esclerosis 2013

8/18/2019 esclerosis 2013

1/14NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION | 1

Centre forRheumatology andConnective TissueDisease, UCL MedicalSchool, Royal FreeHospital, London NW32QG, UK (C. P. Denton,V. H. Ong).

Correspondence to:C. P. [email protected]

Targeted therapies for systemic sclerosisChristopher P. Denton & Voon H. Ong

Abstract | Pathogenic processes that underlie the development and progression of systemic sclerosis

(SSc) are being defined in preclinical, clinical and genetic studies. Important evidence of interplay between

the vasculature, connective tissue and specialized epithelial structures is emerging, and abnormalities of

both the innate and adaptive immune systems have been identified. In this context, information regarding

pivotal mediators, pathways or cell types that could be targets for therapeutic intervention, and that might

offer potential for true disease modification, is accruing. Precedent for the regression of some aspects of

the pathology has been set in clinical studies showing that potential exists to improve tissue structure and

function as well as to prevent disease progression. This article reviews the concept of targeted therapies and

considers potential pathways and processes that might be attenuated by therapeutic intervention in SSc. As

well as improving outcomes, such approaches will undoubtedly provide information about pathogenesis. The

concept of translational medicine is especially relevant in SSc, and we anticipate that the elusive goal of aneffective antifibrotic treatment will emerge from one of the several clinical trials currently underway or planned

in this disease. Therapeutic advances in SSc would have implications and potential beyond autoimmune

rheumatic diseases.

Denton, C. P. & Ong, V. H. Nat. Rev. Rheumatol. advance online publication 9 April 2013; doi:10.1038/nrrheum.2013.46

Introduction

Systemic sclerosis (SSc; also termed scleroderma) is acomplex, multisystem rheumatic disease in which auto-immunity, inflammation, fibrosis and vasculopathy leadto a complex pattern of organ-based complications withhigh mortality and morbidity.1,2 Studies using tissuesamples and increasingly diverse and sophisticated

animal models, as well as genetic analysis, are helping toelucidate the pathologic mechanisms.3 Susceptibilityto SSc clearly depends on complex host factors as wellas environmental triggers; these predisposing factorsoverlap with those of other disease states, especiallyother autoimmune rheumatic diseases.4,5 The processesby which tissue damage occurs and the key mediators,pathways and cell types involved are being delineated.More enigmatic are the fundamental determinants ofthe disease and a clear explanation of the clinical hetero-geneity in terms of the pattern of organ involvement,severity of the individual disease components and thebasis for different outcomes that may sometimes b e

independent of therapeutic intervention. These keyscientific challenges, together with the inherent diffi-culty of assessing clinical benefit and conducting rigo-rous clinical trials in an uncommon heterogeneousdisease, pose a major barrier to progress. Such obstaclesare important to overcome, because SSc remains a con-dition with the highest case-specific mortality of any of

the autoimmune rheumatic diseases; indeed, more thanhalf of patients diagnosed with the condition eventuallydie as a direct consequence of it.6 Thus, SSc is an orphandisease with high unmet medical need.

In this Review, we outline pathogenic pathways andprocesses whose attenuation could be the target of thera-

peutic intervention in SSc. We consider how preclini-cal and clinical studies are providing information aboutpathogenesis, how outcomes might be improved, andwhether the elusive goal of an effective antifibrotic treat-ment will emerge from one of the several clinical trialscurrently underway or planned in this disease.

Dysregulated tissue repair in SSc

Pathological mechanisms identified in SSc are converg-ing on a unifying concept: dysregulation of tissue repair.The fundamental pathologies of the disease share fea-tures with other medical conditions; indeed, fibrosis orscarring represents a common pathological response to

tissue damage in many other conditions, and SSc is oftenregarded as a prototypic multisystem fibrotic disease.7 Great progress has been made in understanding theprocesses of normal tissue growth and development,fuelled by molecular genetics and developmental biologystudies that have substantially advanced our knowledgeof complex basic processes such as genetic and epigeneticregulation.8–10 Many biological mechanisms that governnormal embryonic and fetal development are now recog-nized as being central to postnatal repair and injuryresponses. Moreover, these same pathways seem to berecruited in disease states, with aberrant expression oractivity of key mediators.11

Competing interests

C. P. Denton declares an association with the followingcompanies: Actelion Pharmaceuticals, GSK, Pfizer, Novartis,Sanofi-Aventis and Merck-Serono. V. H. Ong declares anassociation with Actelion Pharmaceuticals. See the articleonline for details of the relationships.

