therapeutic relationship under non-urgent
Vascular Surgery conditions) for patients at high risk for vascular or wound complications
including:
Critical ischemia
DUs/calcinosis complicated by infection
Calcinosis complicated by nerve entrapment
Macrovascular occlusion
For procedures including sympathectomy, botulin toxin injections
Physiotherapy For building muscle strength, muscle endurance and aerobic capacity
Increasing physical capacity and activity
Balance, joint/skin mobility
Education on fatigue and pain
Pulmonary Rehabilitation For enhancing aerobic capacity, endurance and education on cardiopulmonary
efficiency
Includes Singing, Yoga, Dance for Lung Health programs
Dental care/Oral surgery At least twice yearly
Access to pediatric dendistry is a consideration
Dry mouth care
Preservation of dentition
Speech For swallowing, mouth strengthening exercises and speech production
Nutrition/Dietetic Care To enhance calorie intake, detailed counselling on gastroparesis and food
tolerance strategies
Wound Care Management of DUs, calcinosis
Hyperbaric Therapy For DUs, avascular necrosis, general wound healing
Psychological Support and Counselling For managing anxiety, depression, impact of changing appearance on body
image and self-esteem
Developing coping skills to manage changing ability, uncertainty
28
Fig. 8. The Renal Crisis Prevention Card may help patients direct emergency healthcare providers to abort a crisis and avoid adverse
outcomes [83].
Potential transplant candidates with SSc undergo extensive testing to identify needed interventions for
SSc manifestations that might overtime injure the allograft, e.g., partial/modified Nissen fundoplication for
severe GERD or heart-lung transplantation with coexistent irreversible myocardial disease. Severe
esophageal dysmotility or GERD (lower esophageal sphincter incompetency) lead to chronic aspiration
which poses significant risk for acute and chronic allograft rejection, may also warrant GI tube for nutrition
post-transplantation.
C. Muscle Involvement in SSc is under-recognized, prevalent and multifactorial. It ranges from
atrophy, inflammatory, vasculopathic, fibrotic to necrotic pathology. Both muscle strength and
endurance in proximal muscles are commonly reduced, especially in patients with significant lung
disease [86]. Systemic treatment and exercise can improve SSc myopathy, with physical therapy that
targets strengthening and prevention of large joint contracture, particularly in the shoulders (Table 14).
Consideration of medication-related myopathy culprits, such as statins, steroids, and hydroxy-
chloroquine, is a mainstay of assessment. SSc-myopathy predicts SS-related cardiac involvement
[79,82e85].
D. Hands in SSc are especially subject to diffuse morphological changes, impairment, and pain due
to inflammation, vasculopathy and fibrosis. These pathological processes result in bony, periarticular
and cutaneous destruction with infection, ulceration, calcinosis, acro-osteolysis, flexion contractures,
29
Table 15
Essential counselling on exercise in SSc. Note: in many countries, physiotherapists also teach breathing exercises to optimize
breath patterns and strength of breath. General exercise applications are also a part of cardiopulmonary rehabilitation programs.
EXERCISE GENERAL STRETCHING RESISTANCE AEROBIC MONITOR

