Systemic Sclerosis - 2015

PRIMER
Systemic sclerosis
Yannick Allanore1, Robert Simms2, Oliver Distler3, Maria Trojanowska2, Janet Pope4,
Christopher P. Denton5 and John Varga6
Abstract | Systemic sclerosis is a complex autoimmune disease characterized by a chronic and frequently
progressive course and by extensive patient-to‑patient variability. Like other autoimmune diseases,
systemic sclerosis occurs more frequently in women, with a peak of onset in the fifth decade of life. The
exact cause of systemic sclerosis remains elusive but is likely to involve environmental factors in a
genetically primed individual. Pathogenesis is dominated by vascular changes; evidence of autoimmunity
with distinct autoantibodies and activation of both innate and adaptive immunity; and fibrosis of the skin
and visceral organs that results in irreversible scarring and organ failure. Intractable progression of
vascular and fibrotic organ damage accounts for the chronic morbidity and high mortality. Early and
accurate diagnosis and classification might improve patient outcomes. Screening strategies facilitate
timely recognition of life-threatening complications and initiation of targeted therapies to halt their
progression. Effective treatments of organ-based complications are now within reach. Discovery of
biomarkers — including autoantibodies that identify patient subsets at high risk for particular disease
complications or rapid progression — is a research priority. Understanding the key pathogenetic
pathways, cell types and mediators underlying disease manifestations opens the door for the development
of targeted therapies with true disease-modifying potential. For an illustrated summary of this Primer,
visit: http://go.nature.com/lchkcA
Systemic sclerosis is an autoimmune disease that is systemic sclerosis for both diagnosis and classification.
characterized by the distinctive pathogenetic triad of lcSSc is commonly associated with centromere-specific
microvascular damage, dysregulation of innate and antibodies, whereas dcSSc is more often associated
adaptive immunity, and generalized fibrosis in multi- with topoisomerase I- or RNA polymerase III-specific
ple organs. Although skin fibrosis is the distinguishing antibodies4. However, not all patients with systemic
hallmark, the pathological changes in the lungs, gastro- sclerosis fall clearly into one of these two disease sub-
intestinal tract, kidneys and heart determine the clini- sets, and some can change their subset assignment
cal outcome. In general, the extent of skin involvement over time. Furthermore, some individuals present with
and its rate of progression reflect the severity of visceral hallmark clinical and serological features of systemic
organ complications1,2. sclerosis in the absence of detectable skin involvement
A striking feature of systemic sclerosis is its patient- (systemic sclerosis sine scleroderma); others manifest
to‑patient variability, and heterogeneity has been features of another connective tissue disease, such as
observed in clinical manifestations, autoantibody pro- rheumatoid arthritis or polymyositis, in overlap with
files, tempo of disease progression, response to treat- systemic sclerosis (overlap syndrome).
ment and survival (TABLE 1). On the basis of the extent In 2013, revised classification criteria — the
of their skin involvement, patients are grouped into American College of Rheumatology (ACR)–European
limited cutaneous systemic sclerosis (lcSSc) and diffuse League Against Rheumatism (EULAR) criteria — were
Correspondence to J.V.
e-mail: j‑varga@
cutaneous systemic sclerosis (dcSSc) subsets3. In lcSSc, proposed to address some of the difficulties in classi-
northwestern.edu skin fibrosis is restricted to the fingers (sclerodactyly), fication5,6. However, none of the currently used classifi-
Department of Medicine, distal extremities and face, whereas in dcSSc, the trunk cation schemes adequately captures disease complexity
Feinberg School of Medicine, and proximal extremities are also affected. In patients and heterogeneity in systemic sclerosis, suggesting that
Northwestern University,
240 E Huron Street, Chicago,
with lcSSc, Raynaud phenomenon (BOX 1) typically pre- a clinically useful, new taxonomy based on genetic or
Illinois 60612, USA. cedes skin involvement and other disease manifesta- molecular disease determinants needs to be developed
tions by months to years, whereas patients with dcSSc and implemented in future clinical practice and trials.
Article number: 15002
doi:10.1038/nrdp.2015.2
have rapid disease progression with extensive skin In this Primer, we describe the epidemiology and
Published online changes and early development of visceral organ com- genetic risks of systemic sclerosis, current views of
23 April 2015 plications. Autoantibodies are particularly helpful in pathogenesis, and approaches to screening, diagnosis and
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1
© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER
Author addresses
(OR 1.28; 95% CI 1.11–1.47; P < 0.001) and pulmonary
arterial hypertension (PAH; OR 3.01; 95% CI 1.47–6.20;
1
Rheumatology A Department, Cochin Hospital, Paris, France. P < 0.003). In a longitudinal study (mean follow‑up
2
Department of Medicine, Boston University School of Medicine, Boston, 4.9 ± 2.7 years), male sex was predictive of new onset
Massachusetts, USA. of PAH (hazard ratio (HR) 2.70; 95% CI 1.38–5.29;
3
Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
P = 0.004), heart failure (HR 2.15; 95% CI 1.03–4.48;
4
Department of Medicine, St. Joseph’s Health Centre, London Ontario, Canada.
5
University College London Division of Medicine and Royal Free Hospital, London, UK.
P = 0.04) and all-cause mortality (HR 1.48; 95% CI 1.19–
6
Department of Medicine, Feinberg School of Medicine, Northwestern University, 1.84; P < 0.001). Male sex has been consistently shown to
Chicago, Illinois, USA. be a poor prognostic factor in systemic sclerosis.
As in other connective tissue disorders such as sys-
prevention of organ complications. We end by presenting temic lupus erythematosus, ethnicity has a role in
an outlook for the future. systemic sclerosis. A large US study 10 showed that Afri
can American patients presented at a younger mean age
Epidemiology than white patients (47 years versus 53 years; P <0.001).
Prevalence and incidence estimates of systemic scle- Furthermore, two-thirds of white patients exhibited
rosis around the world vary substantially. Lower esti- lcSSc, whereas the majority of black patients had dcSSc
mates of prevalence (<150 per million) and incidence (P < 0.001). The race differential was mirrored by the find-
(<10 per million per year) have been observed in north- ing that African Americans with systemic sclerosis were
ern Europe and Japan, whereas higher estimates of more likely to have antibodies against topoisomerase I
prevalence (276–443 per million) and incidence (14–21 and less likely to be positive for centromere-specific anti-
per million per year) have been reported in southern bodies. In addition, African American patients experi
Europe, North America and Australia7. The 2013 ACR– enced an increase in risk of mortality (relative risk (RR)
EULAR classification criteria are more sensitive than 1.8; 95% CI 1.4–2.2) after adjustment for age at disease
the criteria published in the 1980s because they include onset and disease duration. Thus, race is related to a dis-
patients who are positive for centromere-specific anti- tinct phenotypic profile, and there is a trend towards less
bodies and who have limited cutaneous involvement 8. favourable outcomes in African American patients.
As a consequence, the estimated prevalence of systemic The overlap between systemic sclerosis and other
sclerosis based on the ACR–EULAR classification cri connective tissue disorders has been recognized for
teria (for example, 88 per million in men, 514 per mil- some time. The links between connective tissue diseases
lion in women and overall 305 per million in Sweden) are further supported by the results from genome-wide
was much higher than previously published estimates7,8. association studies (GWASs) that highlight the criti-
The development of systemic sclerosis is sex depend- cal role of shared autoimmunity. The co‑occurrence of
ent and, as is true for all connective tissue diseases, is another autoimmune disease with systemic sclerosis
much more common in women (FIG. 1). However, the was investigated in a meta-analysis of 6,102 patients
EULAR Scleroderma Trials and Research (EUSTAR) with systemic sclerosis obtained from 10 studies11. Of
cohort (see the EUSTAR website) has revealed some these patients, 1,432 had one or more additional auto
unusual features in men9. In a cross-sectional study of immune disease corresponding to a weighted prevalence
9,182 patients with systemic sclerosis, including 1,321 of poly-autoimmunity of 26% (95% CI 20–32%). Thus,
men, male sex was independently associated with these results confirm that poly-autoimmunity is fre-
a higher risk of dcSSc (odds ratio (OR) 1.68; 95% CI quent in systemic sclerosis, affecting 25% of patients. It
1.45–1.94; P < 0.001), a higher frequency of digital ulcers remains to be determined how this finding might affect
Table 1 | Clinical subsets in systemic sclerosis

Clinical subset Clinical manifestations Primary targets of autoantibodies Disease course
Limited cutaneous • Distal skin fibrosis, sclerodactyly, Centromere proteins • Raynaud phenomenon may precede
systemic sclerosis telangiectasia and calcinosis cutis other manifestations
may be prominent • Slow progression with late
• Severe interstitial lung disease and development of PAH
scleroderma renal crisis are very rare
Diffuse cutaneous • Proximal skin fibrosis up to elbows Topoisomerase I and RNA • Rapidly progressive skin fibrosis
systemic sclerosis and knees, including trunk polymerase III • Early occurrence of renal, cardiac and
• Tendon friction rubs may be present pulmonary complications
Systemic sclerosis No detectable skin involvement Nuclear and centromere proteins Raynaud phenomenon, nailfold capillary
sine scleroderma abnormalities and PAH
Overlap syndrome Features of another connective U1 RNP, PM–Scl, Ro and La • Prominent musculoskeletal
tissue disease in the setting of involvement
systemic sclerosis • Lung fibrosis and scleroderma renal
crisis are uncommon
PAH, pulmonary arterial hypertension; RNP, ribonucleoprotein.
2 | 2015 | VOLUME 1 www.nature.com/nrdp

PRIMER
Box 1 | Raynaud phenomenon

and the precise contribution of these interactions to
disease susceptibility and phenotype.
• Raynaud phenomenon refers to reversible vasospasm
of arteries, such as digital arteries Vascular injury and microangiopathy
• In systemic sclerosis, the vasospasms are Microvascular injury and endothelial cell activation that
accompanied by progressive structural damage, results in vascular damage are the earliest, and possi-
including proliferation of the arterial intima, bly primary, events in systemic sclerosis14. Progressive
adventitial fibrosis and collagen deposition vascular damage causes a reduction in the number of
• Vasodilators target vasospasm, especially calcium capillaries (rarefaction), thickening of the vessel wall
channel blockers, phosphodiesterase 5 inhibitors due to intimal and smooth muscle cell proliferation,
and prostacyclins
and luminal narrowing, which lead to tissue hypoxia and
oxidative stress14. In addition, activated endothelial cells
show increased expression of the adhesion molecules
the outcomes and how it could be used to guide the vascular cell adhesion protein 1 (VCAM1), intercellular
choice of treatments and also the positioning of potential adhesion molecule (ICAM) and E‑selectin, resulting
biologic agents. in recruitment of inflammatory cells. They also secrete
endothelin 1, connective tissue growth factor (CTGF;
Mechanisms/pathophysiology also known as CCN2) and other profibrotic factors that
Systemic sclerosis is thought to be caused by environ- stimulate vascular smooth muscle cell proliferation
mental events in a genetically susceptible individual and extracellular matrix production. Inflammatory cell
that trigger a chronic and self-amplifying multifocal infiltration in the lesions can be prominent in patients
process characterized by vascular alterations, inflamma- with early-stage disease, and inflammatory and immune
tion and autoimmunity, and fibrosis12 (FIG. 2). Cell types cells are an important source of TGFβ, PDGF, IL‑1, IL‑6
prominently implicated in the disease process include and other profibrotic mediators (FIG. 2).
endothelial cells, platelets, structural cells (pericytes,
vascular smooth muscle cells, fibroblasts and myofibro- Inflammation and immune response
blasts) and immune cells (T cells, B cells, monocytes, Dysregulation of both innate and adaptive immunity
macrophages and dendritic cells). Prominent mediators plays a prominent part in systemic sclerosis. Evidence
of cell activation include transforming growth factor-β of (auto)immunity includes the presence of inflamma-
(TGFβ), platelet-derived growth factor (PDGF), IL‑6 tory cells and inflammatory signatures in target tissues
and IL‑13, endothelin 1, angiotensin II, lipid media- such as the skin and lungs; alterations in the number
tors and autoantibodies, along with reactive oxygen and function of circulating immune cells; the pres-
species (ROS) and numerous other biologically active ence of a prominent type I interferon (IFN) signature
substances13. Still poorly understood is the pathogenetic in circulating and tissue-infiltrating immune cells;
basis for female predominance, the disease heterogeneity and characteristic and distinct serum autoantibodies
and variable outcomes, the nature of environmental trig- detected in most patients. Furthermore, genetic stud-
gers and their interplay with the genetic background, ies identified that polymorphisms of IRF5 (interferon
regulatory factor 5) and STAT4 (signal transducer and
2,500 activator of transcription 4), along with several other
Male immune pathway genes, are prominently associated
Female with systemic sclerosis15.
2,000
Cellular response. Circulating and tissue-infiltrating
Number of patients
monocytes and macrophages, plasmacytoid dendritic