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© 2013 Macmillan Publishers Limited. All rights reserved

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Heterogeneity exists in physiological processes of tissuerepair. Traits that can contribute to pathogenesis in someindividuals might, under other circumstances, provide a

selective advantage, such as enabling rapid scar forma-tion. These mechanisms of repair, as well as key processesof cellular differentiation, morphogenesis and connectivetissue remodelling, are emerging as candidate targets forantifibrotic therapy. The immune system also clearly hasan impact on diseases such as SSc, and this influence islikely to include both the innate and adaptive immunesystems. Moreover, certain factors involved in innate andadaptive immune processes and their regulation can alsocontrol or influence tissue repair, and the expression ofautoantibodies in patients with SSc is associated withkey clinical features.12,13 These overlapping immune andrepair processes are perhaps best regarded as an inte-

grated and coordinated damage monitoring and repairsystem, involving multiple positive and negative feedbackpathways as well as feed-forward amplification systemswith multiple checks and balances. This interdependenceis clearly critical for proper function, and is perhaps asimportant to fibrosis as the fundamental regulation ofcell division, differentiation and cell death is to malignantdisease. Indeed, at a molecular level, the same processesand pathways operate in tumorigenesis and tissue repair.

The concept of SSc as a disease of tissue repair hassupport from data emerging in experimental studiesin vivo, as well as genetic and functional analyses, andindicates that targeting key components of the process

Key points

■ Therapeutic goals in systemic sclerosis (SSc) include minimization of damage

from early inflammation and autoimmunity, restoration of vascular homeostasis,

promotion of repair of structural connective tissue and resolution of scarring

■ Cardinal pathogenic processes in SSc—autoimmunity, vascular dysfunction andextracellular matrix overproduction—are interdependent; therapeutic targeting

of any of them individually is likely to be of broader benefit

■ Current treatments for SSc, such as broad-spectrum immunosuppression, are

adopted from the management of other rheumatic diseases; biologic agentsand intracellular signalling inhibitors might also be translated into SSc

■ Increasing understanding of the pathobiology of SSc has identified other

relevant biological processes and their signalling pathways, such as stem cell

biology and epithelial regeneration, as potential targets for therapy ■ New candidate therapies and advances in clinical trial methodology have made

targeted therapy a realistic goal that can be tested robustly, underpinning future

progress in SSc management

might offer potential to remediate the disease (Box 1).Targeted biologic agents and molecular therapies are agrowth area in many medical fields; in particular, theparadigm of targeting specific cell types and mediatorshas proven effective in other autoimmune rheumatic dis-eases that may exist in clinical overlap with SSc. Theseoverlap syndromes have often previously been ignoredand have challenged the classification and diagnosis ofSSc. Their existence underlies the need for the develop-ment of new classification criteria for SSc, a process that isunderway. Potentially, they might also provide real insightinto whether agents that have been shown to be effec-tive in other autoimmune rheumatic diseases might beof benefit in SSc itself.4 Lessons from other diseases show,however, that these targeted approaches differ in efficacybetween ostensibly similar conditions, with often vari-able clinical effects. Such agents provide excellent oppor-tunities to understand disease biology, as they modulateprocesses in an exquisitely precise manner that was previously the preserve of in vitro experimental systems andanimal models. It is striking that, in several rheumatic

diseases, similar clinical benefit has arisen from targetingquite distinct cell types, processes and mediators, but thatrelatively subtle differences between individual agentsthat target the same pathway or mediator can result insubstantially different clinical effects.

Targeted therapies for SSc

Lessons from trials and from related diseases

Given the routine use of biologic therapies in other rheu-matic diseases, it is timely to consider how targeted thera-pies might be applied in SSc. Their use has the potentialto generate substantial progress in our understanding ofthe disease process and aetiopathogenesis. A growing

number of treatments in preclinical evaluation or inclinical use could be considered as targeted treatments.Fundamental advances that have informed understand-ing in SSc have, as in many branches of medicine, oftenbeen serendipitous. At the same time, however, conduct-ing clinical trials in a manner designed to inform ourunderstanding alongside advancing patient managementis an important and challenging consideration.14 Indeed,poorly conducted trials may lead to uninterpretable dataand impede rather than accelerate progress in under-standing the disease (Box 2). Furthermore, with numer-ous potential targeted approaches, together with thedifficulties inherent to clinical trials in a heterogeneous

and uncommon disease, methods should be estab-lished to provide clear signals about potential efficacyand permit the triage of novel therapies such that thosewith the best risk–benefit profile are evaluated further.An additional point to consider is that some targetedapproaches in SSc might be specific to a particular subsetof patients or stage of disease, or might need to be usedsequentially or in combination.

Identification and integration of targets

The rationale for any targeted therapy for SSc must beconsistent with our present understanding of the under-lying pathology; aetiology is less relevant in a chronic

Box 1 | Scarring and connective tissue repair: impact on organ function

■ Connective tissue repair is crucial to survival but excessive or inappropriate

scar formation can damage the integrity and function of tissues and organs

■ In therapeutically targeting tissue repair processes, the need to avoid impact

on beneficial repair might ultimately necessitate modulation rather thanblockade of key pathways ■ Besides being fibrotic, inflammatory processes are often also antifibrotic and

many pathways that are important in resolution of scarring are regulated by the

same molecules that promote fibrosis, such as TGF β

■ Different organs may have varied capacities for repair, depending on theirarchitecture and anatomy as well as their location and function; thus, skin is

well placed to recover function and structure, whereas lung, kidney and bowel

function is easily compromised by increased fibrous connective tissue

Abbreviation: TGF β, transforming growth factor β.