APPLICATION
GENERAL
Both upper and lower Ideally >15 reps for 3 Warm-up and cool- At least initially with PAH
extremities with sets at least twice a down important and/or ILD: SpO2, heart
dedicated focus on week esp PAH, treadmill, rate, blood pressure.
areas with impaired To gain muscle mass ergometer cycle Dyspnea and muscle
range of motion (e.g. To preserve overall Ideally 30 min, 3 tiredness with Borg CR-10
shoulders/pectorals, muscle strength days/week and exertion with Borg RPE
calves, hamstrings and
external rotators in
hip).
Easier to do when
warm, after exercise or
sauna
OROFACIAL
Emphasize Isometric-hold positons N/A -use ruler to monitor
-mouth opening - see resources - see resources section
-facial grimaces such as
smile, pucker lips, etc
HANDS
Emphasize -Squeezing foam, N/A Hand tracings:
-Flexion MCP and IP dough, putty - In extension
joints -Finger extension with - In fist
-Extension PIP joints rubber bands/putty for Grip and pinch strength
-First commissure resistance - see resources section
-Finger web spaces -Rolling out dough/
(interdigit) putty with finger
-Wrist flexion and -Pinch with foam,
extension dough, putty (finger
tips to thumb, thumb to
side of index finger)
Heat modalities prior to
stretching enhances
practice (e.g. paraffin
wax, warm water, etc)
Abbreviations: N/A ¼ not applicable, MCP ¼ metacarpophalangeal joint, PIP ¼ proximal interphalangeal joint.
synovitis, tendinopathy and amputation. Arthritis, contractures, tendon friction rubs come early during
the disease course, therefore require early intervention. The role of hand exercises in SSc is critically
important. Exercise improves circulation, healthy vascular and skin repair, increases warmth, reduces
local inflammation and stiffness, and very importantly, increases muscle strength and hand function.
Preventive strategies to maintain hand warmth may help to prevent further vascular injury (Table 14).
E. Renal Involvement in SSc: prior to the availability of Angiotensin Converting Enzyme (ACE)
inhibitors renal crisis was the leading cause of death in SSc. Early intervention with ACE inhibitor
therapy and rapid control of blood pressure may abort a “crisis” and minimize renal damage. However,
with close monitoring of high risk patients including prednisone use >10 mg/day, abrupt and severe BP
elevation, presence of anti-RNA polymerase III, we can identify and aggressively treat SRC. Late
recognition, delayed or inappropriate therapy persist and result in renal failure and other complica-
tions of malignant hypertension. Despite progression to end-stage disease, with continued treatment
with ACE modulation, renal function may return months even after initiating dialysis. Educating pa-
tients at higher SRC risk on warning signs and plan of action is crucial to improving outcomes, including
consideration of home blood pressure monitoring, and providing the “renal crisis prevention card”
(Fig. 8) on a patient's first visit for use in emergent situations [87].
30
Table 16
Key Elements of Recurrent Counselling (Courtesy of LA Saketkoo, rights reserved).
Category Sub-Category Item Advisements for Patients
VASCULAR
Raynaud Prevention is key - Related complications include DUs, calcinosis,
osteolysis and core temperature loss
- Initiate protective measure in anticipation of and upon
noticing a cold atmosphere, before allowing oneself to
‘feel’ cold
- Immediate action can result in decreased recovery
time, pain and the sequela associated with loss of core
warmth (fatigue, headache, incapacity etc.)
- Avoid extreme temperature changes, e.g. from cold to
warmth
- Anticipate cold environments, e.g. air conditioning in
summer, grocery store freezer aisle, hospitals etc.
Core Temperature - Exercise/movement increases circulation and body
heat
- Clothes layering and use of insulated vests
Peripheral - Gloves/socks always at hand
- Should allow for a thin space to trap a warming layer
of air
- Pocket hand warmers, can be placed in pockets, gloves,
socks, undergarments
- Heated gloves/insoles/shoes
Digital Ulcers/Calcinosis Protection Cushioned bandages for high friction areas
Waterproof gloves for washing or handling wet items
Bandage and gloves for handling dry household items
potentially snagging healing ulcers and to protect from
bacteria and chemical irritants
Exercise gloves for use of gym equipment
Pain management - Protection as above - Topical lidocaine
- Cleansing routine
Signs of infection - Increased pain/tenderness
- Redness
- Purulence
Prevention As much as possible avoid:
- Cold exposure
- Trauma
Topical antibiotics with signs of infection
Additional calcinosis Advisement - Avoid digging to prevent infection
- If intolerable can try repeated soaking in warm Epsom
salt water
- Topical antibiotics
Erectile dysfunction - Increased physical activity may help protect
circulatory and neuronal function
- Preventive measures as for RP might have a protective
effect
NUTRITION
Calorie intake Nutritious - Avocado
- Nuts, nut butters
- Cheeses, butter
- Potatoes, rice
- Olive and other oils
Food Tolerance Nutritious - Pureed foods (soups, dips, stews)
- Smaller amounts of a food
- Foods softened (marinated) with small amounts of
citrus or vinegar
- Mobility after eating to increase motility
HEENT
Oro-facial Facial Exercises and Massage for skin tightness, mobility
and circulation
Oral
(continued on next page)
31
High risk for dental complications:

- Essential follow-up with a dental clinician sensitive to
SSc care or perhaps pediatric dentist
- Proactive dental care
- Keeping mouth moist
- Adapted and powered devices for teeth and oral care
SICCA Wetting and pro-salivation products
Possibly singing, humming, chanting and exercise
CARDIOPULMONARY
Graded exercise essential to health
Control of GERD and PND to avoid lung injury from
micro-aspiration
Vaccination for prevention of infection
PH and Cardiac Monitor for symptoms Daily weights as needed; recording of post-void
of heart failure morning weight
Alert MD of new onset lower extremity edema
GASTROINTESTINAL
GERD Esophageal Injury &Reflux in SSc is a serious issue of which related injury
Lung Risks can lead to multiple complications that impact
mortality.
- Often exists without pain
- Pain not equate severity
- Esophagitis
- Esophageal cancer
- Dysphagia and potential loss of swallow function
- Strictures & Webbing
- Need for esophageal stretching
- Acid aggravates lung disease
Medications - PPI daily or twice daily, especially with esophagitis or
esophageal ulcer
- Adding PRN or OTC agents (e.g. sucralfate, H2
blockade)
– it is perceived that in SSc the benefits of PPIs greatly
outweigh associated risks
Sleep Essentials - Head of Bed Elevation (wedge pillow, leveraging
mattress, bricks/books under bed legs)
- Avoid right side lying
Reflux hygiene - Smaller, more frequent meals
- Avoid meals 2e3 h before lying
- Avoid sphincter relaxants at end of day e.g. alcohol,
chocolate, caffeine, mint etc.
Gastroparesis - Sleep and hygiene as for GERD
- Exercise/walking may help
- Gravity strategies for passive digestion
- Upright position
- Attention to food consistency e.g. thinner foods
- Gastroparesis dietary suggestions for food tolerance
Bloating - Exercise for motility
- Small frequent meals
Nausea SSc or Medication related - Mobility/exercise to decrease nausea
- Ginger sweets, drink
- Sucking candies
- Cold pops
- Instruction on PRN anti-emetics
Diarrhea SSc or Medication related Logistics until controlled: change of clothes, time
planning
Medication use: risks/benefits/when
MEDICATION See Appendix of Medications
VACCINES
See Table 17 Pneumococcal immunizations per CDC guidelines
Influenza annually
32
Herpes zoster (killed only i.e. Shingrix)