1,500
cells and stromal cells show a type I IFN signature,
defined by increased expression of IFN-regulated
1,000 genes, which reflects activation of Toll-like receptor
(TLR)-mediated immune signalling 16–18. TLR activation
in these cells is thought to be triggered by endogenous
500 ligands, such as nucleic acid-containing immune com-
plexes, as well as by damage-associated molecular pat-
0
terns (DAMPs), such as variants of extracellular matrix
<30 30–39 40–49 50–59 60–69 70–79 >80 components generated during tissue injury.
Age (years) Fibrotic tissue also displays prominent infiltration
| Disease of bone marrow-derived immune cells that include
Figure 1 | Characteristics of the EUSTAR cohort. FigureNature Reviews
shows the gender andPrimers
age
CD4+ T cells, macrophages, activated B cells, plasma-
distribution of the European League Against Rheumatism (EULAR) Scleroderma Trials
and Research (EUSTAR) cohort in 2013. The EUSTAR registry contains baseline and yearly
cytoid dendritic cells and mast cells. Among CD4+
follow‑up data of approximately 10,000 patients with systemic sclerosis from about T cells, type 2 T helper (TH2) cells — characterized by
200 centres. However, inclusion and exclusion criteria may vary between studies, which secretion of IL‑4 and IL‑13 — predominate over TH1
leads to differences in sample size. More information on cohort characteristics and cells, which primarily secrete anti-fibrotic IFNγ19. The
quality control is available at www.eustar.org. role of TH17 cells remains to be defined, with some

PRIMER
Endothelial Adhesion are increased in the serum and fibrotic tissue, and they
activation molecule Platelets stimulate fibroblast proliferation and extracellular
matrix synthesis in cell cultures25. These findings are
1 supported by studies in animal models, as illustrated
Endothelin 1 Thrombin IFNα by the attenuation of fibrosis in mice with the genetic
Chemokines Thromboxane PF4 deletion of Il13, whereas targeted overexpression of Il13
PDGF results in pulmonary fibrosis26.
Of special interest in systemic sclerosis is IL‑6, a
B T multifunctional cytokine produced by T cells and
cell cell
B cells, fibroblasts, fibrocytes and endothelial cells.
Autoantibodies
2 IL‑6 signals through the widely expressed GP130
Macrophage TLR4 Dendritic receptor that forms a heterodimer with IL‑6 receptor
TH2 cell subunit-α, which activates the JAK/STAT and mitogen-
cell activated protein kinase (MAPK) pathways and induces
TH2‑dominant immunity, inflammation and fibrotic
TGFβ
responses. High levels of IL‑6 in systemic sclerosis
IL-13 correlate with the extent of skin involvement and por-
IL-6 tend poor long-term outcomes27. In vitro, an antibody
against human IL‑6 reduced type I collagen levels in
Fibroblast fibroblasts derived from patients with systemic sclero-
sis, whereas mice with the genetic deletion of Il‑6 had
reduced inflammation and fibrosis after a profibrotic
3 ROS
challenge (bleomycin). Moreover, administration of
TGFβ an IL‑6 receptor-specific antibody in mice prevented
CTGF
development of fibrosis induced either by bleo
mycin or by immunization with topoisomerase I28,29.
These observations provide the rationale for ongo-
ECM ing clinical trials of IL‑6 receptor-specific antibody
Myofibroblast Collagen, fibronectin, (tocilizumab) in systemic sclerosis (ClinicalTrials.gov
periostin and tenascin-C
identifier NCT01532869).
Figure 2 | The disease process in systemic sclerosis. The fibroblast activation and
Nature Reviews | Disease Primers Chemokines have important roles in angiogenesis,
fibrosis underlying systemic sclerosis are induced by vascular injury and endothelial wound healing and fibrosis. Serum and tissue lev-
activation, leading to an uncontrolled inflammatory reaction. Step 1: the vascular
els of C-C motif chemokine 2 (CCL2; also known as
response to injury consists of endothelial activation; production of endothelin 1 and
chemokines; increased expression of adhesion molecules; and platelet activation. MCP1), CCL3 (also known as MIP1α), IL‑8 and CCL18
Step 2: in response to chemokines and adhesion receptors, several types of are increased in patients with systemic sclerosis, cor-
inflammatory cells are recruited. Activated type 2 T helper (TH2) cells secrete TGFβ relate with disease severity and can predict progres-
and IL‑13; B cells produce autoantibodies and IL‑6; macrophages release sion30–32. Plasmacytoid dendritic cells from patients
transforming growth factor-β (TGFβ); and dendritic cells secrete interferon-α (IFNα) were found to secrete markedly elevated amounts of
and platelet factor 4 (PF4). Step 3: resident fibroblasts, activated by this cytokine the small chemokine platelet factor 4 (PF4; also known
‘cocktail’, generate reactive oxygen species (ROS) and undergo differentiation into as CXCL4); under physiological conditions, PF4 is pri-
myofibroblasts, which are responsible for the excessive extracellular matrix (ECM) marily localized in α‑granules of activated platelets33.
production. Activation of Toll-like receptor 4 (TLR4) on immune cells and Levels of PF4 were elevated in the sera and skin from
myofibroblasts by the ECM further exacerbates this reaction. CTGF, connective
patients with systemic sclerosis and were good predic-
tissue growth factor; PDGF, platelet-derived growth factor.
tors of the risk of pulmonary complications, including
lung fibrosis and PAH33.
studies implicating IL‑17 in fibrosis and other studies
indicating an anti-fibrotic effect 20. Finally, emerging Autoantibodies. Nearly all patients with systemic scle-
evidence suggests an important pathogenetic role of rosis have highly specific circulating autoantibodies
tissue macrophages with an ‘alternatively activated’ M2 (TABLE 2). Most commonly, these autoantibodies are
phenotype. Levels of soluble CD163, a marker for directed against intracellular nuclear and nucleolar
M2 macrophages, are elevated in the sera of patients components, but they can also be directed against cell
with systemic sclerosis, as well as on macrophages in surface receptors and extracellular antigens, includ-
the affected skin and lungs21–24. The mechanisms of ing fibrillin 1, matrix metalloprotease 1 (MMP1) and
how these polarized macrophages are differentiated — MMP3 (REF. 34). Although the diagnostic importance
as well as how they contribute to the induction, pro- of nuclear- and nucleolar-specific antibodies in sys-
gression and possibly resolution of vascular damage temic sclerosis is well recognized, their potential role
and tissue fibrosis — remain to be determined. in contributing to pathogenesis and tissue damage
is not. However, of interest is that patients with sys-
Cytokines and chemokines. TH2 cytokines, including temic sclerosis have been reported to have circulating
IL‑4 and IL‑13, have prominent roles in the pathogen- autoantibodies to cell surface receptors for acetylcho-
esis of systemic sclerosis. The levels of TH2 cytokines line (the muscarinic acetylcholine receptor M3), PDGF,