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disease that is likely to be well established at the time ofdiagnosis, before therapeutic intervention. The cell types,processes and pathways that might be targeted in SSc areshown in Figure 1, which summarizes key concepts inan integrated model that builds on previous conceptsof tripartite pathogenesis.7 This increasing integration ofimplicated processes and pathways in SSc reflects growingoverlap between the biology of inflammation, vasculo-pathy and scarring or tissue repair. Individual therapiesthat act on one facet of the disease, such as inflammationor vasculopathy, are likely to also influence other pro-cesses. This interdependency challenges conventionalconcepts of disease modification, and suggests that the vascular, immune and mesenchymal compartments con-stitute an integrated target for therapy. Individual poten-tial molecular targets in SSc are summarized in Table 1and are discussed in the ‘Current molecular targets in SSc’section of this article.

Developmental clinical approaches

As we have mentioned, multiple c andidate targeted

therapeutics—from many areas of medicine—mighthave promise in SSc and are at different stages of clinical

development. Some of these agents are already approvedfor use in other diseases, such as tocilizumab in rheuma-toid arthritis; some are in clinical evaluation in patientswith SSc (Table 2). The developmental pathway of thera-pies for SSc is likely to be fastest for treatments that arelicensed for other autoimmune rheumatic diseases;furthermore, the prescription of such agents for overlap

syndromes provides clinical experience of their effectsin SSc.15

Box 2 | Challenges for clinical trials in systemic sclerosis

■ Clinical heterogeneity—comparative studies are difficultacross disease subsets

■ Natural history—assessment of true therapeutic

response may be complicated by stability or

spontaneous improvement in skin and lung fibrosis ■ Diagnosis is often delayed such that early intervention

is difficult

■ Lack of fully validated outcome measures ■ No clear pathway to regulatory approval for agents

targeting skin or lung fibrosis

■ Complex biology with interlinked pathogenetic

processes

Inflammation and autoimmunity

Aberrant tissue repair and regeneration

Vascular abnormalities

Endothelialcell

Potentialmolecular targetsEndothelin,serotonin,prostanoids,PDGF signalling,guanylate cyclase,PDE5, VEGF

MyofibroblastMastcell Potential

molecular targetsIL-1, TNF, IL-6,CCL2, IL-17,eicosanoids,adenosine

Pericyte

Platelet

Lymphocyte

Monocyte

Residentfibroblast

Attenuate autoantigen-driven inflammationand antibody-mediated pathology

Stimulate controlled vascular regenerationand repair endothelial damage

Reduce inappropriateor excessive ECM deposition

Promote epithelial repairand tissue homeostasis

ECM

Potential molecular targetsEndothelin, serotonin, LPA,cannabinoids, CCL2, CTGF,TGF β, Wnt, Notch, Hedgehog,PPARγ, integrins

Figure 1 | Targeting pathogenic processes in SSc. Pathogenesis of SSc involves the aberrant initiation and/or sustainment ofinflammatory and autoimmune processes, which results in inappropriate or excessive deposition of ECM, attenuated repairof specialized structures and proliferative abnormalities in the vasculature. This figure illustrates the emerging concept of a‘pathogenic unit’ in SSc that involves immune, vascular and mesenchymal components that are interdependent and likely toreciprocally interact when targeted therapeutically. These interlinked cardinal pathogenic processes (shown in red boxes) arethought to be the driving mechanisms that underlie disease development and progression. The goals of therapy are to diminishinflammatory damage and autoimmunity, restore vascular homeostasis and facilitate structural connective tissue repair andresolution of scar formation (as shown in green boxes). Common pathways might underlie, or integrate, a number of possibletargeted strategies and, conversely, effective targeted approaches are likely to attenuate or improve more than one aspect ofSSc pathology. These processes are thus the key targets for therapy to halt damage within, or to heal, lesional tissue in SSc.Abbreviations: CCL2, CC-chemokine ligand 2; CTGF, connective tissue growth factor; ECM, extracellular matrix; LPA,lysophosphatidic acid; PDE5, phosphodiesterase type 5; PDGF, platelet-derived growth factor; PPARγ, peroxisome proliferator-activated receptor γ; SSc, systemic sclerosis; TGF β, transforming growth factor β; VEGF, vascular endothelial growth factor.