COVID-19
EXERCISE
Improves:
- Circulation and vascular responsiveness
- Body warmth
- Sleep
- Self-Esteem
- Breathlessness
- Joint mobility stiffness and lubrication
- Skin function
- GI function
- Possibly erectile function
- Nausea
- Salivation
- Respiratory performance
- Cognitive clarity
Decreases:
- inflammation
- Pain (anywhere)
- Joint stiffness
- Possibly contractures
- Possibly skin tightness
- Depression
- Stress
- Fatigue
WOMEN OF CHILD-BEARING AGE
Medication toxicity - Use of contraception essential with specific IS and PAH
medications
- Discontinuation of specific IS or PAH medications prior
to conception
Conception - Must be a planned
- Medication washout pre-conception
- Discuss assessing extent of ILD, PH, cardiac or renal
involvement in light of safe pregnancy
Care of children - Adaptations for child care
- Strategies to manage fatigue
PSYCHOLOGICAL
Advocacy/Education Groups
Local support groups
Online self-management program (see resources)
Important non-pharmacological therapeutic considerations
Exercise as an essential multi-modal disease-modifying medicine
Physical function and activity are key predictors of HRQoL and survival. Available evidence on ex-
ercise strongly supports diverse and diffuse benefits of physical activity as a potential cornerstone to
SSc management [88] (Table 15). Exercise reduces inflammation and increases circulation (and body
heat), which address essential drivers of SSc symptoms, in addition to enhancing mobility through
improving strength, stiffness, endurance and aerobic capacity. Physical activity is critical for all levels of
ability and for modulating the biochemical impact of depression/anxiety, stress and physical pain e
while improving self-esteem in a disease notorious for diminished self-image. Exercise's muscle and
vascular benefits likely contribute to its beneficial impact on sleep and fatigue [89]. Increasing physical
activity and reduction of a sedentary lifestyle in SSc is crucial to self-management of multiple SSc-
manifestations, including pulmonary involvement [90]. Patients with SSc desire physician/clinician
counselling and tend to augment their physical activity accordingly. A routine visit should document a
patient's physical activity, counsel on the medicinal effects of exercise and advise that exercise be
33
Box 1
Checklist to Support Shared Decision-Making (Courtesy of LA Saketkoo, rights reserved)
Shared Decision-Making Checklist
, Name the patient's items of concern as presented by the patient and if possible which are
highest priority
, Ascertain patient's thoughts on the potential underlying cause/s
, Name the items of concern from the clinical perspective including short and long-term (e.g.
potential progressive damage, associated abrupt complications etc)
, Respond to patient's perceptions of potential cause in support of & clarifying divergence
from patient perceptions. Remain transparent in what is known, unknown, yet to be known and
that which requires literature research by the clinician.
, Name the treatment options available, including any non-pharmacological with particular
attention those suggested by the patient
, Discuss safety, side effects and efficacy (including anticipated onset) of available therapies
and those suggested by the patient.
, Assess patient expectations of treatment
, Set treatment expectations including prognosis, anticipated degree of symptom/impair-
ments resolution, cure versus slowing progression, disease activity versus damage
Table 17
Routine Health Maintenance in SSc. Courtesy of N Sandorfi, rights reserved.
Immunization HPV (ages 16e26), Influenza (yearly), Hepatitis B, Pneumococcus (at any age with immune
disease), Diphtheria/Tetanus/Pertussis (ages 19e64), Varicella Zoster killed (ages 50 or older),
(*) COVID-19
Age, sex and risk factor Gynecological, prostate, gastrointestinal, skin (*)
based cancer screening Higher risk exists around the time of disease onset for those with anti-RNA polymerase III
positivity (with consideration of breast, lung, prostate and tongue cancer)
General Hypertension, diabetes cholesterol, sexually transmitted diseases (*)
Osteoporosis Women aged 65< or earlier if risk factors exist (special considerations in SSc: malabsorption,
corticosteroid use, prolonged use of proton pump inhibitors) (*)
Ophthalmology Special considerations: sicca symptom related complications, hydroxychloroquine associated
toxicity (**)
Dental Routine exam and sicca symptom related complications (***)
Psychological Chronic disease related psychological conditions (depression/anxiety) (****)
Laboratory Tuberculosis, hepatitis C/B screening related to pharmacological therapies
pleasurable, working up to "30-min/day, 5 days weekly; with hand, face and feet exercises to increase
circulation, mobility and anti-inflammatory profiles regularly reviewed. (See resource list) Further, a
long-term physically active lifestyle improves GI motility and favors enhancement of gut flora [91].
Anticipatory and preventive education
Keys to Patient-Centered Outcomes

Counselling and education (Table 16) based upon models of shared decision-making (SDM) (Box 1)
provide patients with insight into this complex disease as pertains to their circumstances, cultivates
clinician-patient partnership, and increases patient trust, adherence, self-efficacy, and mental health e
all essential to patient outcomes. SDM is an ongoing process requiring time to ensure clinicians un-
derstand and address the patient's perceptions, priorities, and self-management activities of their
disease experience. SDM enables effective palliation and protection against disease progression and
complications. Patients with SSc often feel fearful, scared and isolated especially as families, friends,
and many healthcare providers are not familiar with SSc. SDM and provision of resources on self-
management strategies and support groups are imperative [92,93].
34
Table 18
Patient-centered visit preparations.
Environment
Temperature Cold can be injurious in SSc

