Seminars in Arthritis and Rheumatism 46 (2017) 767–774

Contents lists available at ScienceDirect

Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

Evidence-based management of systemic sclerosis: Navigating

recommendations and guidelines
Russell Edward Pellar, MDa, Janet Elizabeth Pope, MD, MPH, FRCPCa,b,n
a
Department of Medicine, University of Western Ontario, London, ON, Canada
b
St Joseph Health Care, London, ON, Canada

a r t i c l e i n fo a b s t r a c t

Objectives: Systemic sclerosis (SSc) is a rare heterogeneous connective tissue disease. Recommendations
addressing the major issues in the management of SSc including screening and treatment of organ
Keywords:
Systemic sclerosis
complications are needed.
Scleroderma Methods: The updated European League Against Rheumatism/European Scleroderma Trial and Research
Guidelines (EULAR/EUSTAR) and the British Society of Rheumatology (BSR) and British Health Professionals in
Recommendations Rheumatology (BHPR) guidelines were compared and contrasted.
Treatment Results: The updated EULAR/EUSTAR guidelines focus specifically on the management of SSc features and
Management include data on newer therapeutic modalities and mention a research agenda. These recommendations
Evidence based are pharmacologic, with few guidelines regarding investigations and non-pharmacologic management.
Best practices
Recommendations from BSR/BHPR are similar to the organ manifestations mentioned in the EULAR/
PAH
EUSTAR recommendations, and expand on several domains of treatment, including general measures,
ILD
RP non-pharmacologic treatment, cardiac involvement, calcinosis, and musculoskeletal features. The guide-
European Scleroderma Research Group lines usually agree with one another. Limitations include the lack of guidance for combination or second-
British Society of Rheumatology line therapy, algorithmic suggestions, the absence of evidence-based recommendations regarding the
treatment of specific complications (i.e., gastric antral ectasia and erectile dysfunction). Consensus for
when to treat interstitial lung disease in SSc is lacking. There are differences between Europe and North
American experts due to access and indications for certain therapies.
Conclusions: Care gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines
can promote best practices. Certain complications warrant active investigation to further improve
outcomes in SSc and future updates of these recommendations.
Care gaps in SSc have been demonstrated so the EULAR/EUSTAR and BSR/BHP guidelines can promote
best practices. Certain complications warrant active investigation to further improve outcomes in SSc
& 2017 Elsevier Inc. All rights reserved.

Introduction
Scleroderma [systemic sclerosis (SSc)] is an autoimmune con-
nective tissue disorder characterized by progressive fibrosis and
thickening of the skin, vascular damage and autoantibodies with
variable involvement of major internal organs such as the lungs,
kidneys, gastrointestinal tract, and heart. Several vascular mani-
festations are seen, including Raynaud's Phenomenon (RP), digital
ulcers (DU), pulmonary arterial hypertension (PAH), and SSc renal
crisis (SRC) [1,2]. SSc is rare, affecting approximately 2 per 10,000
☆
There was no funding for this study. Ethics approval was not needed as this is a
review of SSc guidelines/recommendations.
n
Corresponding author at: Janet Elizabeth Pope, MD, MPH, FRCPC, St. Joseph’s
Health Care, D2 Rheumatology, 268 Grosvenor St., London, ON N6A 4V2.
E-mail address: janet.pope@sjhc.london.on.ca (J.E. Pope).
individuals, most of whom are women ( 480%), and is one of the
most severe connective tissue diseases, with significant disability
and mortality [3–6]. The etiology of SSc is unclear and the clinical
presentation is heterogeneous and complex [1].
SSc is classified using criteria published in 2013 by the
American College of Rheumatology (ACR) and the European
League Against Rheumatism (EULAR), and is based on the presence
or absence of certain findings. Individuals with skin thickening of
the fingers that extends proximal to the metacarpophalangeal
joints are considered to have SSc. If this is not present, then
classification is based on the following weighted findings: skin
thickening of the fingers, fingertip lesions, telangiectasia, abnor-
mal nailfold capillaries, interstitial lung disease (ILD) or pulmonary
arterial hypertension (PAH), Raynaud's phenomenon, and SSc-
related autoantibodies [7]. There are additional signs and symp-
toms of SSc not included in these criteria, such as calcinosis,