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Table 1 | Potential targeted therapies for SSc: mechanisms, rationale and feasibility

Targets Therapeutic potential: implicated mechanisms and

evidence of efficacy

Clinical feasibility: existing and developmental

agents*

Endothelin Non-selective ERA seem to reduce skin fibrosis in SSc;37,38 lack of efficacy in SSc–ILD39,40

The non-selective ERA bosentan is approved for use inPAH; the selective ERA ambrisentan (approved in PAH)and macitentan (in development)

Serotonin Blockade of serotonin signalling by terguride improved lungfunction and histology and reduced collagen content in a

preclinical model of lung fibrosis43,44

Terguride is approved for use in pulmonary hypertension

Adenosine Selective adenosine A2A receptor antagonism with ZM-241385can protect against development of fibrosis in mice48

Targeting the relevant adenosine receptor might be anovel therapeutic option in SSc

Phosphodiesterases Phosphodiesterase type 4 inhibitors reduce early-stageinflammation and fibrosis in a bleomycin-induced fibrosismodel, and potentiate TGF β1-induced PGE2 production51,52

The concept of phosphodiesterase inhibition in fibroticdiseases is under investigation; the phosphodiesterasetype 5 inhibitor sildenafil is being trialled in SSc withischaemic digital ulcers137

PDGF Imatinib mesylate (inhibitor of PDGF receptor signalling)delayed wound closure, with reduced myofibroblast numbers54

Several tyrosine kinase inhibitors that block PDGFreceptor signalling have been evaluated in clinicaltrials124,125,134

LPA Inhibition of LPAR1 reduces bleomycin-induced dermalfibrosis61

The LPA–LPAR1 axis can be blocked with currently theavailable antagonists AM966 and AM09559,60

Eicosanoids—prostanoids Preclinical models suggest that the synthetic PGI2 agonistiloprost downregulates profibrotic cytokines in lung fibrosis

Currently available PGI2 analogues including iloprostpotentially represent novel agents for fibrosis

Eicosanoids—leukotrienes Targeting leukotriene B4 receptor or cysteinyl-leukotrienereceptor 1 prevented experimental lung fibrosis65

Zileuton and montelukast are examples of therapeuticagents that target leukotrienes

Cannabinoids Preclinical models suggest that inhibition of the cannabinoidsystem via its two key receptors CB1 and CB2 reducescollagen synthesis and reduces inflammation66–68

Proof-of-concept studies with synthetic analogues oftetrahydrocannabinol, such as ajulemic acid, are beingconsidered

PPARγ In bleomycin-induced fibrosis, the natural PPARγ ligand15-deoxy-prostaglandin J2 suppressed collagen productionand fibroblast activation70,71

Potent synthetic PPARγ agonists includethiazolidinediones (rosiglitazone, pioglitazone)

CCL2 Targeting CCL2 might be effective in patients with SSc with aninflammatory gene expression signature77

Specific inhibitors targeting CCL2—NOX-E36 andCNTO 888—are currently in trials

IL-17 Evidence from preclinical models suggests increased dermaland cardiac fibroblast proliferation in response to exogenousIL-1786–88

Human monoclonal antibodies against IL-17A or IL-17receptor (for example, ixekizumab and brodalumab) arecurrently in clinical trials in other autoimmune diseases

IL-13 Experimental evidence from bleomycin- induced fibrosis in skinand lung suggests a functional role for IL-1381,82

Clinical trials of tralokinumab (a human monoclonalantibody against IL-13) in lung fibrosis are currentlyunderway

IL-1 IL-1β deficiency abrogates bleomycin-induced lung fibrosis97 Targeting IL-1 ligand–receptor axis might be consideredin SSc

IL-6 Several case reports suggests potential benefit fromtocilizumab, with clinical improvement in skin score98

RCT of tocilizumab in early-stage diffuse SSc is ongoing29

TGF β Targeted inhibition with anti-TGF β antibodies has not beenshown to be beneficial in diffuse SSc, but selective blockadeof downstream mediators to TGF β signalling may be analternative approach114

Trials with monoclonal antibodies against TGF β (GC1008and LY2382770) are in progress for myelofibrosis andother inflammatory diseases

CTGF CTGF polymorphisms might contribute to susceptibilityto SSc135,136

Drugs targeting CTGF (FG3019) are undergoing clinicaltrials in lung fibrosis and scar-revision surgery

Epigenetic pathways HDAC inhibitors reduce TGF β-induced and PDGF-induced

fibrosis in experimental models of SSc100HDAC inhibitors include trichostatin A; such agents and

DNA methyltransferase inhibitors such as 5-aza-2-deoxycytidine might have therapeutic potential

Morphogen (Wnt, Hedgehogand Notch) pathways

Experimental models indicate that these pathways havefibrogenic effects and targeting these pathways inhibitscollagen production103–108

Morphogen pathway inhibitors are in clinical evaluation;vismodegib is approved for advanced basal cellcarcinoma but concerns about its tolerability 109 may limitits development in SSc

Integrin signalling Specific inhibition of α5β6 integrin prevents fibrosis in mousemodels of bleomycin- and radiation-induced lung fibrosis119,120