Control clinic temperature exposure via either:
- thermostat adjusted to >72F/22C
- or with blankets for dedicated patient use
Patients should be advised to bring clothing layers to maintain warmth for areas outside of clinic
control
Fragrance-free A perfume-free policy maintains a safe environment for patients, family members and clinic
staff:
- fragrance can trigger dyspneic coughing episodes in patients with ILD
- fragrance can impede PFT performance for that patient and other nearby patients or those who
subsequently in the suite
Advisement occurs prior to visit, during scheduling.
Supplemental Many patients with SSc use supplemental oxygen tanks that hold a limited oxygen supply.
Oxygen Availability Upon patient arrival, switching their tank to a clinic tank:
- assures sufficient supply for their visit
- preserves supply for the patient's journey home
If this can't be done, patients should be advised of anticipated length of time at the facility for
which they will need to have sufficient supply.
Wait Times Multiple procedures on a single day can be exhaustive and unanticipated. Helping patients and
families anticipate their needs with the following advisements creates a more comfortable (and
safe) experience:
Nutrition Needs - Bringing snacks and lunch
Hydration - Having water or preferred beverages available
Down time - Reading materials etc. to pass time waiting between tests and visits
Visit Times Assessment, intervention and counselling in SSc that is sufficient to reduce SSc-related
symptoms and complications requires time.
New Patients "90 min but can require 3 h, depending on disease extent, complications and initiating
management
Established Patients 45e90 min as even stable patients with SSc requires multi-organ assessment and SSc-specific
counselling that is beyond a usual visit for most other conditions
Chart Review SSc management is often time-sensitive and relies upon diagnostic testing and symptom history
trended overtime. New patients often require extensive data organization; while Interval
history is often dense for established patients.
Appropriate chart review requires pre-visit attainment of past and interval medical records.
Documentation of serial data points prior to visit facilitates proactive management, freeing up
clinician attention for meaningful patient-centered discussions.
Real-time interventions and counselling may result in:
- fairly immediate relief of some disabling symptoms
- prevention of disease progression
Chart review is reimbursable in the US, whether on same day or other day.
See resources list for medical record intake template and other clinic support documents.
Consolidating Testing Consolidating SSc diagnostic testing in as few visits as possible reduces travel burden,
employment impact on patient and family
Out-patient Past records, pre-visit labs, PFTs, HRCT or echo, ordered prior to scheduled visit, with results
forwarded for clinician review, expedites management during the visit.
Same day SSc-diagnostic testing, prior to clinician visit:
- Common approach at SSc centers: coordinating SSc testing to occur same day, prior to
scheduled visit
In-patient An alternate approach for new and established patients at SSc centers in some countries with:
- Approximate 2 day hospital admission
- All routine SSc diagnostic testing and any further testing as indicated by
- Evaluation and teaching by PT/OT
- Management with counselling over one or both days
Patients also visit as out-patients for interim monitoring, repeat testing
35
Table 19
Quality healthcare provision sufficient to address the most pressing and essential aspects of SSc care and other complex
multi-system disorders, demands time. Accounting for time usage is foundational for reimbursement or, especially for
countries and provinces where complexity is not accounted for, an advocacy metric for policy revision. Using the 2021 policies
from U.S. Centers for Medicare & Medicaid Services is used as an example below, similar constructs may exist in other countries.
Discrete Care Events Stipulations for billing Coding

in the US
Chart Review/Pre-visit If occurs same day as See Clinic Visit Coding Tabulate
Charting/Post-visit patient clinic visitt below time-based
Charting visit coding adding
prolonged visit codes
If occurs on a day other Stand alone codes for - 99358 for 31e74 min
than actual clinic visit non-face-to-face on non-direct patient care
activity
If occurs as a non-visit - 99359 for
consultation each additional
15e30 min i.e. added
for 75e90 min and
again for 104e120
min (maximum)
Clinic Visit No longer requires total Complexity-based See below
time to be 100% ‘face- Time-based
to-face’
Primary code to which
other codes are added
e.g. prolonged clinician
or staff codes
Patient-initiated Telephone or internet- Time-based for 99441 5e10 min
queries based communication communication and 99442 11e20 min
with patient that is tasks related to query 99443 21e30 min
unrelated to a visit 7
days prior nor leads to
visit in next 24 hours
Clinic Staff Time Added to clinic visit 99415 45e74 min
code, for prolonged 99416, each additional 15e30 min
services by staff beyond
the typical time
Clinic Visit Breakdown for Time-based Coding
New Patient Established Patient
99202 15e29 min 99212 10e19 min
99203 30e44 min 99213 20e29 min
99204 45e59 min 99214 30e39 min
99205 60e74 min 99215 40e54 min
Prolonged Visit Coding
99205 or 99215 need to be fulfilled then additional codes may be added:
Codes that may be 99354 additional 30e74 min Possible new 2021 codes CMS Code: G212
obsolete in 2021 99355 for each further Added for each additional 15 min increment AMA Code 99417
15e30 min increments
Routine health maintenance