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768 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774
gastroesophageal reflux disorder (GERD), dysphagia, tendon fric-
tion rubs, and scleroderma renal crisis (SRC) and as such these
criteria are not intended to be used for diagnosis, but rather for
inclusion of appropriate SSc patients in research trials. If a better
explanation can account for the signs and symptoms, then the
criteria are not to be applied. Also the criteria are for classification
and not likely identical to diagnostic criteria [7]. SSc is often
divided into either diffuse or limited subtypes primarily according
to the degree of skin involvement. In limited cutaneous SSc (lcSSc),
the skin thickening is only found distal to the elbows and knees
and may also be superior to the clavicles on the face and neck. In
diffuse cutaneous SSc (dcSSc), the skin thickening is found both
proximal and distal to the elbows and knees and/or on the trunk,
and is typically associated with more severe organ involvement
[8,9].
There is a need for comprehensive, evidence-based guidelines
and recommendations for the management of SSc due to its
clinical heterogeneity, rarity and high morbidity and mortality.
There are few effective disease modifying medications/treatments,
and thus therapy is typically symptomatic and/or based on the
organs involved, further highlighting the need for evidence-based
guidelines, especially for those who lack expertise in the specific
management of SSc [10]. This review discusses the updated/new
guidelines, interpretation and use of guidelines in SSc manage-
ment and gaps in care. The main guidelines from various societies
are compared.
Recommendations and guidelines are used somewhat inter-
changeably. They are considered suggestions about best practices.
The European League Against Rheumatism (EULAR) and the
EULAR Scleroderma Trial and Research (EUSTAR) group published
recommendations in 2009 [11]. These have been updated and
recently published [12]. The British Society of Rheumatology (BSR)
and British Health Professionals in Rheumatology (BHPR) have also
developed recommendations presented at the BSR annual meeting
in Manchester, 2015 [13]. A summary is on the internet at http://
www.rheumatology.org.uk/includes/documents/cm_docs/2012/0/
0915_development_of_expert_consensus_best_practice_manage
ment_for_systemic_sclerosis.pdf. They are discussed below.
EULAR/EUSTAR recommendations
The first set of comprehensive SSc recommendations was
created by the EULAR/EUSTAR in 2009. The guidelines were
created based on evidence from 281 publications and were
supplemented by consensus-driven expert opinion. Only data
available prior to December 2006 were used to generate the
original recommendations. Since the initial publication, the
EULAR/EUSTAR group has updated them by reviewing data up to
2014 and this review is based on the update and original
publication [11,12].
SSc-related digital vasculopathy
(1) The recommended first-line therapy for SSc-related Raynaud's
phenomenon (RP) is an oral dihydropyridine-type calcium
channel blocker (CCB) (usually nifedipine) and for severe
SSc-related RP the recommended therapy is intravenous pros-
tanoids (usually IV iloprost). These recommendations are
based on the findings from meta-analyses of randomized
control trials (RCTs) [14,15]. Both treatments reduce the
frequency and severity of RP attacks in SSc. Combining
prostanoids with CCBs can increase hypotension. The new
recommendations also suggest that selective type 5 phos-
phodiesterase inhibitors (PDE5 inhibitors) and fluoxetine
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[a selective serotonin reuptake inhibitor (SSRI)] can be used in
RP [12].
(2) The recommended therapy for the healing of active SSc-related
digital ulcers (DU) is IV prostanoids (particularly IV iloprost)
based on two RCTs [16,17]. The update also recommended the
use of PDE5 inhibitors [12].
(3) The prevention of DU in diffuse cutaneous SSc patients,
particularly those with multiple DUs, is bosentan [a dual
endothelin receptor antagonist (ERA)], after treatment failure
of CCBs and usually prostanoids. This recommendation was
based on two high quality RCTs [18,19]. Potential side effects of
bosentan include teratogenicity, some drug interactions and
hepatoxicity [20,21]. Interestingly macicentan has negative
data with respect to the prevention of DU in SSc.
SSc-related pulmonary arterial hypertension (PAH)
(1) It is recommended that bosentan (an ERA) be considered in
the treatment of SSc-related PAH based on two high quality
RCTs, which found improvement in exercise capacity, func-