PRIMER
Table 2 | Selected autoantibodies linked to complications in systemic sclerosis integrins and changes in cytoskeletal tension mediated
by focal adhesion kinase (FAK) and RHO-associated
Primary target of Immunofluorescence Clinical association kinase. These signals activate the downstream effectors
autoantibody pattern
YAP (Yes-associated protein) and TAZ (transcriptional
Diffuse cutaneous systemic sclerosis co-activator with PDZ-binding motif), which perpetu-
DNA topoisomerase I Speckled Interstitial lung disease ate fibroblast activation and further exacerbate the
RNA polymerase III Speckled Renal crisis and cancer fibrotic process40.
In addition, high levels of alternatively spliced
Fibrillarin (ribonucleolarprotein; Nucleolar PAH and myositis
targets U3 RNP) isoforms of extracellular matrix molecules such as
fibronectin (fibronectin-EDA (FnEDA)) and tenascin‑C
Limited cutaneous systemic sclerosis are known to accumulate within fibrotic lesions. One
Centromere proteins Centromeric Ischaemic digital ulcers study demonstrated that these isoforms can directly
and telangiectasia bind to TLR4 on stromal cells and induce fibro-
blast activation and myofibroblast differentiation41.
Blocking TLR4 signalling might therefore represent a
Th/To ribonucleoprotein Nucleolar Interstitial lung disease
novel therapeutic opportunity for halting fibrosis.
PAH, pulmonary arterial hypertension; RNP, ribonucleoprotein. Of the multitude of soluble mediators implicated
in systemic sclerosis, TGFβ is commonly viewed as
the master regulator of fibrosis 42. This pleiotropic
endothelin 1 and angiotensin II, among others. These cytokine is secreted from macrophages and other cells
autoantibodies have been shown in some studies to be as an inactive precursor complexed to latent TGFβ-
functional, as they were capable of triggering receptor binding protein and deposited within the extracellular
activation and eliciting profibrotic responses35,36. matrix; it is converted to its biologically active form via
integrin-mediated activation. Canonical TGFβ signal-
Fibrosis ling involves sequential phosphorylation of the type I
The distinguishing hallmark of systemic sclerosis is TGFβ receptor (TGFR1; also known as ALK5), activa-
progressive tissue accumulation of fibrous matrix tion of cytosolic signal transducers SMAD2–SMAD3,
composed of collagen, elastin, glycosaminoglycan and and their binding to a consensus SMAD-binding ele-
fibronectin. The process leads to permanent scarring ment found in TGFβ‑inducible profibrotic genes. The
and replacement of normal tissue architecture with com- SMAD pathway is positively and negatively regulated
pact, mechanically stressed, rigid connective tissue13. by various factors, including SMAD7, which blocks
Excessive accumulation of extracellular matrix results SMAD signalling, and the nuclear receptor NR4A1,
from a combination of increased synthesis by activated which promotes SMAD7 degradation and modulates
stromal cells; enhanced assembly and crosslinking cata- TGFβ signalling 43,44. Fibrotic TGFβ responses can also
lysed by prolyl and lysyl oxidase and transglutaminase 2; be mediated via the transcription factor early growth
and defective degradation37. response 1 (EGR1), the non-receptor tyrosine kinases
Fibrotic tissue is characterized by the presence of ABL1 (previously known as c‑ABL) and FAK, and
α‑smooth muscle actin-positive, apoptosis-resistant potentiated via inactivation of transcriptional repressors
myofibroblasts. These contractile cells secrete not only such as peroxisome proliferator-activated receptor-γ
matrix molecules but also TGFβ and other profibrotic (PPARγ), friend leukaemia integration 1 (FLI1) and
mediators, further promoting extracellular matrix accu- krüppel-like factor (KLF) family members13. Fibroblasts
mulation and remodelling. The origin of activated mes- derived from patients with systemic sclerosis show con-
enchymal cells in fibrosis is of great research interest stitutive FAK activation, which integrates TGFβ sig-
and has therapeutic implications38. Monocyte-derived nalling and integrin-mediated mechanotransduction
circulating mesenchymal progenitor cells (fibrocytes) to drive persistent myofibroblast differentiation and
— as well as tissue-specific transdifferentiation from ROS generation45. Other identified intracellular TGFβ
pericytes, telocytes and endothelial cells — might each signalling pathways implicated in systemic sclerosis
contribute to expansion of the reservoir of disease- include MAPK1 and MAPK3 (also known as ERK2 and
causing myofibroblasts. A recent study using lineage ERK1, respectively), p38, phosphatidylinositol 3‑kinase
tracing indicates that the majority of myofibroblasts (PI3K), AKT and TGFβ-activated kinase 1 (TAK)42. As
in the fibrotic dermis in mice arise from intradermal integrins, ABL1, FAK and other TGFβ mediators can all
adipocyte progenitors39. be selectively targeted by pharmacological inhibitors,
Fibroblast differentiation, recruitment, prolifera- they represent potential therapeutic targets.
tion and activation in systemic sclerosis are controlled CTGF is a cysteine-rich matricellular protein
by a combination of mechanical factors and paracrine that functions in conjunction with TGFβ to enhance
and/or autocrine mediators (FIG. 3). Excessive collagen fibrotic responses. CTGF is expressed at low levels in
deposition and crosslinking increases tissue stiffness normal tissues but is markedly increased in the sera
and reduces elasticity of affected organs, resulting in of patients with systemic sclerosis, and levels corre-
mechanical stress. Fibroblasts sense and respond to late with the extent of skin and pulmonary fibrosis46.
mechanical forces in their environment through a pro- TGFβ, endothelin 1 and angiotensin II are potent
cess of mechanotransduction that involves cell surface inducers of CTGF47.

PRIMER
a TGFβ d e Endothelin 1
b Angiotensin II
Hypoxia ECM
ITG S1P/LPA
CTGF
NOX4
TGFR1 TGFR2 ILK
FAK/SRC
ABL1 RHO ROCK
ROS PI3K/AKT
(H2O2; O2–) SMAD2/3 MAPK1/3 miR-21
SMAD4
LRP5/6 α-SMA
CREBBP/p300 CTGF
WIF1 EGR1 ETS1 SMAD2/3 SP1 Tenascin-C
WNT CTGF YAP/WWTR1 MKL f
PKCδ FLI1 HDAC1 PPARγ Collagen SRF
MYD88/TCAM1
DKK1 TEAD 1/2
HDAC7 Other ECM CD14
Frizzled FnEDA
c proteins Tenascin-C
β-catenin TCF/LEF α-SMA Stiff matrix
Collagen
TLR4
proliferation NF-κB JUN IRF3
miR-29
Nucleus STAT6 STAT3
Collagen
PI3K RAS α-SMA
Survival PDPK1 RAF
AKT ERK miR-29 suppression
Collagen
TGFβ
PDGFR JAK1 JAK Cytoplasm
TYK2
IL-4R IL-13R-α1 GP130 IL-6R
Migration g
h PDGF Proliferation IL-13 IL-6
Figure 3 | Molecular mechanisms of fibroblast activation in systemic multiprotein signalling complex composed of FAK, SRC, MEK,
195 | Disease Primers
sclerosis. Fibroblast activation and their transdifferentiation to integrin-linked protein kinase (ILK), RHOANature Reviews
and F‑actin . Moreover, the
myofibroblasts are regulated by various paracrine and/or autocrine profibrotic effects of CTGF are mediated through the ITG and SRC in dermal
molecules and mechanical stimuli, and this process involves a highly fibroblasts196. Two known transcriptional regulatory pathways mediate the
complex and interconnected intracellular signalling cascade50. cellular response to mechanical signals: myocardin-related transcription
a | Transforming growth factor-β (TGFβ) signalling has a central role by factors, MKL/myocardin-like protein 1 (MKL1), MKL2 and serum response
inducing profibrotic gene expression through activation of canonical factor (SRF); and the components of the Hippo pathway, YAP1 and WW
(SMAD2–SMAD3 (SMAD2/3)- and SMAD4‑dependent) and non-canonical domain-containing transcription regulator protein 1 (WWTR1)197.
pathways, and through crosstalk with other intracellular signalling e | Alternatively, this pathway can be stimulated by RHO small GTPase and
pathways. SMAD2/3 cooperates with other transcriptional activators (for F‑actin signalling, which is activated by endothelin 1, angiotensin II and
example, ETS1) to induce the expression of connective tissue growth factor sphingosine 1 phosphate/lysophosphatidic acid (S1P/LPA). f | Connective
(CTGF), collagen and other profibrotic genes189–191. Of note, the transcription tissue molecules, such as an alternately spliced variant of fibronectin (FnEDA)
co‑activators p300 (a histone acetyltransferase) and CREB-binding protein and tenascin‑C, which are induced by TGFβ and constitutively upregulated
(CREBBP), which are also present in the transcriptional complex at the in systemic sclerosis, represent damage-associated molecular patterns
promoter region of these genes, are constitutively elevated in fibroblasts (DAMPs) that serve as endogenous ligands of Toll-like receptor 4 (TLR4)41.
isolated from patients with systemic sclerosis67. In addition, TGFβ signalling The TLR4‑mediated profibrotic pathway is not yet fully understood, but it
promotes profibrotic gene expression by inactivating the transcriptional might involve suppression of anti-fibrotic microRNA‑29 (miR‑29). Of note,
repressors friend leukaemia integration 1 (FLI1) and peroxisome miR‑21 is suggested to be involved in promoting the fibrotic response by
proliferator-activated receptor-γ (PPARγ)144,192. Non-canonical TGFβ suppressing an inhibitor of the TGFβ non-canonical pathway — specifically,
signalling pathways with relevance to fibrosis include focal adhesion kinase SMAD7 (REF. 68). g | IL‑6 and IL‑13 are pleiotropic cytokines, which directly
(FAK), ABL1, phosphatidylinositol 3‑kinase (PI3K), mitogen-activated protein or indirectly through TGFβ, drive collagen production and promote fibrotic
kinase 1 (MAPK1)–MAPK3 (MAPK1/3), p38, endoglin and SMAD1 matrix deposition198,199. h | Finally, platelet-derived growth factor (PDGF)
pathways193. The ABL1 pathway, for example, regulates the profibrotic signalling stimulates fibroblast migration, proliferation, survival and matrix
transcription factor early growth response 1 (EGR1)194. b | TGFβ and hypoxia gene expression48. DKK1, dickkopf WNT signalling pathway inhibitor 1;
converge on EGR1 to stimulate NADPH oxidase 4 (NOX4) expression, ECM, extracellular matrix; GP130, envelope glycoprotein 130; HDAC,
leading to reactive oxygen species (ROS) generation194. c | In addition to histone deacetylase; IL‑4R, IL‑4 receptor; IRF3, interferon regulatory
TGFβ, canonical WNT signalling promotes fibrosis. This pathway is found to factor 3; LEF, lymphoid enhancer-binding factor; LRP, low-density
be hyperactivated in fibrotic lesions53. WNT3A induces a fibrogenic lipoprotein receptor-related protein; MYD88, myeloid differentiation
response in dermal fibroblasts53. WNT inhibitory factor 1 (WIF1) is a ROS primary response protein 88; NF‑κB, nuclear factor‑κB; PDGFR, PDGF
target and is constitutively downregulated in fibroblasts derived from receptor; PDPK1, 3‑phosphoinositide-dependent protein kinase 1; PKCγ,
patients with systemic sclerosis50. d | Mechanical stress, sensed by integrins protein kinase C‑γ; ROCK, RHO-associated protein kinase; STAT, signal
(ITGs), also has a pivotal role in the formation of myofibroblasts through transducer and activator of transcription; TCAM1, TIR domain-containing
induction of α‑smooth muscle actin (α‑SMA), CTGF and tenascin‑C, among adaptor molecule 1; TCF, transcription factor; TEAD, transcriptional
others. Mechanical stimulation triggers the formation of an intracellular enhancer factor; TGFR, TGF receptor.

PRIMER
PDGFs also have a role in fibrosis. PDGFs are hetero of skin biopsy samples provide further evidence for acti-
dimeric peptides secreted by platelets, macrophages, vated WNT–β-catenin pathways in systemic sclerosis,
endothelial cells and fibroblasts that function as potent suggesting that therapeutic blockade of WNT signalling
mitogens and chemo-attractants for mesenchymal cells48. might be a possible therapeutic approach.
Transgenic mice expressing a constitutively active PDGF
receptor-α (Pdgfra) develop fibrosis in multiple organs49. Genetic factors
Patients with systemic sclerosis show increased expres- Although the exact cause that triggers the onset of the
sion of PDGFRα and PDGFRβ in the skin and broncho microvascular damage and the associated immune
alveolar lavage fluid and, as noted above, have circulating response and fibrosis remains elusive, interplay
antibodies that trigger PDGFR-mediated fibroblast acti- between genetic factors and environmental events is
vation and ROS generation35. Explanted systemic sclero- likely to play a part. Although systemic sclerosis is not
sis fibroblasts constitutively produce ROS, which might considered to be a Mendelian disorder, in a study of 703
directly contribute to persistent fibrosis via DNA dam- families, first-degree relatives of patients with systemic
age and autocrine amplification of TGFβ, as well as to sclerosis had a RR of 13 (95% CI 2.9–48.6; P < 0.001)
WNT-mediated fibrotic responses in these cells50. for developing systemic sclerosis54; they are also more
The evolutionarily conserved WNT signalling net- likely to develop Raynaud phenomenon, systemic lupus
work controls developmental processes and the mainte- erythematosus and other autoimmune diseases55.
nance of adult tissue homeostasis. Through the canonical
β-catenin intracellular signalling pathways, WNT pro- Single-nucleotide polymorphisms. GWASs and immuno
teins elicit fibrotic responses both directly and through ChIP (chromatin immunoprecipitation) analyses have
TGFβ51. Aberrantly elevated expression of nuclear (acti- identified single-nucleotide polymorphisms (SNPs) at
vated) β‑catenin and its target gene AXIN2 occur in the multiple loci that are associated with susceptibility to
skin and lungs of patients with systemic sclerosis, as well systemic sclerosis in general, and with specific clinical
as in animal models of the disease52,53. Microarray studies and autoantibody-defined disease subsets. In particular,
Table 3 | Selected genetic variants identified as risk factors for systemic sclerosis*
Gene Clinical association Putative function of encoded Study approach Refs
proteins
Major histocompatibility region Systemic sclerosis positive Histocompatibility complex and GWAS and immunoChIP 15
genes (HLA‑DQ1B, HLA‑DQA1, for topoisomerase I- and/or immune regulation
DBP1, DRB1 and NOTCH4) centromere-specific antibodies
IRF5‡ Systemic sclerosis Transcription factor regulating GWAS and immunoChIP 200
inflammatory gene expression
CD247 Systemic sclerosis T cell receptor and antigen recognition GWAS and immunoChIP 201
STAT4 ‡
Systemic sclerosis Signal transducer for type I interferon GWAS and immunoChIP 200
signalling in T cells
BANK1 dcSSc Scaffolding for B cell signalling Candidate gene study 202
A20‑binding inhibitor of NF‑κB Systemic sclerosis Blocks NF‑κB ImmunoChIP 203