The medical complexity of SSc often overshadows the importance of routine health maintenance
(RHM). RHM addresses preventive strategies (Table 17) directly related to SSc complications. Vacci-
nations prevent severe pneumonia and influenza in ILD/PH. Age-appropriate cancer screening be-
comes increasingly significant given the higher malignancy risk in SSc particularly with anti-
polymerase III positivity. Screening for cardiovascular disease and OSA may prevent worse outcomes
in those already with cardiopulmonary and circulatory impairment. SSc portends a higher risk of
osteoporosis [94,95] and fractures, and lower vitamin D absorption with chronic PPI use.
Other essential pre-treatment RHM include infectious hepatitis and tuberculosis screening,
consideration of antibiotic prophylaxis, and continued pregnancy planning with females on immu-
nosuppression. As with exercise, keeping RHM as part routine documentation framework will protect
health outcomes in SSc.
36
Practical considerations for patient and clinician support
Pre-visit preparations
Patients require time to be heard and time to hear important concepts related to the condition they
are living with. Protecting one's attention and time to address pivotal patient care issues is crucial to
outcomes when caring for people with multiorgan system disease with diverse debilitating manifes-
tations. Attention to patient environment and comfort, anticipatory scheduling to consolidate medical
appointments and employing operational throughputs, e.g., medical record attainment and chart re-
view that support pre-visit data collection, scheduling for realistic appointment durations (with
appropriate billing) facilitate a greater ease of pivotal communication for patient and clinician (Tables
18 and 19 and resources).
Implementing the plan
SSc is a health condition whereby timely treatment of active disease is key to reversibility of
impairment and prevention of permanent damage, whereby even palliative intervention of irreversible
damage can immediately optimize HRQoL, workability, nutrition, mental health, and physical well-
being and function. Patient education on self-management and engagement with SSc education and
advocacy organizations such as the Scleroderma Foundation, Scleroderma and Raynaud's UK (SRUK),
Federation of European Scleroderma Associations (FESCA), Scleroderma Australia and Scleroderma
India, are central to successful care.
Delays in scheduling diagnostic procedures, therapist and consultant referrals, and treatment
initiation greatly impact patient outcomes. Enlisting an “extended team” of scheduling contacts in
other hospital areas who understand the precarious nature of SSc facilitates teamwork in proactive,
timely and patient-centered scheduling and prior-authorizations.
Prior Authorizations (PAs): Advocacy for streamlining PAs [96] is essential to improve patient sur-
vival and outcomes. Further, denials lead to higher insurance company costs [97], as most clinicians
finally attain authorization [98]. An organized approach can expedite most procedures and medication
authorizations, including an appeal, within 72 h in the US. Correspondence logs to track initiation,
requests for additional information and appeals (see Appendix) streamline response times. In the US,
any licensed health professional (medical assistant, nurse) are considered ‘peers’ in a ‘peer-to-peer’
review; and can obtain approval with increasing efficiency overtime.
The Scleroderma Foundation attained Medicare recognition for MMF as a first-line therapy in SSc
and SSc-ILD. However important treatments, e.g., rituximab, may not initially receive authorization.
However, insurance peer reviewers will advise that adding “co-existent diagnoses” that satisfy
authorization requirements is reasonable, e.g., “seronegative rheumatoid arthritis” or “lupus,” as long
as manifestations (e.g., inflammatory arthritis, ANA positivity) can be supported with documentation
[99] that states “clinical features consistent with___” (co-existent diagnosis). Insurance company re-
quirements for TNF-inhibitors failure before rituximab or tocilizumab, are easily refuted explaining
contraindication in patients at high risk for fibrotic lung disease. Conveying SSc statistics, e.g., "50%
mortality and ensuing disability without appropriate treatment is generally effective.
Proactive Procedure Scheduling: Again, consolidating procedures and clinic appointments en-
hances overall HRQoL. Appointments can be costly to patients and their families in terms of travel
expenditures and time, work productivity and income loss [100] but also over-medicalizes patients’
lives.
Referral Fulfillment: Clinician-to-clinician communication is key to conveying the expeditious nature
of clinical concerns. “Extended teams,” mentioned above, serve to expedite timely scheduling for
therapy and specialist consultations.
Benefits of concurrent care between SSc specialists and general/local specialists
Concurrent care, mutual decision-making, and close communication between a recognized SSc-
center and a patients' local rheumatologists, pulmonologists and other specialists, benefit SSc
37
patients. SSc remains a complex disease, with professional education disproportionately represented
by industry's easily misinterpreted therapeutic messaging. Patient volume at SSc-centers habituates
attention to the subtleties and complexities of SSc care and therapeutics. SSc centers offer specialty and
experimental treatments, availability of clinical trials, registries, and consultation with specialty PT/OT/
nutritionists.
Future of SSc care
Telehealth offsets the frequency of travel burden for patients and family (e.g., time, logistics,
financial, work) with its immediacy possibly expediting initiation of appropriate care. During the
COVID-19 pandemic, supplementing history to target physical exam findings and guiding patients
in physical exam elements has proven helpful to establish degree of vascular, cutaneous and
musculoskeletal complications. Home spirometry may also support expansion of telehealth visits
[101].
Patient self-management promises to be a critical aspect of SSc health outcomes, including newer
well-being and therapeutic practices that appear to influence inflammation, fibrotic mechanisms,
respiratory function, fatigue, and pain, such as home exercise practices and therapeutic singing
[102e104].
Practice points:
! Serial screening detects potentially lethal complications and is key to decrease disability and
mortality in SSc
! Organ-based documentation optimizes comprehensive assessment, treatment and
counselling.
! Documenting serial patient metrics, such as testing and symptoms, detects ominous early
trends of progressive disease that warrants aggressive intervention, such as dropping PFTs
despite normal values
! Coexistent ILD and PH is common. Co-existent WHO PH groups is also common. Clinical
tools exist to help detect and distinguish pulmonary involvement in SSc
! SSc is very heterogeneous and requires an individualized approach to patient care
! Concurrent care between SSc centers and general/local rheumatologists and pulmonologists
is an increasingly common care model that may enhance patient health outcomes
! Patient-centered and outcome-centered care in SSc demands time. Optimizing clinical
infrastructure and appropriate billing can help protect clinical time with SSc patients
! Optimal health outcomes in SSc demands a multispecialty multidisciplinary approach
! Exercise has multiple-organ based benefits in SSc and may be a disease modifying
intervention
Research agenda
! Investigate the impact of standardized clinical data collection using customizable open
source interfaces like OpenEMR [105] on health outcomes and health disparities in SSc and
other complex multi-organ diseases
! Investigate health economics, health outcomes when clinicians optimize appropriate billing
to protect clinician-patient visits time related to optimized in SSc
! Investigate the potential of early systemic treatment as preventive in the development of
severe gastrointestinal SSc disease (and other manifestations association with disease
duration)
! Characterize the degree and dosage of exercise on SSc local and systemic effects.
! Assess the use of pre-visit intake apps (compared to no app) on patients' clinic visit experi-
ences and health outcomes.
38
Summary
SSc is a devastating multisystem disease requiring extensive, thoughtful assessment, organized