tional class, and hemodynamis [22,23]. Other ERAs have been
approved and are reflected in the updated recommendations
including ambrisentan and macitentan [12]. Sitaxsentan has
been removed from the market. In addition, PAH is a severe
and lethal complication of SSc so pregnancy in patients with
severe PAH is not recommended (authors' opinion).
(2) Sildenafil (a selective type 5 phosphodiesterase inhibitor)
should also be considered in the treatment of SSc-related
PAH, particularly for those who have failed treatment with
bosentan or cannot take bosentan due to safety concerns. This
is based on one high quality RCT, which found improved
exercise capacity, functional class and some hemodynamic
measurements for those taking sildenafil [24]. There are also
other RCTs of sildenafil and tadalafil that were published after
the initial recommendations. Tadalafil (a PDE5 inhibitor) is also
recommended in the management of SSc-related PAH [12].
(3) Intravenous epoprostenol (a prostanoid) is recommended for
treatment of severe SSc-related PAH, based on one high quality
RCT, which demonstrated an improvement in exercise
capacity, functional class and hemodynamic measurements
for those receiving continuous IV epoprostenol [25]. Epopros-
tenol has a short half-life and is administered through a
permanent central venous catheter, which may lead to adverse
events [25]. Sudden withdrawal of IV epoprostenol may lead to
life-threatening rebound PAH. In the update, other prostacy-
clin analogues such as iloprost and treprostinil are recom-
mended in the management of severe SSc-related PAH [12].
Epoprostenol now has a more stable variant so the drug may
be pre-mixed in advance of use.
(4) An additional recommended medication included for SSc-
related PAH is riociguat, a soluble guanylate cyclase stimulator
[12,26].
In all cases, PAH must be diagnosed via a right heart catheter-
ization as there can be pulmonary hypertension for other reasons
requiring different treatment. The trends in PAH are for earlier
intervention (class II symptoms), targeted treatment and use of
combination therapies. There are no recommendations with
respect to using warfarin in PAH from SSc due to a lack of data
and potential GI bleeding.
SSc-related skin involvement
Methotrexate can be considered for the treatment of skin
involvement of early dcSSc, based on two RCTs that demonstrated
 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774
improvements in skin score [27,28]. Methotrexate trials had only
borderline efficacy and one trial was negative (p value vs. placebo
on skin score of p ¼ 0.06) [28].
SSc-related interstitial lung disease (ILD)
(1) Cyclophosphamide (CYC) can be considered for the treatment
of SSc-related ILD, based on evidence from two high quality
RCTs [29,30]. Cyclophosphamide can cause teratogenicity,
gonadal failure, bone marrow suppression, infection, and
hemorrhagic cystitis [31].
Once treatment is discontinued, there is regression of the
benefit so after induction, maintenance with another drug is
needed.
(2) Additionally, hematopoietic stem cell transplantation (HSCT) for
the treatment of both SSc-related skin and lung disease was
mentioned in the updated EULAR/EUSTAR recommendations [12].
Scleroderma renal crisis (SRC)
(1) The recommended treatment for scleroderma renal crisis is an
angiotensin converting enzyme inhibitor (ACEi) based on
expert opinion and evidence from non-randomized studies
[32–34]. Due to the rarity and high mortality of SRC, it is
unlikely that RCTs will be performed regarding its treatment.
ACEi do not prevent SRC and may delay diagnsosis of SRC.
ACEi should not be discontinued as that increases the risk of SRC.
(2) It is recommended that patients on steroids should be moni-
tored for the development of SRC by following renal function
and blood pressure, based on evidence from four retrospective
where use increases SRC, particularly for patients with early
dcSSc [35–38]. Other risk factors for the development of SRC
include high skin score, rapidly progressive dcSSc, RNA poly-
merase3 antibody, male, tendon friction rubs, joint contrac-
tures, pericardial effusions, and other organ involvement [36].
SSc-related gastrointestinal disease
(1) It is recommended that proton pump inhibitors (PPIs) should
be used for the prevention of SSc-related gastroesophageal
reflux disease (GERD), esophageal ulcers, and strictures. There
is a lack of specific RCTs for PPI use in scleroderma, however,
efficacy for the use of PPIs for GERD in the general population
is well established [39,40].
(2) Prokinetic drugs should be used for the management of SSc-