activation (TNIP1)‡
TNFAIP3‡ Systemic sclerosis positive for Blocks NF‑κB activation ImmunoChIP 204
centromere-specific antibodies
PTPN22‡ Systemic sclerosis positive Intracellular protein tyrosine ImmunoChIP and 205
for topoisomerase I‑specific phosphatase and negative regulator meta-analysis
antibodies of T cell activation; variants show
increased phosphatase activity that
enhances T cell receptor signalling
PPARG Systemic sclerosis Controls adipogenesis and suppresses GWAS, meta-analysis 206
fibrotic responses and candidate gene
study
MECP2 (located on the dcSSc DNA methylation Meta-analysis 207
X chromosome)
IRAK1 (located on the dcSSc and interstitial lung Intracellular IL‑1 receptor signalling Meta-analysis 208
X chromosome)‡ disease and inflammation
BANK1, B cell scaffold protein with ankyrin repeats 1; ChIP, chromatin immunoprecipitation; dcSSc, diffuse cutaneous systemic sclerosis; GWAS, genome-wide
association study; HLA, human leukocyte antigen; IRAK1, IL‑1 receptor-associated kinase 1; IRF5, interferon regulatory factor 5; MECP2, methyl CpG-binding
protein 2; NF-κB, nuclear factor-κB; PPARG, peroxisome proliferator-activated receptor gamma; PTPN22, tyrosine protein phosphatase non-receptor type 22;
STAT4, signal transducer and activator of transcription 4; TNFAIP3, tumour necrosis factor α‑induced protein 3; TNIP1, TNFAIP3‑interacting protein 1. *Genetic
abnormalities associated with systemic sclerosis and identified by GWASs, meta-analyses, candidate gene studies and ChIP analyses. ‡Loci also associated with
systemic lupus erythematosus.

PRIMER
SNPs in the major histocompatibility complex (MHC) pharmacological HDAC inhibition in wild-type fibro-
class II region showed strong associations56. In addition, blasts resulted in suppression of fibrotic responses65,66.
high-density SNP genotyping of autoimmune disease- Indeed, the acetyltransferase p300 has been shown
associated loci identified multiple non-MHC susceptibil- to promote fibrotic responses by enhancing collagen
ity loci (TABLE 3). A majority of these genetic variants are transcription. Importantly, p300 levels are elevated in
functionally implicated in immune regulation. However, systemic sclerosis fibroblasts67.
as most SNPs were located outside gene-coding or regula- MicroRNAs (miRNAs) are non-coding RNAs of
tory regions, their causal role remains to be established. 18–23 nucleotides in length that function as intracel-
In addition, these studies show that systemic sclerosis lular regulators of gene expression. Of particular inter-
is a complex multigenic disease that shares genetic risk est in systemic sclerosis are miR‑21 and miR‑29, which
factors with systemic lupus erythematosus and other show aberrant expression in patients and might contrib-
autoimmune diseases12, and indicate that immune dysreg- ute to pathogenesis. On the one hand, miR‑21, the level
ulation and autoimmunity are fundamental in the patho- of which is elevated in fibrotic fibroblasts, suppresses
genesis. A major unanswered question is why patients the expression of anti-fibrotic SMAD7, thereby promot-
with systemic sclerosis and systemic lupus erythemato- ing expression of profibrotic genes68. On the other hand,
sus, despite their genetic overlap, display such markedly miR‑29 has inhibitory effects on fibrotic gene expres-
different phenotypes. Moreover, the direct contribution sion; its levels are suppressed by fibrotic stimuli and
of the genetic variants to disease susceptibility and mani- are lower in fibroblasts isolated from patients with sys-
festations, as well as the underlying mechanisms, remains temic sclerosis than in those from healthy controls69,70.
largely unknown. Environmental events and consequent miRNAs can be detected in the circulation and exert
epigenetic changes are likely to have a major role. biological activities when incorporated into micro
vesicles. Although much remains to be learned about
Epigenetic modifications. The relatively modest genetic the spectrum and mechanisms of action of aberrantly
contribution to disease susceptibility has increasingly regulated miRNAs in systemic sclerosis, these regula-
drawn attention to the role of environmentally induced tory non-coding RNAs might be used as biomarkers
epigenetic modifications that stably influence gene and therapeutic targets in the future.
expression without changes in the genetic code. Best
studied among these are DNA methylation, histone Environmental factors
modifications and non-coding RNAs. Several of these Little is known about the environmental, dietary and life-
epigenetic abnormalities have been found in systemic style exposures that might trigger the onset of systemic
sclerosis57,58. A genome-wide DNA methylation analy- sclerosis in genetically susceptible individuals. Although
sis revealed a large number of differentially methylated smoking and alcohol have not been shown to increase
CpG sites in fibroblasts derived from patients with sys- disease risk, occupational exposures to silica dust, vinyl
temic sclerosis59. Two transcription factors shown to chloride and organic solvents might play a part. However,
inhibit fibrotic gene expression, KLF5 and FLI1, were the absence of robust temporal or spatial disease clusters
simultaneously repressed at the epigenetic level owing to argues against the importance of these environmental
promoter methylation and silencing 60. The pathogenetic factors in the pathogenesis of systemic sclerosis71–73.
significance of altered regulation of these two genes was Viruses and other infectious agents might be
highlighted by the observation that transgenic mice involved and have been investigated as potential envi-
with deletions of a single copy of Klf5 and Fli1 spontane- ronmental triggers. Some patients have serum anti-
ously developed a phenotype that recapitulated all three bodies specific to the UL94 epitope of the herpesvirus
key features of systemic sclerosis: skin fibrosis, vasculo cytomegalovirus. Viral infection might have a causal
pathy and B cell activation with autoantibody produc- role in systemic sclerosis by inducing vascular dam-
tion. Moreover, fibroblasts isolated from patients with age and fibroblast proliferation74. In addition, RNA
systemic sclerosis had elevated levels of methylation- from Epstein–Barr virus, another member of the
regulating genes and global DNA hypermethylation Herpesviridae family, has been found in fibroblasts and
coupled with transcriptional silencing of dickkopf WNT myofibroblasts within fibrotic lesions75.
signalling pathway inhibitor 1 (DKK1), WNT inhibitory
factor 1 (WIF1) and secreted frizzled-related protein 1 Diagnosis, screening and prevention
(SFRP1), genes that are involved in WNT signalling 61,62. Classification
CD4+ T cells isolated from patients showed a general- Classification criteria for systemic sclerosis, first pub-
ized reduction of DNA methylation and of methylation- lished in the 1980s, had the primary goal of achieving a
regulating genes such as DNA (cytosine‑5)-methyl- highly specific definition76. These criteria have been used
transferase 1 (DNMT1)63. By contrast, forkhead box for several decades for inclusion of patients into clinical
P3 (FOXP3), which encodes a transcription factor and experimental studies. However, in clinical practice
controlling CD4+ regulatory T (TReg) cell differentia- and in studies not aiming at treating patients with estab-
tion, was hypermethylated64. Post-translational histone lished or advanced-stage disease, these criteria lacked
modifications, including acetylation, deacetylation and adequate sensitivity, particularly in (non-advanced)
methylation, are also implicated in systemic sclero- patients with limited or no skin fibrosis77.
sis. Although levels of histone deacetylases (HDACs) These obvious limitations led to the afore-
have been reported to be either elevated or reduced, mentioned joint effort of the ACR and EULAR to

PRIMER
Table 4 | The ACR–EULAR criteria for classification of systemic sclerosis* Systemic Sclerosis (VEDOSS) initiative80,81. The results
from their Delphi exercise with a group of international
Item Sub-item Weight experts suggested that individuals who had Raynaud
or score‡
phenomenon in combination with puffy fingers, charac-
Skin thickening of the fingers NA 9 teristic nailfold or systemic sclerosis-specific antibodies
of both hands extending
proximal to the metacarpo (or, alternatively, more than one of these items in the
phalangeal joints§ absence of Raynaud phenomenon) should be referred to
an expert centre for further evaluation. These consen-
Skin thickening of the fingers|| Puffy fingers 2
sus data were supported by a long-term, single-centre
Sclerodactyly of the fingers (distal to 4 Canadian study, which revealed that 65% of patients
the metacarpophalangeal joints but
proximal to the interphalangeal joints) with Raynaud phenomenon, who have an abnormal
pattern on capillaroscopy and/or specific antibodies,
Fingertip lesions|| Digital tip ulcers 2
developed definite systemic sclerosis at 5‑year follow-
Fingertip pitting scars 3 up. By contrast, <1% of the patients who only had
Telangiectasia NA 2 Raynaud phenomenon progressed to definite systemic
Abnormal nailfold capillaries NA 2
sclerosis82. This finding is supported by additional stud-
ies83 and has important implications for clinical practice.
Lung involvement PAH and/or interstitial lung disease 2 Measurement of systemic sclerosis-specific antibodies
Raynaud phenomenon NA 3 and nailfold capillaroscopy is advisable in patients with
Scleroderma-related Any of centromere-, topoisomerase I- and 3 new-onset Raynaud phenomenon, particularly when
autoantibodies RNA polymerase III-specific antibodies additional features such as puffy fingers are present.
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; Considering the high prevalence of Raynaud
NA, not applicable; PAH, pulmonary arterial hypertension. *These criteria are applicable to phenomenon (up to 5.4% in males and 7.5% in females
any patient considered for inclusion in a systemic sclerosis study. The criteria are not
applicable to patients with skin thickening sparing the fingers or to patients who have a
in European populations)84, it might be argued that
scleroderma-like disorder that better explains their manifestations (that is, nephrogenic such an approach is too costly and might lead to over-
sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, diagnosis of mild cases that might never develop severe
scleromyxedema, erythromelalgia, porphyria, lichen sclerosus, graft-versus-host disease and
diabetic cheiroarthropathy). ‡A summary score of ≥9 is sufficient to fulfil the criteria. organ and life-threatening complications. However,
§
Sufficient criterion. ||The higher of the two is counted. Table reproduced from Ann. Rheum. some data underline that patients with early-stage
Dis., Van den Hoogen, F. et al., 72, 1747–1755, 2013 with permission from BMJ Publishing disease have increased prevalence of digital ulcers,
Group Ltd, and from REF. 5, © 2013 by the American College of Rheumatology.
gastrointestinal dysmobility, abnormal heart function
parameters on echocardiograms and a compromised
develop more-sensitive criteria that considered modern diffusing lung capacity for carbon monoxide (DLCO)
diagnostic measures5,6 (TABLE 4). The 2013 ACR–EULAR below 80%85,86. In addition, severe complications of
criteria showed high sensitivity and specificity (0.91 the kidneys, heart, lungs, and gastrointestinal tract
and 0.92, respectively) in an international multicentre generally develop within 3 years of disease onset, par-
validation cohort of patients with systemic sclerosis and ticularly in patients with dcSSc87. These observations
scleroderma-like disorders. This level of sensitivity and highlight the need for prompt referral of patients with
specificity was improved over previously published clas- suspected systemic sclerosis to specialized centres and
sification criteria and has been confirmed in a recent the need for criteria to identify patients with early sys-
analysis from the Canadian Scleroderma Research Group temic sclerosis who are at risk for developing dcSSc
cohort, which pointed to the importance of including and/or major internal organ involvement.
Raynaud phenomenon and puffy fingers as criteria78.
There are several important considerations when Screening and diagnosis
applying the 2013 criteria. First, the classification items Similar to other rheumatic diseases, early diagnosis of
are cumulative, and past medical history must therefore organ involvement enables timely therapeutic inter-
be considered. Second, the criteria should not be applied vention to prevent irreversible organ damage and to
to patients with skin thickening that spares the fingers improve prognosis (FIG. 4). For example, patients with
or those who have a scleroderma-like disorder such as PAH identified through a systematic screening pro-
scleromyxedema or generalized morphea that better gramme showed less-severe PAH at baseline than
explains the skin manifestations. Most importantly, the those identified by routine clinical practice, which led
classification criteria are not meant to be diagnostic. For to improved survival for screened patients88. Although
example, although the 2013 criteria in a patient cohort these observations might be confounded by potential
enriched for early or mild systemic sclerosis clearly out- lead time bias, the results are consistent with benefi-
performed the 1980 criteria, 44% of patients with early cial effects of early treatment of patients with PAH89. In
and mild forms of the disease (according to expert con- patients at high risk for scleroderma renal crisis, includ-
sensus) were still not classified79. These results show that, ing those with early-stage (<4 years from onset) or
although the diagnosis is often straightforward when the progressive disease courses and RNA polymerase III-
disease is advanced and severe, it remains challenging in specific antibodies, regular blood pressure screening
individuals with early or mild disease. is appropriate. However, conclusive evidence showing
As definite criteria for early diagnosis are still lack- that this approach is associated with improved patient
ing, EUSTAR launched the Very Early Diagnosis of outcomes is still lacking. Unfortunately, the situation in