documentation and management of multiple organ-related manifestations that can directly impact a
patient's survival and HRQoL. An optimal approach coordinates healthcare services and empowers
access to disease-related education and resources. The future of SSc care depends on effective
communication along with expeditious assessment and treatment with appropriate pharmacological
and non-pharmacological therapeutics. Quality healthcare in SSc is reliant upon sustainable clinical
operations and policy-making that optimize survival and HRQoL in SSc.
Funding statement
Charles and Elizabeth Wetmore Foundation of Greater New Orleans (LAS), National Institute of
Health Research UK (AMR), National Institutes of Health: L30 HL129466 (MRL) and R01 AR073270
(MH), National Heart, Lung, Blood Institute K23HL150237-02 (ERV); Promobilia Foundation (HA)
Pulmonary Fibrosis Trust UK (AMR), Sarcoidosis Awareness Foundation of Louisiana (SAFOL) (LAS),
Swedish Research Council (HA, HP), Swedish Rheumatism Association (HA, HP), The Victoria Porter
Family Fund for Autoimmunity Research (LJC).
Declaration of competing interest
None of the authors have conflicts of interest to report that are related to the reported content of
this paper.
Appendix A
Appendix of Medication Tables
Please note medications marked with ‘^’ are either formally approved by drug agencies for use in SSc
or part of national formularies e.g. MMF in the US.
Raynaud's and Digital Ulcer Medications
Drug Class Drug Names General Side Effects
Calcium Channel Blocker (CCB) Hypotension, flushing, dizziness, and edema.

Angiotensin Receptor Blocker Losartan Dizziness, diarrhea, hypotension, muscle cramps, and
(ARB) Valsartan headache.
Angiotensin Converting Enzyme Captopril, Enalapril,
(ACE) Inhibitors Quinapril, Ramipril, Lisinopril
Alpha Blockers Prazosin Hypotension, dizziness, drowsiness
Nitrates Topical Nitroglycerin 2% Rash, headache, facial flushing, hypotension, dry mouth,
tachycardia.
Phosphodiesterase-5 Sildenafil Blurred vision, flushing, headache, hypotension, visual
Inhibitors^ Tadalafil impairment, tachycardia.
Prostacyclin/prostacyclin Epoprostenol Hypotension, dizziness, muscle cramps, nausea and
analog^ Treprostinil vomiting, edema, headache
Iloprost
Endothelial Receptor Blockers^ Bosentan Hepatoxicity, headache, flushing, edema, fatigue,
Ambrisentan hypotension, pruritus, and weight gain.
Macitentan
Topical lidocaine Avoid getting into eyes or sensitive areas
Botulin Toxin Injections
39
Analgesic Medications
Drug Class Drug names Concerns for use in SSc
NSAIDS ibuprofen, naproxen, ! Esophageal concerns

! Gastritis/gastric bleeding
! Hypertension
! Kidney impairment
! Gastric bleeding
! Fluid Retention
! Cardiac events with long-term use
Opioids Hydrocodone ! Decreased motility in GI tract
Oxycodone ! Constipation in general population / may be exaggerated in scleroderma
Tramadol patients
! Risk of respiratory depression
! Fractionated sleep, impaired sleep
! Pruritus
Anti-convulsants Gabapentin ! Dizziness
Pregabalin ! Somnolence
! Swelling
Pharmacological Therapy for Gastrointestinal Manifestations in SSc (Courtesy of Monika Lammi, rights
reserved).
Drug Class Drug Name Concerns for use/Comments
GERD
Proton Pump Inhibitors Pantoprazole* *Bioavailability reduced if taken with food
Omeprazole* Take 30e60 min before breakfast.
Lansoprazole* Decreased absorption of: Mg, B12, Fe
Esomeprazole* Risks (prolonged use): renal insufficiency, osteoporosis, atypical
Rabeprazole* fractures, pneumonia, and dementia.
Dexlansoprazole
Histamine 2 Famotidine Possible inhibition of cytochrome P450 with possible enhanced
Antagonists Ranitadine effects of drugs with P450 reliant metabolism
Cimetidine
Antiacids Calcium carbonate Hyperkalemia, alkalosis and acute or chronic renal injury.
Aluminum hydroxide Aluminum retention with neurotoxicity and anemia in renal failure.
Hypophosphatemia.
Surface agents Gaviscon ± alginate
Sucralfate Can bind to other drugs if taken simultaneously.
Combining with antiacids can amplify these side effects.
Promotility/LES Metoclopramide May increase gastric motility in patients with systemic sclerosis.
FDA advised against use for more than 3 months
SE: traditive dyskinesia, cardiac arrythmia (monitor with EKG)
Domperidone Not FDA approved in US. Can be obtained with Investigational New
Drug Application
SE: cardiac arrhythmia
Buspirone Increases the lower esophageal sphincter pressure, amplitude of
esophageal contractions.
Appears more effective for GERD-related symptoms not esophageal
hypomotility symptoms (dysphagia and chest pain).
Baclofen Shown to augment lower esophageal sphincter pressure in patients
with GERD. Not studied in patients with SSc.
Gastroparesis
Promotility agents Metoclopramide May increase gastric motility in patients with systemic sclerosis
Risk: traditive dyskinesia, cardiac arrythmia (monitor with EKG)
40
(continued )
Drug Class Drug Name Concerns for use/Comments
Domperidone Not FDA approved in US. Can be obtained with Investigational New
Drug Application.
SE: cardiac arrhythmia (monitor with EKG)
Erythromycin Not recommended long term: tachyphylaxis, may cause small
bowel dysmotility.
SE: cardiac arrhythmia (monitor with EKG)
Prucalopride Improves gastric, small bowel and colonic transit.
FDA approved for constipation.
Cisapride Improves postprandial symptoms and gastric emptying.
More potent acutely than metoclopramide.
Withdrawn from the US market because of cardiac arrhythmia.
Antiemetics Ondansetron SE: Prolongs GI transit, headache, cardiac arrhythmia.
Granisetron SE: constipation, headache, cardiac arrhythmias
Prochlorperazine SE: Sedation, tardive dyskinesia
Promethazine SE: Central, cardiac arrhythmia
Neuromodulators Buspirone As above for GERD and below for dyspepsia.
Mirtazipine As below for dyspepsia. May improve early satiety, nausea,
dysmotility manifestations such as gastroparesis, and CIPO.
Dyspepsia
Neuromodulators Buspirone Improves gastric accommodation and symptoms of dyspepsia, but
decreases gastric emptying of liquids.
Mirtazapine
Improves dyspepsia, early satiety, nausea, emesis, sleep,
depressionSE: weight gain, drowsiness, some risk of mouth dryness
Herbal FDgard (caraway oil
and I-menthol)
Snall Intestinal Bacterial Overgrowth (SIBO)
Antibiotics Rifaximin Treat for 2 weeks.
Metronidazole High risk of recurrence due to small bowel dysmotility.
Amoxicillin/clavulanic Cycle regimens to limit antibiotic resistance.
acid May consider use of prokinetics, see below.
Norfloxacin Antibiotics, e.g. fluoroquinolones may contribute to clostridium
difficile overgrowth
Chronic Intestinal pseudo-obstruction
Prokinetics Metoclopramide See above.
Erythromycin May also be considered for SIBO.
Prucalopride
Cholinesterase Pyridostigmine SE: bradycardia, excessive bronchial secretions, cholinergic crisis
inhibitor
Somatostatin analog Octreotide Used in patients who failed to respond to other prokinetic agents.
Inhibits gastric motility.
Constipation
Bulk forming laxatives Psyllium Patients with gastric dysmotility and visceral hypersensitivity may
Methylcellulose not be able to tolerate.
Osmotic laxatives Polyethylene glycol SE: abdominal pain, distention, bloating.
Stimulant laxatives Bisacodyl
Glycerol
Guanylate cyclase-C Linaclotide Diarrhea, bloating.
receptor agonists Plecanatide Improves gastric, small bowel and colonic transit.
Diarrhea.
Chloride channel Lubiprostone Nausea, diarrhea.
activator
Promotility agent Prucalopride Improves gastric, small bowel and colonic transit.
FDA approved for constipation.
41
Systemic treatment/immune suppression/anti-fibrotics.
Drug Side Effects Monitoring/Counselling Common uses
Mycophenolate mofetil Diarrhea, increased risk of CBC, serum electrolytes Anti-fibrotic