related symptomatic dismotility, including GERD, dysphagia,
early satiety, bloating, constipation, diarrhea, although there
are no RCTs specific to SSc but some published data demon-
strate benefit in SSc [41–43].
(3) Rotating antibiotics can be considered in the treatment of
malabsorption due to bacterial overgrowth in SSc. There are no
RCTs specific to SSc but data exist in other populations with
small bowel overgrowth [44]. Antibiotic use could likely also
help significant symptoms of bacterial overgrowth such as
bloating, gas and diarrhea.
In general, it is not necessary to perform tests to diagnose small
bowel overgrowth as the history should suffice.
EULAR/EUSTAR recommendation discussion
These recommendations represent evidence-based and/or
experience-based pharmacologic treatments for SSc. Most of the
recommendations are for specific organ manifestations of SSc,
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769
rather than a general approach to management. Certain treatment
recommendations did not have RCTs of SSc patients were extrapo-
lated from other patient populations, such as for gastrointestinal
involvement [40,41,44,45]. Non-pharmacologic and recent clinical
trial results (beyond the search date) were not included in these
recommendations.
Autologous hematopoietic stem cell transplantation (HSCT) was
mentioned for dcSSC and ILD. The ASTIS trial had strict inclusion
criteria [46] and a second trial mainly conducted in the United
States (SCOT trial) is not yet analyzed [47]. Criteria for selecting
appropriate patients have yet to be established, but early dcSSc
with poor prognosis features were included. HSCT may increase
event-free survival, and improve lung and skin involvement
compared to treatment with IV cyclophosphamide. However, it
has a significant early mortality rate of 10% and increases the rate
of adverse events, so proper patient selection is an important
consideration [46]. Although HSCT may be of use for certain SSc
patients, it is not necessarily reimbursed by health insurers and
long-term benefits compared to other treatment are not fully
known. Medications such as other immunosuppressive agents
(mycophenolate mofetil, azathioprine, rituximab, and other anti-
cytokine therapies) were not in the recommendations.
Some treatment for RP, digital ulcers and PAH were included in
the updated recommendations. Drugs for the potential prevention
of digital ulcers, such as statins were not included [48].
The EULAR/EUSTAR recommendations do not include cardiac
and musculoskeletal involvement. Treatment of calcinosis, pain,
fatigue, telangiectasia, and pruritis were also not discussed but
they affect quality of life in SSc [49,50]. Exercise, occupational and
physical therapy, nutritional considerations and other non-
pharmacologic therapies were not included and there is no
consensus in these areas. SSc patients will likely have more
comprehensive treatment if referred to expert centres.
BSR and BHPR guidelines
The BSR and BHPR have developed evidence-based guide-
lines regarding the management of scleroderma using a com-
prehensive literature review up to June 30, 2014. Each
recommendation was through expert consensus informed by
the literature and experience. The recommendations were
finalized when at least 75% of the committee agreed taking into
account the strength of the recommendation and its associated
level of evidence [12].
In general, the BSR/BHPR guidelines cover the same topics
contained within the EULAR/EUSTAR guidelines, but also incorpo-
rate care pathways and treatment not discussed in the latter
publication. The management or SSc-related RP, DU, PAH, SRC,
skin, lung, and gastrointestinal involvement are fairly similar,
usually with the BSR guidelines including more suggestions [12].
A summary of both the EULAR recommendations and BSR guide-
lines can be found in the Table. The Figure compares the overlap
and differences between the two.
The BSR guidelines begin with general SSc management, and
discuss a more comprehensive approach to treatment, covering
also non-pharmacologic treatment, general measures, and educa-
tion. They include management of calcinosis, pruritus, telangiec-
tasia, musculoskeletal involvement, and cardiac disease, which are
not in the EULAR guidelines [12]. However, there are still no
evidence-based recommendations regarding the treatment of
manifestations such as gastric antral vascular ectasia, congestive
heart failure, cardiac arrhythmias, pain, or erectile dysfunction
within SSc. In general, the treatment of these complications is
borrowed from non-SSc etiologies.
770 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774