PRIMER
with (spontaneous) regression or stabilization might not;

Skin
fibrosis that is, any clinical study of skin fibrosis that does not
(>90%) Raynaud also include a control group with the disease has to be
phenomenon
(90%) interpreted with great caution, as improvement might
simply reflect the natural course of the disease rather
than therapy-specific effects.
Interstitial
lung disease A recent analysis of the EUSTAR cohort has created
(40%) evidence-based criteria to identify patients with dcSSc
at high risk for progression of skin involvement 93. This
PAH study identified short disease duration (<15 months) and
(15%) Telangiectasia
(75%) Calcinosis a low mRSS at baseline (<22) as independent predictors
Ulcers (25%) of later skin worsening. These results are of importance
Musculoskeletal
(40%)
problems for both clinical practice and clinical study design, as
(65%)
they indicate a therapeutic window of opportunity in
Renal crisis early dcSSc before severe skin fibrosis has occurred.
(5–10%)
Pulmonary arterial hypertension. PAH, a life-
Gastrointestinal threatening complication of systemic sclerosis, occurs in
complications
(90%) approximately 15% of patients, especially in those with
lcSSc, long-standing Raynaud phenomenon and prom-
Figure 4 | Organ complications associated with systemic Nature | Disease
Reviews The
sclerosis. Primers
uncontrolled inent vascular manifestations94,95. Risk factors include
fibrosis and scaring of the skin and internal organs in systemic sclerosis leads to severe longer disease duration, presence of centromere-specific
and sometimes life-threatening complications. The average frequency of the specific antibodies and high telangiectasia burden96.
complications is indicated in parentheses. PAH, pulmonary arterial hypertension. Recommendations for PAH screening in systemic
sclerosis have been proposed by respiratory medicine
and cardiology societies. These recommendations
systemic sclerosis is more complex than other rheumatic generally rely on symptoms and abnormal echocardio
diseases. As different patient subgroups develop organ grams97,98. However, symptoms associated with PAH
complications at different stages during disease progres- are nonspecific and generally occur late in the disease
sion, screening algorithms need to be adapted for each course. In addition, although echocardiography alone
of the organ manifestations. can identify later, clinically manifest disease stages,
it is not sensitive enough to detect early, preclinical
Skin fibrosis. The extent of skin fibrosis is often quan- conditions. Thus, appropriate indicators (identified
tified using the modified Rodnan skin score (mRSS), by expert consensus) are now available for referring
which assesses skin thickness at 17 body surface areas patients for right heart catheterization when PAH is
with a scale of 0 (normal) to 3 (severe) and has a maxi- suspected 99,100. The recommendations suggest that
mum total score of 51. Measurements using ultrasono right heart catheterization is appropriate for patients
graphy and durometer have been tested, but the mRSS with unexplained or progressive dyspnoea, dispropor-
remains established as the most feasible approach90,91. tionately low DLCO, echocardiographic evidence of
Although the mRSS is routinely used and has been elevated pulmonary artery pressures and/or evidence
found to be reliable, valid and responsive to change, its of right ventricular volume overload, such as increase
substantial interobserver variability limits its utility 91. in serum levels of amino‑terminal pro-brain natriuretic
In patients with dcSSc, the natural course of skin peptide (NT pro-BNP).
fibrosis is generally characterized by a rapid increase, These recommendations are supported by consid-
followed by a stabilization (plateau) period, after which erable evidence from clinical studies. For example, the
skin fibrosis slowly ameliorates. Although this disease Cochin risk prediction score considered simple clini-
course has been confirmed in many clinical trials for the cal measures such as forced vital capacity (FVC), DLCO
overall dcSSc population, the characteristics of the dis- and age to classify patients at high risk for the develop-
tinct stages show a high interindividual variability 92. For ment of PAH — calculated using the formula 0.0001107
example, the time between disease onset and progres- (age) + 0.0207818(100 – FVC) + 0.04905(150 – DLCO/
sion to peak skin score might vary from a few months alveolar volume)101. Values >2.73 put patients at risk
to several years. Similarly, the maximum mRSS ranges of PAH during 24‑month follow-up101. The DETECT
from mild to severe fibrosis associated with contrac- study is the only one that used right heart catheteriza-
ture of large joints and chest wall restriction. To date, tion in all patients to confirm the diagnosis of PAH. The
attempts to enrich clinical studies with patients who have DETECT score (see the DETECT website) is validated in
the same disease trajectory to control for experimental patients with a disease duration of >3 years and DLCO
design have been unsuccessful92. Indeed, the spontane- of <60%102. It recommends a two-step approach with
ous regression of skin fibrosis in late-stage disease cre- clinical and laboratory measures in the first stage. If a
ates challenges for both clinical trial design and clinical certain score is passed, patients are referred to echo
practice. Patients in whom the disease is still progress- cardiography for evaluation of the right atrial area and
ing require therapeutic intervention, whereas patients tricuspid regurgitant jet velocity. Patients deemed to be

PRIMER
high-resolution CT (>20% of lung volume) and clini-

cally meaningful fibrosis with low-lung-function para
meters were associated with worse prognosis in several
studies1,110–112. The presence of topoisomerase I-specific
antibodies is an additional risk factor 113,114. Worsening
of lung function parameters such as FVC might also
be a negative prognostic factor, but this has not been
documented in systemic sclerosis.
Digital ischaemic ulcers. Approval in Europe of an

endothelin receptor antagonist (bosentan) for the pre-
vention of digital ulcers presented a need for predic-
tion algorithms to identify patients who are at risk for
developing new digital ulcers. Several studies showed
that previous or current digital ulcers are one of the
strongest risk factors for recurrent ulcers115. In addition,
Reviews | Disease Primers nailfold capillaroscopy-based indices of microvascular
Figure 5 | Early systemic Nature
sclerosis-associated interstitial
lung disease. High-resolution chest CT scan of a patient alterations have been developed for systemic sclerosis.
with diffuse cutaneous systemic sclerosis is shown. Of The capillaroscopic index (CSURI index) is based on the
note are extensive bilateral subpleural ground glass number and maximum diameter of megacapillaries and
opacities (indicated by black arrows), and early fibrosis capillaries, and is validated in independent cohorts115,116.
and traction bronchiectasis (indicated by yellow arrow Its utility is limited by the fact that megacapillaries have
heads) at the lung bases. These findings are characteristic to be present for calculating the index.
of nonspecific interstitial pneumonia.
Management
Systemic sclerosis involves a wide spectrum of clini-
at risk are further tested by right heart catheterization. The cal features that encompass vascular, immune and
DETECT algorithm outperformed current consensus- fibrotic manifestations, and affects many organs. No
based society guidelines on the identification of PAH single approach to treatment has proved uniformly
and on the resources spend on catheterization. effective, and clinical trials are limited by the lack of
adequate outcome measures and the variable course
Interstitial lung disease. Interstitial lung disease is clini- of the disease. Current therapeutic approaches include
cally significant in approximately 40% of patients and general immunosuppression and complication-specific
accounts, together with PAH, for approximately 50% of therapies. Future studies show promise to use poten-
all systemic sclerosis deaths103. Screening tools used in tially more-sensitive and more-specific biomarkers in
current clinical practice, such as pulmonary function the assessment of optimal therapeutic approaches.
tests (spirometry and DLCO) and 6‑minute walking dis- The initial approach to optimal management of sys-
tance, have low sensitivity to detect systemic sclerosis- temic sclerosis is to determine the disease phenotype and
associated interstitial lung disease. For example, in a disease stage117. Phenotype assessment is important in
recent analysis, >50% of patients who have systemic determining potential complications that differ between
sclerosis and interstitial lung disease had normal lung the two principal systemic phenotypes of the disease
function parameters 104. High-resolution CT scan- (that is, lcSSc and dcSSc)118,119. For example, renal dis-
ning detects interstitial lung disease in most patients ease tends to be much more common in dcSSc, whereas
with abnormal lung function parameters. At disease PAH tends to be observed more frequently in lcSSc.
onset, ‘ground glass opacification’ is observed on high- Observational studies have demonstrated that rapid pro-
resolution CT images of the chest that can progress to gression of organ involvement predominantly occurs in
‘honeycomb’ changes and traction bronchiectasis105 the earlier stages of disease. In late-stage disease, fibrosis
(FIG. 5). The clinical presentation is nonspecific inter in patients with both lcSSc and dcSSc might remain quite
stitial pneumonitis with predominantly basilar involve- stable and, therefore, not require intervention117.
ment 106. Repeat CT imaging should be limited owing to
the radiation dose. Novel approaches that show prom- Immunosuppression and immunomodulation
ise include ultrasonography and high-resolution CT Immunomodulation is the ‘centrepiece’ of current ther-
with lower radiation exposure using reduced number apeutic approaches and is based on the rationale that
of slices107–109. Bronchoalveolar lavage and lung biopsy this resets the immune system. More-targeted therapies
have not been shown to have diagnostic or predictive are currently not yet available.
value and are consequently rarely indicated. Immunomodulatory approaches with myelosup
In many patients with systemic sclerosis, interstitial pression or myeloablation followed by autologous
lung disease remains mild. Thus, identification of those haematopoietic stem cell (HSC) transplantation have
who might show progression towards organ failure been evaluated as a therapeutic strategy in systemic
is an important clinical challenge. Early-stage dcSSc sclerosis. As an example, the ASSIST trial was an open-
(disease duration <3–4 years), extensive fibrosis on label, randomized Phase II trial, in which patients with