Several monoclonal antibody therapies against α5β6,α1β1 and α2β1 integrins are in clinical development122

Co-stimulatory molecules Abatacept selectively inhibits T-cell activation via competitivebinding to CD80 or CD86

A trial of abatacept in dcSSc with active skin disease wascompleted recently 133

*Current trials in SSc are listed in Table 2. Abbreviations: CCL2, CC-chemokine ligand 2; CTGF, connective tissue growth factor; dcSSc, diffuse cutaneous SSc; ERA, endothelin receptorantagonist; HDAC, histone deacetylase; ILD, interstitial lung disease; LPA, lysophosphatidic acid; LPAR1, LPA receptor 1; PAH, pulmonary artery hypertension; PDGF, platelet-derived growthfactor; PGE2, prostaglandin E2; PGI2, prostaglandin I2; PPARγ, peroxisome proliferator-activated receptor γ; RCT, randomized controlled trial; SSc, systemic sclerosis; TGF β, transforming growthfactor β.

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Table 2 | Current clinical trials in SSc*

Study; identifier (date record

updated)

Agent (type) Condition Primary endpoint Inter vention in active

arm

Design Phase

and status

SEDUCE; NCT01295736(Oct 2012)137

Sildenafil (type 5phosphodiesteraseinhibitor)

SSc withischaemic DUs

Time to healing ofischaemic DUs at90 days

20 mg three t imes perday

Double-blindRCT

Phase III,recruiting

SCOT; NCT00114530 (July 2011)138 Autologous SCT dcSSc Event-free survivalat 48 and

54 months postrandomization, FVC,SSc–HAQ, mRSS

Autologous SCTand high-dose

immunosuppressivetherapy

RCT Phase II,ongoing

Allogeneic hematopoietic-celltransplantation after nonmyeloablativeconditioning for patients with severeSSc; NCT00622895 (Oct 2012)21

Allogeneic SCT dcSSc Event-free survivalat 2 years

Allogeneic SCTand high-doseimmunosuppressivetherapy

Open label Phase I/II,ongoing

Study of ambrisentan with antifibroticagent combination therapy in diffuseSSc; NCT01093885 (March 2010)30

Ambrisentan(ERA)

dcSSc mRSS at12 months

5–10 mg daily Open label Phase I

High-dose intravenous NAC versusiloprost for early, rapidly progressivediffuse SSc; NCT00428883(Jan 2007)139

NAC dcSSc mRSS NAC versus iloprost RCT Phase II/III,recruiting

Study of pomalidomide (CC-4047) toevaluate safety, tolerability,pharmacokinetics, pharmacodynamicsand effectiveness for subjects withSSc with ILD; NCT01559129(Oct 2012)22

Pomalidomide(derivative ofthalidomide)

SSc andprogressivelung fibrosis

Change in mRSSand FVC at week52

1 mg daily over52 weeks

Double-blindRCT

Phase II,recruiting

IL1-TRAP, rilonacept, in SSc;NCT01538719 (July 2012)26

Rilanocept (fusionprotein, IL-1inhibitor)

dcSSc 4-gene biomarkerof skin disease andmRSS

320 mg day 0 and160 mg weekly for5 weeks,subcutaneously

Double-blindRCT

Phase I/II,recruiting

A trial of tadalafil in ILD ofscleroderma; NCT01553981(Dec 2012)31

Tadalafil (PDE5inhibitor)

SSc and lungfibrosis

Change in FVC over6 months

20 mg alternate daysover 5 months

Double-blindRCT


Fresolimumab in SSc; NCT01284322(July 2012)115

Fresolimumab(GC1008)

dcSSc Change inTGF β-regulated

gene expression inskin over 7 weeks

One-off intravenousdose of 1 mg/kg or

5 mg/kg

Open label Phase I,recruiting

Rituximab for treatment of SSc–PAH;NCT01086540 (Nov 2012)140

Rituximab(anti-CD20antibody)

SSc–PAH Change in PVR over24 weeks

2 infusions, 1,000 mgeach, 14 days apart

Double-blindRCT

Phase II,recruiting

Macitentan for the treatment of DUs inSSc patients; NCT01474109(Sep 2012)141

Macitentan(selective ERA)

SSc with DUs Reduction of newDUs at 16 weeks

3 mg or 10 mg daily for16 weeks

Double-blindRCT


SLSII; NCT00883129 (Sep 2010)25 MMF;cyclophosphamide

SSc and lungfibrosis

FVC over24 months

MMF max 1.5 g twicedaily for 2 years or oralcyclophosphamide max2 mg/kg for 12 months

RCT Phase II,recruiting

A study of RoActemra/Actemra(tocilizumab) versus placebo in

patients with SSc; NCT01532869(Feb 2013)29

Tocilizumab(anti-IL-6 receptor

antibody)

dcSSc mRSS at 6 months 162 mg once per week,subcutaneously

Double-blindRCT

Phase II,recruiting

A protocol-based treatment for earlyand severe SSc with (anti-CD20),rituximab; NCT00379431(Feb 2013)142