Table
Comparison of guidelines and recommendations in systemic sclerosis

Treatment category EULAR/EUSTAR recommendation BSR/BHPR recommendation

General SSc Diagnosis, classification into subsets, further subgrouping, and defining disease onset
management Early recognition of dcSSc, referral to a specialist centre, treatment of organ involvement, and prompt
initiation of immunomodulating therapy (MTX, MMF, or cyclophosphamide)
Consider hematopoietic stem cell transplantation for select cases.

Non-pharmacologic Physical therapy, massage therapy, and other programs to improve exercise capacity
management

Raynaud's Dihydropyridine-type CCBs Patient education (cold avoidance, staying warm, smoking cessation)
phenomenon Prostanoids (such as IV iloprost) CCBs and Angiotensin II receptor blockers
PDE5 inhibitors SSRIs, alpha blockers, ACE inhibitors and statins
IV prostanoids
PDE5 inhibitors
Fluoxetine (an SSRI) Digital (palmar) sympathectomy (7 botulinum injection)

Digital ulcers IV iloprost Oral vasodilators, analgesia, and treatment of infection

PDE5 inhibitors IV prostanoids
PDE5 inhibitors
Bosentan (an ERA) ERAs
Digital (palmar) sympathectomy (7 botulinum injection)

Pulmonary arterial ERA (bosentan, ambrisentan, Diagnosis based on appropriate workup including right heart catheterisation and cardiopulmonary
hypertension macitentan) disease investigation
PDE5 inhibitor (sildenafil, tadalafil) ERA (bosentan, ambrisentan, macitentan)
IV prostanoids (epoprostenol, iloprost, PDE5 inhibitor (sildenafil, tadalafil)
treprostinil) IV prostanoids
Riociguat (a soluble guanylate cyclase Riociguat (a soluble guanylate cyclase stimulator)
stimulator) Supportive treatment with diuretics, oxygen and anticoagulation if indicated

Skin involvement Methotrexate MTX, MMF, CYC, oral steroids, or rituximab

Autologous hematopoietic stem cell
transplantation (HSCT)
CYC, azathioprine or MMF for maintenance
Moisturization (particularly with lanolin-based products), avoidance of frequent bathing with harsh
detergents
Antihistamines
Treatment of telangiectasia with skin camouflage and laser therapy

Lung involvement Cyclophosphamide Cyclophosphamide

MMF
Autologous hematopoietic stem cell CYC, azathioprine or MMF for maintenance
transplantation (HSCT)

Scleroderma renal ACE inhibitor Identification of risk factors and close monitoring of blood pressure
crisis Blood pressure and renal monitoring ACE inhibitor
for patients on steroids Other antihypertensives for refractory cases

Gastrointestinal PPIs PPIs

disease Prokinetic agents Histamine H2 receptor antagonists
Prokinetic agents
Rotating antibiotics Parenteral nutrition when indicated
Rotating antibiotics
Laxatives and antidiarrheal agents when indicated

Cardiac disease For systolic heart failure

Immunsuppression
Pacemaker and ICD
ACE inhibitor and carvedilol; selective beta blockers used with care
For diastolic heart failure
Diuretics (e.g., spironolactone and furosemide)
CCBs

Calcinosis Antibiotics for superimposed infection

Medications: aluminum hydroxide, CCBs, bisphosphonates, colchicine, IVIG, infliximab, minocycline,
rituximab, and warfarin
Interventional: steroid injection, laser treatment, and lithotripsy
Surgery for severe, refractory cases
Musculoskeletal Immunosuppressive treatments
involvement Treatment of arthritis and myositis follows standard protocol

dcSSC, diffuse cutaneous systemic sclerosis; MTX, methotrexate; MMF, mycophenylate mofetil; CCB, calcium channel blocker; ACE, angiotensin converting enzyme; SSRI,
selective serotonin reuptake inhibitor; IV, intravenous; PDE5, selective type 5 phosphodiesterase inhibitors; ERA, endothelin receptor antagonist; CYC, cyclophosphamide;
PPI, proton pump inhibitor; ICD, implantable cardio defibrillator; IVIg, intravenous gammaglobulin.