(MMF) mycophenolic infection, headache, fatigue, especially with ongoing immunosuppressant
acid^ leukopenia, thrombocytopenia, diarrhea, drug interactions; First-line for progressive
teratogenic REMS (pregnancy) ILD
If side effects occur, decrease Skin-tightening, Joint
dose to side effect free level, involvement
and keep at this dose for longer
period before increasing again.
Use of contraception
Cyclophosphamide Increased risk of infection CBC, urinalysis (monthly if on IV Progressive ILD
Hair loss, GI upset, decreased therapy) Progressive skin-tightening
appetite, stomatitis,
amenorrhea, interstitial cystitis,
infertility, oligospermia/
azoospermia, Stevens-Johnson
syndrome, increased risk of
bladder cancer
Rituximab Risk of infection Progressive skin-tightness
Infusion reaction common Progressive ILD
Very rare, demyelinating Joint involvement, possibly
disorders PH
Tocilizumab^ Risk of Infection Serum lipids Skin-tightness
Transaminitis, hepatotoxicity CBC Joint involvement
Very rare, demyelinating Transaminases Slowing down progressive
disorders ILD
Rare risk of GI perforation Possibly PH
Hyperlipidemia
Intravenous Headache, fatigue, renal Progressive SSc
Immunoglobulin G dysfunction, transient ischemic
episodes, cerebrovascular
event, urticaria, flushing,
hypertension, aseptic
meningitis
Hematopoietic Stem Extreme immunosuppression Per protocol Progressive SSc prior to
Cell Transplantation High risk of infection and sepsis significant organ damage
Heart failure, arrhythmia
Methotrexate Nausea, diarrhea, CBC, Serum creatinine, Joint involvement
hepatotoxicity, stomatitis, Transaminases,
alopecia, myelosuppression, Concomitant use of folic acid
teratogenic Avoidance of alcohol
Medication-induced Use of contraception
pneumonitis, rare
Increased risk of infection
Azathioprine GI upset, myalgia, leukopenia, Signs of bleeding, jaundice, Joint involvement
thrombocytopenia, risk of change in color of stool; TPMT
infection, hepatotoxicity deficiency, drug interactions
Glucocorticoids Scleroderma Renal Crisis Opportunities to lower dose or Restricted use of very low
Amongst many other discontinue doses
potentially detrimental side
effects
Leflunomide Hepatotoxicity CBC and transaminases, signs of Joint involvement
Nausea, Diarrhea, infection
Hypertension, Rash, Headache, Avoid alcohol, use of
Abdominal pain, Alopecia; contraception
Peripheral neuropathy
Sulfasalazine Nausea, Diarrhea, Headache, CBC Joint involvement
Photosensitivity, GI distress, SPF use
Myelosuppression
42
(continued )
Drug Side Effects Monitoring/Counselling Common uses
Hydroxy-chloroquine Nausea, Diarrhea, Headache, Baseline eye exam Joint involvement

vision changes Screening according to
Rarely myopathy published protocols
Rarely myelosuppression Visual changes at night or
peripheral
Anti-Fibrotic e.g. Gastrointestinal distress, Transaminase levels Slowing down lung
nintedanib^, hepatotoxicity, fatigue, swelling Electrolytes with vomiting or progression. Uncertain
pirfenidone diarrhea regarding whether these
have systemic effects, thus
far there has been no
demonstrated
improvement on skin, joint,
or quality of life.
Appendix of Clinician and Patient Resources
Clinical skills resources
Functional Index-2: https://www.youtube.com/watch?v¼qw4XvWKQErU.