Rituximab dcSSc Death or majororgan involvementat 28 weeks

1,000 mg on days 1and 15 and at week26–28, intravenouslywith 100 mgmethylprednisoloneprior to each infusion

RCT Phase II,ongoing

AIMSPRO in established dcSSc;NCT00769028 (Aug 2011)143

AIMSPRO®(hyper immune goatserum)

dcSSc mRSS at week 26 Subcutaneous injectionof serum, 1 ml twiceweekly for 6 months

Double-blindRCT

Phase II,ongoing

*According to ClinicalTrials.gov, as of Feb 2013. Abbreviations: dcSSc, diffuse cutaneous SSc; DUs, digital ulcers; ERA, endothelin receptor antagonists; FVC, forced vital capacity; HAQ, healthassessment questionnaire; ILD, interstitial lung disease; MMF, mycophenolate mofetil; mRSS, modified Rodnan skin score; NAC, N-acetylcysteine; PAH, pulmonary arterial hypertension; PDE5,phosphodiesterase type 5; PVR, pulmonary vascular resistance; RCT, randomized controlled trial; SCOT, scleroderma: cyclophosphamide or transplantation; SCT, stem cell transplantation;SEDUCE, sildenafil effect on digital ulcer healing in scleroderma; SLSII, scleroderma lung study II; SSc, systemic sclerosis.

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Clear rationale supports immunosuppressive treatmentas a potential therapeutic approach in SSc (Box 3). Analternative to established, untargeted DMARDs, such asmethotrexate, is more intense immunosuppressive therapy.One example of such a strategy is the use of immune

ablation followed by autologous stem cell transplantation(ASCT), for which some emerging trial data are encour-aging.16,17 Nevertheless, a more targeted approach is ulti-mately likely to be desirable, in order to minimize toxicity.Indeed, although the therapeutic benefits of and appropri-ate patient selection for intense treatment protocols remaintopics of intense debate,17 such approaches undoubtedlyhave high potential toxicity. First results from the ASTIStrial—in 156 patients with early progressive diffuse cuta-neous SSc (dcSSc), with or without organ involvement—include a 100-day treatment-related mortality of 10%(although, overall, fewer patients in the treatment arm haddied after 2 years than in the placebo arm).18

A comparison of skin biopsies from 23 patients withSSc, 24 control individuals and 7 patients with SSc whohad undergone high-dose immunosuppressive therapyfollowed by haematopoietic ASCT showed that remodel-ling and loss of capillaries occurs in SSc, and that thesechanges are reversible with high-dose immunosuppressivetherapy.19 An intriguing case report published in 201220 raises the possibility that profound immunomodulationassociated with the treatment and resolution of a severesystemic viral infection might affect the activity of SSc.Durable improvement without need for ongoing treat-ment was seen subsequent to human cytomegalovirusinfection in a patient with severe dcSSc who had previ-

ously been dependent on mycophenolate mofetil (MMF).20 Conceivably, sustained clinical improvement in this casemight have been wrought by specific regulatory or suppres-sive cells of the adaptive immune system, such as regulatoryT cells, responding to the infection. This notion, as wellas the ASCT results we have discussed, thus supports theconcept of developing highly specific immunomodulatorystrategies for SSc, such as cell-based targeted therapies.

Therapeutic translation in SSc

Because SSc manifests in distinct yet overlappingimmunological, vascular and fibrogenic pathways, amulti-pronged approach that targets the different aspects

of the disease might be necessary. Several pivotal trialstargeting specific mediators or mechanisms are currentlyunderway (Table 2).

Immunomodulation

Immunomodulatory approaches being adopted in trialsin SSc range from broad and intensive regimens (such asallogeneic stem cell transplantation)21 to more selectiveapproaches, such as the use of pomalidomide, which iscurrently being assessed in an international multicentrephase II clinical trial exploring its safety and tolerability(Table 2).22 The immunomodulatory effect of pomalido-mide is reported to be superior to that of its parent com-pound, thalidomide; although its precise mechanisms areunknown, support for the potential utility of this approachin SSc comes from efficacy in preclinical models of fibro-sis.23 Furthermore, following the pivotal ‘scleroderma lungstudy’ trial24 examining the effect of cyclophosphamidein lung fibrosis, and the growing evidence that MMFmay be effective in lung fibrosis,2 a 2-year comparativetrial between cyclophosphamide and MMF is underway

in patients with SSc-associated interstitial lung disease(SSc–ILD).25

Targeting skin pathology

A novel approach in SSc is targeted IL-1 receptor blockadeusing rilonacept. A phase I/II trial of this agent is recruit-ing and will assess response by means of a four-gene bio-marker of transforming growth factor β (TGFβ)-regulatedand interferon-regulated genes, as a surrogate for modi-fied Rodnan skin score (mRSS),26 the current standard forassessment of skin activity.27 Targeting IL-6—a pluripotentcytokine in the pathophysiological mechanisms in SSc—could also be of potential benefit in early-stage disease,

according to an analysis of serum samples from patients;28 Roche-Genentech has initiated an international trial of theanti-IL-6 receptor antibody tocilizumab to address thisaspect of the disease.29 Endothelin receptor antagonists(ERAs), which have established effects on vasculopathy,might also diminish skin activity in SSc; a trial of the ERAambrisentan with mRSS as the primary outcome measureis underway.30