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 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774 771

EULAR/EUSTAR BSR/BHPR

• Future research Overlap • General SSc

quesons from expert
commiee included • RP recommendaon
• DU recommendaon
• PAH management
• Skin involvement
recommendaons
• Lung disease
recommendaon
• SRC management
• GI disease
recommendaons
management
• Nonpharmacologic
management
• Cardiac disease
recommendaons
• Calcinosis treatment
• MSK management
• Level of evidence
indicated for each
recommendaon

Fig. Comparison of the EULAR/EUSTAR and British SSc recommendations. EULAR, European League Against Rheumatism; EUSTAR, EULAR Scleroderma Trial and Research;
BSR, British Society of Rheumatology (BSR); BHPR, British Health Professionals in Rheumatology.

Treatment approach especially after first-line therapy (where
guidelines are lacking)
Evidence-based treatment guidelines are important for the
management of complex, multi-systemic conditions such as SSc.
However, they often lack data after first-line therapy. Algorithmic
suggestions for management of the primary SSc were created
based on expert consensus [51]. The study used open text ques-
tioning experts about what treatment would be used and in what
order and if there would be adding vs. switching with subsequent
therapy. The frequency and order of treatment was constructed
and experts rated how much they agreed with each organ-based
treatment [51]. For instance, second-line treatment for SRC after
ACEi did not quickly control the hypertension was to add a CCB or
angiotensin receptor blocker (ARB), and then an alpha blocker. If
an ACE inhibitor was causing side effects, most suggested switch-
ing to another ACEi. Two-thirds of experts agreed with the SRC
management algorithm [51]. First-line treatment for mild PAH
were ERAs (72%), and then the addition of a PDE5 inhibitor (77%)
and then a prostanoid (73%). First-line treatment for severe PAH
was usually initiation of combination PAH drugs. Regarding
screening for PAH, most suggested regular screening (68%), which
usually involved symptom monitoring at every visit, annual
pulmonary function tests and annual echocardiograms and
three-quarters of experts were in agreement with the PAH
algorithm [51]. Treatment of mild RP was with a CCB, then
addition of a PDE5 inhibitor, followed by an ARB and lastly a
prostanoid. For severe RP, a PDE5 inhibitor (45%) or prostanoid
(32%) were added to a CCB (92%) assuming partial efficacy of CCBs
and tolerability. Some suggested that selective sympathectomy
may occasionally be recommended for severe RP but only half
agreed [51]. Other potential treatment such as botox injections
around digital arteries to help RP was not discussed.
For the prevention of DUs, first-line treatment was a CCB,
followed by adding a PDE5 inhibitor, then an ERA, and finally a
prostanoid. Treatment varied depending on the clinical severity of
past DU history. Treatment of active DUs was usually with a CCB
and then the addition of a PDE5 inhibitor if tolerated. Some
suggested that a selective hand sympathectomy may occasionally
be recommended for severe DU. Half the experts were in agree-
ment with the treatment pathway of prevention and treatment of
DU [51].
When to treat ILD was not agreed upon and this may be due to
the heterogeneity of ILD where some patients progress and then
stabilize and where some have significant fibrosis and honey-
combing and others have more of an inflammatory phenotype.
Experts suggested that induction therapy for interstitial lung
disease (ILD) was usually IV cyclophosphamide. Occasionally oral
cyclophosphamide, MMF, or azathioprine were considered. Main-
tenance therapy was usually with MMF. Only 1/3 of respondents
would use steroids frequently or occasionally with other drugs in
ILD. We think that in general if steroids are tried they are at a dose
near 1 mg/kg up to approximately 60 mg/day of oral prednisone
and if no improvement in dyspnea they would be rapidly tapered
and stopped whereas if there was a response, low dose steroids
such as 10 mg/day would be maintained. It was noted that most
SSc patients with ILD are not steroid responsive and that this
would yield a better prognosis. Agreement was obtained for the
use of high-resolution CT scan of the lungs (100%) and PFT (99%)
for the diagnosis of ILD. There was 56% agreement with the
algorithm for the treatment of ILD [51].
For skin involvement, methotrexate was used first with MMF
usually chosen after. Cyclophosphamide was increasingly popular
as a second-line choice as severity of skin involvement increased,
however, it was still less popular than MMF; 3/4 said they would
consider using corticosteroids despite increasing the patient's risk
of developing SRC, but only 1/3 agreed [51].
GI involvement was similar to guidelines although exceeding
the maximum approved dose of PPIs in GERD was suggested [51].
For SSc-related inflammatory arthritis, methotrexate was used
first-line, followed by corticosteroids or hydroxychloroquine and
biologic therapies [51].
In practice, treatment choice beyond guidelines is necessary
and agreement among experts varies. These strategies are