PRIMER
Table 5 | Selected clinical trials in systemic sclerosis

Therapeutic Mechanism of action Trial status ClinicalTrials.gov
agent identifier
Interstitial lung disease
Mycophenylate Immunosuppressive Ongoing randomized trial versus NCT00883129
mofetil cyclophophosphamide (SLS II)
Pirfenidone Anti-fibrotic Open-label safety trial completed NCT01933334
Palmolidomide Anti-fibrotic Open-label safety trial in progress NCT01559129
Overall disease
Fresolimumab Anti-fibrotic (TGFβ‑specific antibody) Open-label safety trial completed NCT01284322
Rilonacept IL‑1 inhibitor Randomized trial in progress NCT01538719
Tocilizumab IL‑6 receptor-specific antibody Randomized trial in progress NCT01532869
Abatacept T cell activation inhibitor Randomized trial in progress NCT02161406
TGFβ, transforming growth factor-β.
dcSSc and pulmonary involvement were treated with immunosuppressive or immune ablation treatments are
intravenous cyclophosphamide followed by either HSC urgently needed. No such therapy currently exists, but
transplantation (treatment arm) or monthly pulse intra- there are several promising therapies in development that
venous cyclophosphamide (control arm). At 12‑month target potential drivers of disease pathogenesis. These
follow‑up, all 10 patients who received HSC trans- agents include tocilizumab (which targets IL‑6), abata-
plantation showed improvement in skin score (mRSS cept (T cell activation inhibitor), fresolimumab (which
decreased by at least 25%) and in lung function (FVC targets TGFβ) and rilonacept (IL‑1 inhibitor) (TABLE 5).
increased by at least 10%) compared with none of the 9
patients in the control arm120. Results from a multicentre Interstitial lung disease
European trial (ASTIS) showed that high-dose immuno- The standard of care for systemic sclerosis-associated
suppressive therapy and autologous HSC transplantation interstitial lung disease includes assessment of disease
in patients with early dcSSc who had poor prognoses stage and chronology — more specifically, stability or
(most of whom had either interstitial lung disease or a progression using high-resolution CT and assessment
history of scleroderma renal crisis) experienced a sur- of changes in pulmonary functions with spirometry
vival benefit over conventional immunosuppression121. and DLCO. Immunosuppressive therapy might be
In this study, 156 patients were randomly assigned either appropriate for patients who show evidence of progres-
to conventional immune suppression with monthly sion or early-stage disease. For patients with end-stage
intravenous cyclophosphamide or to high-dose cyclo- disease, lung transplantation can be considered122.
phosphamide followed by autologous HSC transplanta- Several clinical trials have provided evidence to sup-
tion. At a median of 5.8 years of follow‑up, there was a port the use of immunosuppressive agents in the man-
significant event-free (event defined as death or irrevers- agement of systemic sclerosis-associated interstitial lung
ible organ failure) survival benefit in the transplantation disease. One randomized clinical trial compared pla-
group121. Although this approach is clearly of benefit for cebo to oral cyclophosphamide over a 12‑month period
patients with a poor prognosis, it is not for all patients, (Scleroderma Lung Study I123) and showed a signifi-
as 10% of all treatment-related mortality occurred with cant benefit in lung function parameters (FVC) in the
HSC transplantation. Thus, HSC transplantation should experimental arm. However, a follow‑up study showed
be viewed as a potential therapeutic option for patients that this benefit decreased after 2 years, suggesting a
with aggressive systemic sclerosis but should not be con- transient response124. Post-hoc analysis revealed that
sidered a standard of care. Additional trials have also patients with more-extensive lung fibrosis at baseline
been initiated. For example, a large multicentre trial had greater improvement in FVC than those with mod-
comparing monthly intravenous cyclophosphamide to est lung fibrosis. Of note, patients with diffuse skin fibro-
myeloablation with cyclophosphamide and total body sis had a greater reduction in skin scores than patients
irradiation (SCOT) has completed enrolment, but with less skin involvement. Another randomized,
results are not yet available (ClinicalTrials.gov identi- placebo-controlled trial explored monthly intravenous
fier NCT00114530). Another multicentre clinical trial cyclophosphamide administration (for 6 months) fol-
(STAT) of myeloablation followed by HSC transplan- lowed by oral azathioprine (for 6 months) and showed
tation and long-term immunosuppression (myco a trend towards improvement in the treated group with
phenylate) for dcSSc is currently recruiting subjects changes in FVC and DLCO as the primary outcomes125.
(ClinicalTrials.gov identifier NCT01413100). Other therapies currently under evaluation include
Given the modest benefit of conventional immuno mycophenylate mofetil (immunosuppressive), pirfeni-
suppressants, which are associated with risks and done (anti-fibrotic), palmolidomide (anti-fibrotic) and
the efficacy of which decreases over time, targeted rituximab (which targets CD20) (TABLE 5).

PRIMER
Pulmonary arterial hypertension inhibitors, scleroderma renal crisis was associated

Therapy of systemic sclerosis-associated PAH has with progression to end-stage renal disease and high
undergone considerable advances over the past decade. mortality. ACE inhibitors have substantially improved
First-line therapy includes vasodilating, rather than outcomes, although the risk of progression to end-
immunosuppressive, agents. Almost all therapeutic trials stage renal disease remains 50% even with early use of
of PAH included patients with systemic sclerosis; how- these drugs133,135. Approximately 30% of patients who
ever, only one randomized trial has so far exclusively require renal replacement therapy are able to discon-
examined systemic sclerosis-associated PAH126. The tinue haemodialysis within 1 year with continued ACE
pharmacological approaches to PAH include blocking inhibitor treatment 136. The use of ACE inhibitors to pre-
the vasoconstrictive effects of endothelin 1 (ET1 antag- vent renal crisis is paradoxically associated with worse
onists) or enhancing the vasodilatory effects of nitric renal outcomes and increased mortality, perhaps because
oxide (phosphodiesterase (PDE) and guanylate cyclase new or worsening hypertension is masked by incomplete
inhibitors) and prostacyclin (epoprostenol and trepro- inhibition of the renin–angiotensin system137.
stinil). Endothelin antagonists (including bosentan,
ambrisentan and macitentan), PDE inhibitors (sildenafil Digital ulcers and Raynaud phenomenon
and tadalafil) and guanylate cyclase inhibitors (riociguat) Raynaud phenomenon and digital ischaemic ulcers
have shown marked haemodynamic and symptomatic occur in approximately 90% and 40% of patients with
improvement in PAH127. However, only the most recent systemic sclerosis, respectively, and account for substan-
ET1 inhibitor, macitentan, has shown a significant tial morbidity with pain and limitation of hand func-
improvement in event-free (event defined as death or tion138,139. First-line therapy for symptomatic Raynaud
hospitalization from PAH) survival in a trial of predomi- phenomenon commonly includes calcium channel
nately idiopathic and connective tissue disease-associated blockade. Resistant or severe Raynaud phenomenon
PAH compared with placebo128. Early evidence suggests can be treated with PDE5 inhibitors such as tadalafil
that combination oral therapies — for example, ET1 or sildenafil, which have also shown to be of benefit
antagonists combined with PDE5 inhibitors — might be for digital ischaemic ulcers140,141. Endothelin antago-
more effective than single agents129. nists seem to be helpful in preventing digital ischaemic
The current standard of care for symptomatic ulcers but not in healing established ulcers142,143. Other
patients with NYHA (New York Heart Association) treatment options reported to be effective include topi-
functional class II (mild to moderate impairment) is to cal nitrates (Raynaud phenomenon), intradigital injec-
start with ET1 or PDE5 inhibitors. For patients with tions of botulinum toxin (severe digital ischaemia and
advanced-stage disease or NYHA functional classes III– ulceration) and intravenous prostanoids (threatened
IV, continuous intravenous infusion with prostacyclin digital ischaemia)144.
derivatives, such as epoprostenol, can be considered130.
Lung transplantation is an option for some patients with Musculoskeletal complications
end-stage disease122. A notable proportion of patients with systemic sclerosis
develop arthropathy or myositis, which may contribute
Skin fibrosis substantially to extremity dysfunction and disability.
The assessment of skin disease, a cardinal manifestation Physical and occupational therapy to maintain finger
of systemic sclerosis, is hampered by the lack of sensi- mobility and extremity function are important adjunc-
tive and specific outcome measures, and by the vary- tive therapies. Low-dose prednisone can provide symp-
ing natural history of the disease. No single therapy has tomatic and functional benefit for both inflammatory
yet been shown to be conclusively effective. In patients arthritis and myositis. Prednisone at doses >15 mg
with dcSSc, the mRSS typically decreases over time, daily is generally avoided in patients with dcSSc owing
complicating the assessment of the skin as an outcome to concern about precipitating renal crisis145. Weekly
in clinical trials131. A multicentre trial of methotrexate methotrexate treatment can be used for musculoskeletal
versus placebo showed a trend towards improvement complications. Open-label studies of TNF-blocking
in the methotrexate arm at 24 months132. In the SLS I agents, abatacept and tocilizumab suggest that these
trial, a modest but significant improvement in mRSS agents may be of benefit in some cases117,146.
was observed in cyclophosphamide-treated patients with
dcSSc compared with controls123. Gastrointestinal involvement
Upper gastrointestinal involvement occurs in approxi-
Scleroderma renal crisis mately 90% of patients with systemic sclerosis. The
Scleroderma renal crisis occurs in approximately 5% most common complication is gastroesophageal reflux
of patients, most commonly in those with dcSSc and disease owing to disordered oesophageal motility and
early-stage (<4 years) disease. The use of steroids is to incompetence of the lower oesophageal sphincter,
recognized as a risk factor, as is the presence of RNA which results in oesophagitis, oesophageal strictures and
polymerase III-specific antibodies133. Renal crisis onset Barrett oesophagus. Varying degrees of gastrointestinal
is generally heralded by the sudden development of dysmotility can occur almost anywhere along the gastro-
hypertension, progressive renal insufficiency, protein intestinal tract and lead to aspiration, pseudo-obstruction
uria and evidence of microangiopathy 134. Prior to the and bacterial overgrowth147,148. Gastric antral venous
introduction of angiotensin-converting enzyme (ACE) ectasia can be a cause of gastrointestinal haemorrhage149.