Targeting lung pathology and vasculopathy

As well as ambrisentan, the phosphodiesterase type 5inhibitor tadalafil is another agent with an establishedeffect on vasculopathy; a phase III trial of its effects on

lung fibrosis is recruiting.31 These approaches providea rationale for targeting vasculopathy as a strategy fordisease modification in SSc (Box 4), which underpins theroutine use of inhibitors of angiotensin converting enzymein scleroderma renal crisis.32

Current molecular targets in SSc

Endothelin

Endothelin is a potent vasoconstrictor; it stimulates theproliferation of smooth muscle cells and the productionof collagen by fibroblasts, and downregulates the expres-sion of matrix metalloproteinase (MMP) 1.11 ERAs havebecome established therapies for vascular complications

Box 3 | Immunomodulatory strategies in treating SSc

Several observations support the rationale forimmunomodulation as a therapeutic approach in SSc: ■ Clinical overlap of SSc with other autoimmune

rheumatic diseases, including vasculitis andrheumatoid arthritis, in which immunosuppression ismanifestly effective

■ Skin of patients with early-stage SSc has clinical and

histological features of active inflammation76

■ Presence of markers of inflammation in lung samples,including bronchoalveolar lavage fluid24

■ Cyclophosphamide, methotrexate and, in the lastdecade, high-dose immunosuppressive strategies withtransplant-conditioning regimens have demonstrated

efficacy in diffuse cutaneous SSc17,144

Abbreviation: SSc, systemic sclerosis.

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PDGF signalling is essential for the normal differentia-tion and activation of pericytes and might be importantin the pathogenesis of SSc.7 In addition, a number oftyrosine kinase inhibitor agents that have been evaluatedin SSc (as discussed in the ‘Tyrosine kinases’ section ofthis manuscript) have potent activity in the inhibitionof PDGF receptor signalling.54

Lipid mediators

Bioactive lipid mediators such as lysophosphatidic acid(LPA) have been implicated in the pathogenesis of fibro-sis, as drivers of vasculopathy and as potential therapeutictargets in SSc.57 LPA acts at a cellular level via G-protein-coupled receptor signalling. In lung fibrosis, it seemsto promote re-epithelialization while also increasingmyofibroblast transdifferentiation as well as the produc-tion of profibrotic mediators and matricellular proteinssuch as connective tissue growth factor (CTGF; alsoknown as CCN family member 2).57,58 Preclinical modelshave supported the use of LPA receptor 1 antagonists inexperimental lung fibrosis.59,60

Eicosanoid signalling: prostanoids

Augmentation of prostanoid signalling through recep-tor agonism is another potential approach in SSc. A2012 study in mice showed that prostaglandin I2 (PGI2)inhibits fibroblast proliferation, migration and collagensynthesis.61 Accordingly, synthetic prostacyclin deriva-tives such as iloprost, a stable prostacyclin analogue andPGI2 receptor agonist, have been used for the treatmentof SSc-associated vascular disease and complications suchas PAH.62 Intravenous iloprost is approved for this use insome countries, such as New Zealand and the UK. Thedrug has similar haemodynamic effects to those of epo-

prostenol. In addition, an inhaled preparation of iloprostis approved in several countries for those with severe limi-tation in functional lung capacity.62 The effects of PGI2 onfibroblasts and the extracellular matrix61 build on earlierstudies of skin samples from patients with SSc that high-lighted the ability of iloprost to block upregulation of theTGFβ-inducible matricellular protein CTGF.63

Eicosanoid signalling: leukotrienes

Conversely, another family of eicosanoids, leukotrienes,are thought to promote fibroblast migration, prolifera-tion and collagen synthesis, and the levels of varioussubclasses of leukotrienes are elevated in lung homo-

genates from patients with idiopathic pulmonary fibro-sis.64 Targeting the receptors of these leukotrienes withmontelukast (an antagonist of cysteinyl-leukotrienereceptor 1) has been shown to limit bleomycin-inducedlung fibrosis.65 An alternative strategy is to non-selectively block leukotriene biosynthesis with zileuton,although evidence for this approach is lacking.