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772 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774
suggestions rather than strict guidelines. In many cases, strong
consensus was not achieved.
Guidelines in practice
Dissemination and use of SSc recommendations, as well as
agreement and compliance to them, is important to reduce
practice variability, especially for non-experts who see fewer SSc
patients [52].
Expert agreement to most of the original EULAR/EUSTAR
recommendations was quite positive, with variations possibly
due to regional availability of certain pharmacologic agents [53].
Although the guidelines were generally well accepted by experts,
it is not clear if the recommendations are followed in practice.
Research has shown that prior to the availability of the EULAR
guidelines, there was site variation in SSc for both investigations
and treatment practices, such as the use of PDE5 inhibitors and
immunosuppressants. Larger centers reported higher rates of PAH,
possibly suggesting better detection programs and care gaps
especially in smaller SSc sites [54]. Variability among non-expert
rheumatology centres included different rates of annual echocar-
diograms (from 10% to 90%) and use of CCBs (from 10% to 60%)
[52]. When examining compliance to the guidelines, only 25–40%
of patients received the recommended treatment for various
manifestations of SSc if the SSc patients qualified for its use. This
trend of non-adherence to guidelines has been previously docu-
mented [55], often with 50% adherence [56].
It has been shown in the past that SSc experts treat more SSc
patients than general rheumatologists, and are more likely to use
unproven treatments, but less likely to use treatments that have
been proven ineffective [10]. However, the gap between expert
sites and other rheumatologists for SSc management may be small
[10,52,54,55]. As the updated EULAR/EUSTAR recommendations
and the BSR guidelines are disseminated, gaps in care can be
studied.
Expert commentary
There are mostly similarities between the EULAR/EUSTAR
recommendations and the British guidelines. The British guide-
lines include health care delivery. Often guidelines cannot account
for every possible scenario and treatment and good clinical judg-
ment cannot be replaced by guidelines. Guidelines have fairly good
agreement by experts but are not fully adopted in routine clinical
practice. Because SSc is rare, expert sites are likely to give state of
the art care for complex SSc patients (but not necessarily all
patients with SSc).
What could happen in SSc over the next 5 years
There will be changes to treatment in the next 5 years in SSc.
There are several RCTs of anti-cytokine therapy in early dcSSc
(such as trials of tocilizumab and abatacept). Although stem cell
transplantation may be more widely considered for poor prognosis
early dcSSc patients, there needs to be other treatment with more
selective targets. Specific cells in SSc may be targeted (dendritic,
mesenchymal, pericytes, etc.). In SSc we can learn that mono-
therapy for overall disease modification is unlikely to be as
effective as the rational use of combination therapies as is often
true in rheumatoid arthritis. Large databases may help to deter-
mine treatment protocols that appear successful, which can then
be tested in robust trials. The role of steroids in SSc will need to be
defined. The most favorable drug treatment combinations for PAH,
use of anticoagulation, immune modulation, benefits of treating
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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
elevated PA pressures and PAH in asymptomatic SSc patients, and
the most appropriate screening tests are yet to be determined. The
exclusion of SSc patients with significant ILD from PAH treatment
protocols leaves a gap in knowledge for the treatment of these
patients. ILD treatment will continue to evolve with induction
followed by maintenance therapy. Patients are often selected for
trials in the first 5 years of SSc but most will die of their ILD at
7–10 years so there are no RCT data on how to treat these patients
in later disease and trials have not been designed to include them.