PRIMER
Treatment of gastrointestinal complications remains is more difficult to treat, and options consist of anti-
largely symptomatic. In addition to anti-acid treatment, histamines, lubrication of the skin, less bathing to
pro-motility agents (such as metchlopramide, domperi- prevent the skin from drying out, heat, massage and
done, octreotide and erythromycin), antibiotics for bac- exercise. Fatigue is usually multifactorial. If it is associ-
terial overgrowth and argon laser ablation for lesions are ated with iron deficiency, treating the underlying cause
occasionally effective147. can provide relief: erosive oesophagitis can be treated
with proton pump inhibitors and pro-motility agents,
Calcinosis cutis whereas repeated laser therapy can alleviate the gastric
Tumoral calcinosis or calcinosis cutis occurs in up antral vascular ectasia. Administration of iron or blood
to 25% of patients with systemic sclerosis. Calcinosis transfusions might be necessary. Anaemia caused by
has a broad spectrum of severity ranging from tiny chronic disease is likely to improve upon suppression
asymptomatic lesions detected as incidental radio- of inflammation. In 15% of patients, secondary Sjögren
logic findings, to large bulky deposits associated with syndrome develops with dry eyes and mouth, which
severe symptoms150,151. No treatment has been shown can be treated with artificial tears and frequent dental
to be uniformly effective. Surgical removal or debulking visits169. Most men with systemic sclerosis experience
may be options for patients with especially troublesome erectile dysfunction164.
lesions152. The development of a validated radiographic The increased risk of malignancy is a concern in sys-
scoring system to evaluate calcinosis may facilitate the temic sclerosis, as is the case in other chronic inflamma-
systematic assessment of therapeutic options153. tory conditions. A meta-analysis showed that the pooled
standardized incidence ratio (SIR) for cancer in patients
Quality of life with systemic sclerosis was 1.41 (95% CI 1.18–1.68)170.
Systemic sclerosis is associated with an increase in The most common were lung, liver, haematological and
mortality, but this has been improving during the past bladder cancers, although absolute risk is lower than the
few decades154. As systemic sclerosis is a multisympto- general population. Of note, men are at higher risk than
matic disease, quality of life of patients may be severely women for developing cancers. In both groups, the pres-
affected147. A review on how to measure quality of life ence of RNA polymerase III-specific antibodies seems
in systemic sclerosis is beyond the scope of this Primer to be associated with an increased risk for cancers, par-
but has been covered elsewhere139,155,156. Overall, gen- ticularly those developing at an early stage in the natu-
eral health, as measured by the SF‑36 health survey, is ral history of systemic sclerosis171,172. Moreover, patients
reduced in systemic sclerosis compared with the age- and with RNA polymerase III-specific antibodies who have
sex-matched controls157. Patients with systemic sclerosis developed cancers often have somatic alterations in the
also have poor quality of life as measured by a reduced POLR3A gene, which encodes RNA polymerase III173,
patient global assessment of health, chronic pain, fatigue and show specific immune responses directed against
and sleep disturbance157–159. Functional impairment often the mutated RNA polymerase III subunit (RPC1) anti-
worsens over time (as measured by the Health Assessment gen. These findings suggest that the mutations triggered
Questionnaire Disability Index (HAQ‑DI))160. cellular immunity and cross-reactive humoral immune
Many symptoms affect quality of life in systemic responses that might have a role in disease pathogenesis.
sclerosis — for example, pain161, gastrointestinal symp- In addition to these physical morbidities, many
toms, pruritus (itch)162, fatigue, sleep problems, work patients develop psychological complications, includ-
disability 163 and sexual dysfunction164. Work disabil- ing symptoms of depression, anxiety, fear of disease
ity in systemic sclerosis is higher than in rheumatoid progression and dying, and body image concerns from
arthritis165. The pain experience can have many causes, disfigurement 174,175. Clinical depression is not preva-
such as skin inflammation, Raynaud phenomenon, dig- lent, but depressive symptoms are increased compared
ital ulcers, inflamed calcinosis and joint and/or tendon with the general population; this is a common feature
swelling. Pain scores averaged around four out of ten of chronic diseases in which chronic pain occurs176,177.
on a visual analogue scale in a population of patients If there is clinical depression in systemic sclerosis, the
with systemic sclerosis on treatment (outpatients who usual treatment would be similar to other people diag-
were attending a follow-up visits)157. Pain management nosed with depression, such as use of antidepressants177.
comprises chronic pain medication (pregabalin, gaba As systemic sclerosis often causes visible changes to
pentin, serotonin–noradrenaline reuptake inhibitor the patient’s face — for example, telangiectasia, tight
(duloxetine) and selective serotonin reuptake inhibi- skin, increased wrinkles around the mouth when skin
tors), as well as treatments targeting the underlying softens, small upper lip, and loss of subcutaneous fat
cause. Gastrointestinal complications impair quality of around the cheeks and nose — a stigma is associated
life substantially 166. Symptoms include faecal inconti- with systemic sclerosis. There is a questionnaire that
nence, choking, aspiration, bloating, gas, constipation, has been developed for patients with systemic sclerosis
diarrhoea, early satiety and gastric dumping. Treatment with respect to their appearance178. Patients also experi-
directed at the pathology can help and includes treat- ence tightening of their hands, with swollen fingers or
ment of small-bowel overgrowth with antibiotics, stool contractures, or with ulcers or digital loss. All of these
softeners, laxatives and pro-motility agents for severe changes may have an impact on self-esteem and can
constipation. A validated instrument to measure vari- enhance a fear of dying in the patient. Trials are under-
ous gastrointestinal symptoms is often used167,168. Itch way to improve hand function, body image and mood

PRIMER
Enrolment per arm 6–12 months 1–2 years

Phase I/II n = 10–20
Phase II/III n = 30–60
Phase III pivotal n = 40–80
Interim
Treatment end-point Treatment
assessment
Parallel-group design
Early biomarker
Random Continue blinded
Cohort Traditional assessment to
assignment study — additional
design explore molecular
standard treatments
mechanisms
if clinically needed
Interim
Placebo end-point Placebo
assessment Final
end-point
assessment
Cohort defined according Treatment
to drug and target organ
• Subset Crossover design Clinical end points
Interim Additional standard
• Disease duration end-point • Modified Rodnan
• Markers of acute phase treatments if skin score
assessment clinically needed
• Nuclear-specific • Scleroderma HAQ
antibody subtype • Digital ulcer count
• Systemic sclerosis Placebo • Lung function (FVC)
complications • Dyspnoea questionnaire
(for example, lung fibrosis, • Potential composite
PAH and digital ulcers) response index
Figure 6 | Future of clinical trial design in systemic sclerosis. The validation of potential medications
Nature Reviews or treatment
| Disease Primers
strategies to tackle systemic sclerosis requires the development of a novel and robust clinical trial design. Essential
parameters to implement such a novel scheme include an improved definition of patient subgroups, biomarker validation
and better end-point assessment. The strategy proposed here is still speculative and might have to be refined in the future,
but it illustrates several key areas in which progress is feasible. First, study cohorts should be defined in greater detail to
enrich for the population that has progressive disease or that has the specific complication under evaluation.
Second, the inclusion of a placebo control arm would reduce difficulties in evaluating variable clinical outcomes.
Third, implementation of a crossover design in which patients are randomly assigned to active drug treatment after a
placebo phase will strengthen data emerging from Phase I/II studies. Last, traditional clinical end-point assessment — such
as examination of skin, digital ulcerations, lung fibrosis and other potential aspects of systemic sclerosis — requires
updating. Possible tools that can be used are disease-specific patient-reported outcomes and composite disease response
indices that incorporate multiple end points such as skin score, lung function and a health assessment questionnaire (HAQ),
and may be more responsive than individual outcomes. For interim end points, biomarker validation in the blood and/or
skin biopsy is preferred over clinical parameters. Interim end points can be assessed early for evidence of
pharmacodynamic effects or biomarker assessment: at 6 months in early-phase trials (Phase I/II) or 12 months for later
studies (Phase II/III). A follow‑up by a crossover or an open-label study for an additional 6 months can enhance the power of
the interim trial. If required, adding additional standard treatments for the skin or lung will help to sustain the
parallel-grouped, blinded, placebo-controlled design for at least 12 months, which is likely to be the minimum timeframe to
obtain clinically meaningful benefits for these conditions. FVC, forced vital capacity; PAH, pulmonary arterial hypertension.
through an innovative Internet network (Scleroderma set‑up, as well as to the nature of the agents tested. The
Patient-centered Intervention Network (SPIN))179. development of a standard design for clinical trials
in systemic sclerosis is still required and proves to be
Outlook difficult (FIG. 6). Standardization is important because,
Although systemic sclerosis remains a major clinical by analogy with other areas of rheumatology, estab-
and research challenge, there are reasons to be opti- lishment of a reliable trial template will enable drug
mistic about progress in the next few years. Substantial development to progress, which will be central to
advances in the past decade have demonstrated the improvements in disease management 180.
feasibility of progress and pointed to new avenues for Recent studies show that high-intensity immuno-
future success in understanding the disease process and suppression is a key addition to evidence-based treat-
in improving clinical outcomes. Below, we focus our ment in systemic sclerosis121. Nonetheless, finding better
discussion on areas in which we envision progress. and less-toxic ways of achieving the same therapeutic
outcome is essential121. Research should also focus on
Advances in clinical trials regenerative medicine and prevention of complications.
After many years of frustration in developing feasible Indeed, the non-lethal burden of systemic sclerosis is
and robust clinical studies, the outlook finally shows considerable and will only increase as treatments that
promise. Clinical trials are being completed that are target lethal complications improve. Research on clinical
able to differentiate active treatment from placebo outcomes needs to be re‑evaluated to take this eventu-
owing to better design and understanding of the trial ality into account, and better clinical strategies to treat