Manual Muscle Test 8 (MMT-8): https://www.niehs.nih.gov/research/resources/assets/docs/
mmt8_grading_and_testing_procedures_for_the_abbreviated_8_muscle_groups_508.pdf.
Modified Rodnan Skin Score: https://www.youtube.com/watch?v¼Bl3EX_2PaUc.
Timed Up and Go Test: https://youtu.be/auqAb_AWM1U.
TImed sit to stand test: https://www.youtube.com/watch?v¼puJhQXUlbdA.
30-s Sit to Stand Test: https://www.youtube.com/watch?v¼PzCTwkJVhWg.
DETECT Algorithm for PH Screening: https://www.suspectpahctd.com/DETECT/ NOTICE: this tool
does not replace clinical judgement. Only right heart catheterization is currently able to determine
presence of pulmonary hypertension.
Examples of Clinic Operations Documents
Medical Records Intake Form for Scheduling New Patients: https://www.dropbox.com/s/

wapuv8p8dkoz2n3/PATIENT%20SCHEDULING%20INTERVIEW.docx?dl¼0.
New Patient Questionnaire:
https://www.dropbox.com/s/jynfaq5ax3cyo8a/SSc%20Patient%20Intake%20Form.docx?dl¼0.
Infusion Order Record:
https://www.dropbox.com/s/v1vkwiegpjhead4/INFUSION%20ORDER%20RECORD.docx?dl¼0.
Oral Medication Authorization Record: https://www.dropbox.com/s/algr06i6upndtmf/RECORD%
20ORAL%20MEDS%20PRIOR%20AUTH.docx?dl¼0.
Patient Questionnaires:
StopBang questionnaire online calculator: http://stopbang.ca/osa/screening.php

Epworth Sleepiness Scale
https://www.thecalculator.co/health/Epworth-Sleepiness-Scale-Calculator-905.html
http://epworthsleepinessscale.com/
Scleroderma Health Assessment Questionnaire: https://www.dropbox.com/s/gd9847e9bw82101/
SHAQ%20-%20SF36%20-%20Cochin%20Hand%20Function.doc?dl¼0.
SF-36 form: https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html
https://www.rand36calculator.com/
Cochin Hand Function Questionnaire: https://www.dropbox.com/s/gd9847e9bw82101/SHAQ%
20-%20SF36%20-%20Cochin%20Hand%20Function.doc?dl¼0.
43

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Best Practice & Research Clinical Rheumatology 35 (2021) 101707

Contents lists available at ScienceDirect

Best Practice & Research Clinical

A comprehensive framework for navigating

Matthew R. Lammi a, c, d, Jennifer Mansour b,

Pathologic drivers in SSc that impact treatment decisions

Inﬂammation-ﬁbrosis axis: from preventable to irreversible damage

Circulation and mechanisms of disease

Best Practice & Research Clinical Rheumatology 35 (2021) 101707

Best Practice & Research Clinical Rheumatology 35 (2021) 101707

Considerations that drive management in SSc

Goals of SSc management

Risk awareness in SSc

Risk factors with Associated Findings

Heart Diffuse cutaneous SSc

Risk factors with Associated Findings

Digital ulcers Diffuse cutaneous SSc

Tracking symptoms and metrics for recognition, monitoring and intervention

Domains Sub-Domains Assessment Considerations

Background Biological sex

Domains Sub-Domains Assessment Considerations

Category Speciﬁc Lab Common Implications

Category Assessment Area Observed Finding Comment

CONSTITUTIONAL Nutrition Weight

Category Assessment Area Observed Finding Comment

Muscle Observation Mobility Muscle involvement is:

Category Assessment Area Observed Finding Comment

Telangiectasias (here or detailed

L.A. Saketkoo, T. Frech, C. Varjú et al.

*Ulcers can appear in other locations

Best Practice & Research Clinical Rheumatology 35 (2021) 101707

System-based symptomatology and management

Symptom System/Origin Potential Causes Team Involvement/Interventions

Fatigue Anemia GI loss, chronic inﬂammatory

Dyspnea screening Cough screening for ILD

ILD ILD e dry inspiratory

Best Practice & Research Clinical Rheumatology 35 (2021) 101707

Pulmonary involvement in SSc

Cardiac Involvement in SSc

Best Practice & Research Clinical Rheumatology 35 (2021) 101707

When to consider transplantation

Diagnosis Indications for Referral

Interstitial lung disease ! Radiographic or biopsy proven disease

Obesity ! BMI <35, preferably <30 and transplant center dependent

Abbreviations: BMI, body mass index; GJ, gastrostomy-jejunostomy

Occupational Therapy For hand, face and oral health

EXERCISE GENERAL STRETCHING RESISTANCE AEROBIC MONITOR

Category Sub-Category Item Advisements for Patients

Category Sub-Category Item Advisements for Patients

High risk for dental complications:

Category Sub-Category Item Advisements for Patients

Herpes zoster (killed only i.e. Shingrix)

Important non-pharmacological therapeutic considerations

Exercise as an essential multi-modal disease-modifying medicine

Anticipatory and preventive education

Keys to Patient-Centered Outcomes

Temperature Cold can be injurious in SSc

Discrete Care Events Stipulations for billing Coding