The treatment of RP and digital ulcers has evolved where PDE5
inhibitors are commonly used in moderate to severe cases.
Prevention of digital ulcers may include high dose statins and
vasodilator treatment. Cardiac MRI may be utilized more to
determine cardiac involvement. We may not be further ahead in
5 years for calcinosis, pain, pruritus, and GI treatment. Inflamma-
tory arthritis could be divided by phenotype (RA overlap, non-
erosive SLE like, and highly destructive like psoriatic arthritis with
mutilans) and treatment borrowed accordingly form those dis-
eases. New classification of subsets of SSc patients may help in
identifying at risk patients. Although there has been hope that
personalized medicine will help to find high-risk subsets and
determine who will respond to specific treatments, it is unlikely
that in a complex polygenic disease that we will have biomarkers,
gene tests, proteomics, etc. that will be available and clinically
relevant in SSc. Access for patients with SSc to early diagnosis,
appropriate often expensive medications and care will require
awareness and advocacy.
Key issues
 Systemic sclerosis (SSc) is a rare and serious connective tissue
disease of unknown origin involving fibrosis of the skin and
visceral organs, vascular damage, and production of
autoantibodies.
 The clinical heterogeneity, rarity, and severity of SSc contribute
to the necessity for guidelines particularly evidence-based
where possible.
 The first comprehensive recommendations were created by the
European League Against Rheumatism (EULAR) and EULAR
Scleroderma Trials and Research group (EUSTAR) in 2009,
based on the best evidence published up to December 2006.
These recommendations have been updated and recently
presented and are awaiting publication.
 The EULAR/EUSTAR recommendations pertain to the manage-
ment of SSc features such as Raynaud's phenomenon (RP),
digital ulcers (DU), pulmonary arterial hypertension (PAH), skin
involvement, lung involvement, scleroderma renal crisis (SRC),
and gastrointestinal involvement.
 EULAR/EUSTAR recommendations are pharmacologic, and do
not include many suggestions regarding investigations and
non-pharmacologic management.
 SSc guidelines created by the British Society for Rheumatology
(BSR) and British Health Professionals in Rheumatology (BHPR)
are based on data collected up to June 2014.
 The BSR guidelines are similar to the organ manifestations
mentioned in the EULAR/EUSTAR recommendations, and
expand on several domains of treatment, including general
measures, non-pharmacologic treatment, cardiac involvement,
calcinosis, and musculoskeletal features.
 Research performed by Walker et al. attempted to synthesize
an algorithmic approach to management based on expert
agreement especially after first-line treatment was not effective
where RCT data are often lacking.
 The EULAR/EUSTAR recommendations were generally accepted
by SSc experts, with variations probably attributable to regional
 R.E. Pellar, J.E. Pope / Seminars in Arthritis and Rheumatism 46 (2017) 767–774
access to certain medications and perhaps modest efficacy for
some treatments.
 There are gaps in care for SSc treatment especially since it is a
rare disease that is very heterogeneous and involves many
different organs, especially for the rheumatologist who is not at
an expert SSc center.
 Care gaps such as systematic screening for pulmonary hyper-
tension have been identified with site variation for investiga-
tions and treatment of some features of SSc.
 Current research has indicated a potential benefit of autologous
hematopoietic stem cell transplantation (HSCT) in select cases
of early diffuse cutaneous SSc patients with poor prognosis
features, however, further research is required to properly
define appropriate patients. There is a significant early mortal-
ity (10%) of HSCT but in selected patients, there is a survival
advantage at 3 years.
Acknowledgments
Russell Pellar—nothing to disclose. Janet Pope—consulting for
Actelion, Bayer, Biogen, BMS, Roche. Clinical trials for Actelion,
Bayer, BMS, Roche.
Appendix A. Supplenmentary information
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.semarthrit.2016.
12.003.
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