PRIMER
calcinosis, ulcerations, gut disease and fatigue need to susceptibility factors or phenotype modifiers. Antibody-
be developed. based subgroups will also help to define disease subsets
Triage of new potential therapies can be facilitated and elucidate pivotal biological mechanisms, including
by the development of molecular markers and predic- the potential role of autoantibodies that target relevant
tive scores that can be applied in the clinic1. Biomarkers cell surface proteins and receptors.
are important, as there are many promising therapeutic Moreover, despite similarities between organ-based
avenues to explore; however, there are limited numbers pathologies — such as pulmonary fibrosis, PAH and
of patients available for trials, and centres with the essen- accelerated hypertension occurring outside the context
tial infrastructure and capacity to perform such trials. of systemic sclerosis — there remain key differences that
The number of new therapies, together with the poten- have yet to be understood. Better insights in the disease
tial repurposing of existing drugs, is likely to lead to an process will be important when considering transla-
inevitable ‘bottleneck’ for early-phase studies. Although tion or repurposing of emerging or existing therapies.
the development of better assessment tools, such as Advances in the past two decades have already improved
validated biomarkers and composite clinical scores, is the overall survival of patients with dcSSc, including a
challenging, it is essential for countering this problem181. more systematic approach to monitoring that enables
earlier detection of significant complications that may
Better definition of disease subgroups be treated; use of specific therapies for complications
Systemic sclerosis is characterized by a very hetero such as PAH or scleroderma renal crisis; and advances
geneous array of symptoms, even within the currently in chronic supportive care.
classified subgroups. Indeed, although certain compli-
cations are more frequent in dcSSc, this is not always the Dysfunctional tissue remodelling
case. Moreover, it remains unknown why some mani- Progress in understanding the biology of systemic scle-
festations such as gastroesophageal reflux or secondary rosis has depended on drawing appropriate analogies
Raynaud phenomenon are universal in systemic sclero- from other areas of science, especially developmental
sis, whereas others affect only a proportion of patients. biology and genetics. It is compelling to view systemic
Novel classification criteria are required to better predict sclerosis as an almost inevitable consequence of having
the risk of complications and to justify early monitor- a connective tissue repair pathway that is essential for
ing and preventive treatment strategies, in addition to survival. It is intriguing that this might have some selec-
tailoring treatment and stratifying patients for inclusion tive advantage in the population. In addition, this may
in clinical trials182,183. Subgroups are likely to be defined, provide an explanation for the persistence of the trait
to a large extent, on the basis of autoantibody subtypes, and the observed ethnic and racial differences.
either in isolation or in combination with clinical or Furthermore, the pathological mechanisms are likely
other variables. For example, topoisomerase I- and RNA to be shared with other conditions, including other
polymerase III-specific antibodies seem to be strong autoimmune diseases and other forms of fibrosis. Key
predictors of lung fibrosis and scleroderma renal crisis, questions are how these processes in systemic sclerosis
respectively, and are now included in the 2013 classifica- differ from other conditions and what the triggers or
tion criteria. Other antibodies associated with disease aetiopathological factors are. Moreover, the advances in
subtypes are likely to be identified through the use of reparative niche microenvironments, plasticity of pro-
proteomic and other molecular approaches, and these genitor cells and location-specific cellular programming
might complement gene or protein expression-based will help to better understand the role of progenitor and
systemic sclerosis subsets. stem cells in systemic fibrosis41. Indeed, delineating the
disease process might be sufficient to progress therapy,
Molecular basis of disease especially in an era of targeted biological approaches.
A better understanding of the disease process and con-
nection between the complications in the different Bidirectional research translation
organs will help to better tailor treatments to individual Animal models have been useful to extending our
patients. Although deciphering the link between cuta- knowledge of the pathophysiology of systemic sclerosis,
neous involvement and internal organ complications is but it is likely that optimal use of patient samples will
prominent, it remains an important challenge. Research have more potential to lead to bidirectional research
efforts of consortia aim to have sufficient biological translation184. The disease process and its similarity to
samples linked to clinical annotation, which will lead the human pathology need to be validated in animal
to better insights of the autoimmune process, includ- models. If these models are validated, they will become
ing the intriguing link between cancer and systemic platforms for preclinical evaluation of novel treatments
sclerosis172,173. Furthermore, elucidating the impact of of specific complications such as PAH185. Thus, it is
the microbiome and the potential role of infection or likely that as the understanding of disease biology in
colonization in triggering or progressing the pathology systemic sclerosis grows, substantial clinical develop-
might herald new therapeutic options. ment will follow. Ultimately, the non-lethal burden of
We envision additional focus on epigenetics, which systemic sclerosis might gain increasing importance
will complement the advances in genetics. Challenges because patients will survive longer. In addition, dis-
are the identification of disease-specific features and ease management could be improved through use of
the determination of, for example, whether they are targeted therapeutics that may differentially benefit

PRIMER
Cellular mechanisms Cell–cell interactions Organ-specific treatment
Soluble Cytokine Lipid Peptide

Signalling cytokine or growth mediator mediator Mesenchymal cell
molecules receptor factor
LPA Endothelin 1
Fibroblast
IL-6R TGFβ
GP130 IL-13
CTGF Myofibroblast
Cell surface Lung
receptor
Tyrosine kinase Muscle Heart
Endothelin 1R Soluble
and MAPK LPA1R guanylate
IP3R cyclase Kidney
Intracellular Endothelium
signalling Gut
Nuclear hormone
pathways receptor Pericyte
Chromatin or
histone modification PPARγ Smooth muscle cell
Transcriptional
Bromodomain regulators
proteins Skin
Cell adhesion and Integrin B cell

ECM matricellular protein Latent TGFβ
interactions Prolyl hydroxylase T cell
Tissue transglutaminase
Dendritic cell
ECM turnover;
matrix-associated growth factors Macrophage
Figure 7 | Putative therapeutic targets in systemic sclerosis. The design of new therapeutic Reviews | Disease
Nature interventions Primers
will rely on a
greater understanding of relevant signalling molecules, pathways and extracellular matrix (ECM) interactions implicated
in the development and/or progression of systemic sclerosis. Unravelling the key target cells and cellular interactions
between the different cell types involved in the pathology may also lead to new lines of inquiry. Finally, we may be able to
capitalize on our knowledge of existing organ-based treatments that may be useful in systemic sclerosis-specific
complications. CTGF, connective tissue growth factor; GP130, envelope glycoprotein 130; IL‑6R, IL‑6 receptor;
IP3R, inositol trisphosphate receptor; LPA, lipoprotein; MAPK, mitogen-activated protein kinase; PPARγ, peroxisome
proliferator-activated receptor-γ; TGFβ, transforming growth factor-β.
different aspects of the condition. It is encouraging real challenge and opportunity are for targeted and
that novel biological interventions are demonstrating logical disease-modifying therapy. As outlined above,
treatment effect for skin fibrosis186. better patient stratification, advances in biological
understanding, availability of candidate therapeutics
Targeted disease-modifying therapy and improved clinical trial design make the prospect
Historically, major therapeutic advances in systemic feasible, and the first tentative steps towards this have
sclerosis have arisen through the management of spe- already been taken188. It seems more likely than not that
cific, organ-based complications. Acid-suppressive at least one effective novel therapy will emerge in the
medication has transformed the impact and conse- next decade (FIG. 7). This, together with a better under-
quences of severe gastro-oesophageal reflux disease. standing of disease impact and risk stratification, will
Targeted therapies for PAH have benefitted functional make systemic sclerosis much more manageable. The
outcomes and survival, and routine use of ACE inhibi- remaining challenge then will be a health-economical
tors in scleroderma renal crisis means that this com- one, as treatments and longer survival are likely to
plication is no longer almost always lethal187. Other increase the costs, which will need to be addressed by
organ-based treatment advances are likely, but the health-care systems and policy makers.
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PRIMER
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systemic sclerosis. X chromosome to systemic sclerosis susceptibility: Squibb, Inventiva, Medac, Pfizer, Roche/Genentech, Sanofi-
202. Dieudé, P. et al. BANK1 is a genetic risk factor for association with the functional IRAK1 196Phe/532Ser Aventis and Servier. R.S. has/had consultancy relationships
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3447–3454 (2009). Acknowledgements Hoffman–La Roche, Intermune, MedImmune, Novartis,
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TNIP1, PSORS1C1, and RHOB as novel risk loci for Institute of Arthritis and Musculoskeletal and Skin Diseases tancy relationships and/or has received research funding in
systemic sclerosis. PLoS Genet. 7, e1002091 (NIAMS), 1P50AR060780‑01. O.D. is supported by funding the area of systemic sclerosis and related conditions from 4D
(2011). from the European League Against Rheumatism orphan dis- Science, Actelion, Active Biotec, Bayer, Biogen, Biovitrium,
204. Koumakis, E. et al. Brief report: candidate gene ease programme, Swiss National Science Foundation Bristol–Meyers Squibb, Boehringer, EpiPharm, Ergonex,
study in systemic sclerosis identifies a rare and Sinergia, European Union FP‑7 DeSScipher and Rare Disease GlaxoSmithKline, Inventiva, Medac, Novartis, Pfizer,
functional variant of the TNFAIP3 locus as a risk Initiative Zurich (RADIZ). M.T. is supported by grants NIAMS Pharmacyclics, Roche/Genentech, Sanofi-Aventis,
factor for polyautoimmunity. Arthritis Rheum. 64, RO1 AR042334 and P50 AR060780. J.V. is supported by Serodapharm, Sinoxa and United BioSource. J.P. has/had con-
2746–2752 (2012). grants NIAMS AR042309 and AR064925. sultancy relationships and/or has received research funding in
205. Diaz-Gallo, L. M. et al. Analysis of the influence of the area of systemic sclerosis and related conditions from
PTPN22 gene polymorphisms in systemic sclerosis. Author contributions Actelion, Bayer, Biogen, and Roche/Genentech. C.P.D. has/had
Ann. Rheum. Dis. 70, 454–462 (2011). Introduction (J.V.); Epidemiology (Y.A.); Mechanisms/patho- consultancy relationships and/or has received research fund-
206. López-Isac, E. et al. A genome-wide association study physiology (J.V., M.T.); Diagnosis, screening and prevention ing in the area of systemic sclerosis and related conditions
follow‑up suggests a possible role for PPARG in (O.D.); Management (R.S.); Quality of life (J.P.); Outlook from Actelion, Biogen, Biovitrum, Boehringer Ingelheim, CSL
systemic sclerosis susceptibility. Arthritis Res. Ther. (C.P.D.); overview of Primer (J.V.). Behring, GlaxoSmithKline, Inventiva, Novartis, Pfizer, Roche/
16, R6 (2014). Genetech and Sanofi-Aventis. J.V. has acted as a consultant or
207. Carmona, F. D. et al. New insight on the Xq28 Competing interests statement received research funding from Biogen/Idec, Takeda, the US
association with systemic sclerosis. Ann. Rheum. Dis. Y.A. has/had consultancy relationships and/or has received National Institutes of Health, US Department of Defense. M.T.
72, 2032–2038 (2013). research funding in the area of systemic sclerosis and related declares no competing interests.

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PRIMER

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1

© 2015 Macmillan Publishers Limited. All rights reserved

Table 1 | Clinical subsets in systemic sclerosis

2 | 2015 | VOLUME 1 www.nature.com/nrdp

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Box 1 | Raynaud phenomenon

monocytes and macrophages, plasmacytoid dendritic

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 3

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4 | 2015 | VOLUME 1 www.nature.com/nrdp

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NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5

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Nucleus STAT6 STAT3

6 | 2015 | VOLUME 1 www.nature.com/nrdp

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A20‑binding inhibitor of NF‑κB Systemic sclerosis Blocks NF‑κB ImmunoChIP 203

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7

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8 | 2015 | VOLUME 1 www.nature.com/nrdp

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NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9

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with (spontaneous) regression or stabilization might not;

10 | 2015 | VOLUME 1 www.nature.com/nrdp

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high-resolution CT (>20% of lung volume) and clini-

Digital ischaemic ulcers. Approval in Europe of an

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Table 5 | Selected clinical trials in systemic sclerosis

12 | 2015 | VOLUME 1 www.nature.com/nrdp

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Pulmonary arterial hypertension inhibitors, scleroderma renal crisis was associated

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13

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14 | 2015 | VOLUME 1 www.nature.com/nrdp

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Enrolment per arm 6–12 months 1–2 years

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15

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16 | 2015 | VOLUME 1 www.nature.com/nrdp

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Cellular mechanisms Cell–cell interactions Organ-speciﬁc treatment

Soluble Cytokine Lipid Peptide

Cell adhesion and Integrin B cell

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 17

© 2015 Macmillan Publishers Limited. All rights reserved

18 | 2015 | VOLUME 1 www.nature.com/nrdp

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NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 19

© 2015 Macmillan Publishers Limited. All rights reserved

20 | 2015 | VOLUME 1 www.nature.com/nrdp

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NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 21

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