Cannabinoids and PPARγ agonistsActivation of the cannabinoid system disrupts TGFβsignalling, with subsequent downregulation of theactivation of dermal fibroblasts, in addition to anti-inflammatory and immunomodulatory effects.66 Studies

in the bleomycin-induced skin and lung fibrosis pre-clinical models of SSc suggest that inhibition of the can-nabinoid system via its two key receptors, cannabinoidreceptor 1 (CB1) and CB2, reduces collagen synthesisand reduces inflammation.66–68 Proof-of-concept clinicalstudies of CB1 and CB2 antagonism with synthetic ana-logues of tetrahydrocannabinol, such as ajulemic acid, toexplore potential benefit for SSc skin fibrosis are beingconsidered, but no results are yet available.

Crosstalk between the cannabinoid system and peroxi-some proliferator-activated receptor γ (PPARγ) signal-ling has been postulated.69 Downregulation of PPARγenhances TGFβ-dependent fibroblast activation, acti- vates epithelial–mesenchymal transition, and stimulatesproduction of collagen from resident fibroblasts.7 PPARγagonists have been shown to have antifibrotic effects ina number of experimental animal models of fibrosis;for example, the natural ligand to PPARγ, 15-deoxy-prostaglandin J2, suppresses collagen production andfibroblast activation in mice with bleomycin-inducedfibrosis.70,71 Potent synthetic PPARγ agonists, includ-

ing thiazolidinediones (such as rosiglitazone), attenuatecollagen production and fibrosis in animal models.72

Chemokines

Strong evidence from studies of cells and tissue samplesfrom patients with SSc73 supports the concept of over-production of CC-chemokines in SSc pathogenesis;these mediators can be produced by multiple cell types,including activated fibroblasts. Crosstalk occurs betweenCC-chemokine family members, such as CCL2 andCCL7, and TGFβ-regulated pathways, which mightenable these mediators to regulate multiple processesrelevant to the pathogenesis of SSc, including leukocyte

trafficking, epithelial cell function, and fibroblast activation and transdifferentiation into myofibroblasts.73 Indeed, the profibrotic activity of CCL2 has been linkedto its ability to recruit monocytes, promote the differen-tiation of type 2 T helper (T

H2) cells, and augment fibro-

blast responsiveness to TGFβ.74 CCL2 also induces thedifferentiation of IL-4-producing T cells.73,75

Expression of CC-chemokine receptor 2 (CCR2) bya subpopulation of activated fibroblasts in skin samplesfrom patients with SSc76 raises the possibility of an auto-crine or paracrine role for CCR2 ligands in fibroblastactivation. Plausibly, such a subpopulation of CCL2-responsive fibroblasts could represent cells derived from

circulating precursors. Although direct evidence for thiscellular origin is not yet available, the concept impliesthat circulating cells contribute to skin fibrosis and mightbe targets for therapy. This notion is supported by datathat suggest that CCL2 is overexpressed in patients withan inflammatory gene expression signature.77

The identification of chemokines as markers of activated fibroblasts in patients with SSc and their asso-ciation with organ-based complications such as lungfibrosis78 provide strong justification for therapeutictargeting of these mediators in SSc. In graft-versus-hostdisease79 and in rheumatoid arthritis,80 however, theeffects of chemokine antagonists have been mixed. This

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apparent lack of efficacy might partly reflect the largeredundancy in ligand–receptor pathways, and it remainsunclear what effects blockade of one chemokine have onother physiological signalling events.

IL-13

Substantial experimental evidence indicates that IL-13,which shares its receptor with IL-4, exerts a profibroticeffect and that the underlying pathways might haveinterplay with those induced by other mediators, includ-ing CCL2 and TGFβ.77 Data from experimental modelssuggest that IL-13 receptor antagonists can attenuate skinor lung fibrosis.81,82 A 2011 study indicated that asthmaticpatients with elevated levels of circulating periostin arelikely to respond to the IL-13 inhibitor lebrikizumab, withimprovement in lung function.83 Periostin levels are alsoreportedly elevated in patients with SSc, and bleomycin-induced pathology was found to be dependent on peri-ostin;84 these data lend support to the evaluation of itsclinical potential in SSc. A phase II dose-ranging studyto evaluate the safety and efficacy of a human recombi-

nant monoclonal antibody against IL-13 (tralokinumab)in patients with mild-to-moderate idiopathic pulmo-nary fibrosis is ongoing and a similar approach might beconsidered in SSc.85

Proinflammatory cytokines

IL-17

IL-17 is implicated in the pathogenesis of many auto-immune and inflammatory diseases. Although its preciserole in SSc is unclear, cell studies indicate a potential rolefor IL-17 in regulating dermal and cardiac fibroblastproliferation,86,87 and altered IL-17 expression has beenreported in cells from patients with SSc.88 Moreover,

growing evidence from experimental models of fibro-sis indicates that expression of IL-17 and of its recep-tor is upregulated in both lung and liver fibrosis, withincreased expression of TGFβ.89,90 The use of biologicagents that target IL-17 is therefore a promising poten-tial strategy in SSc. Clinical trials of agents that targetIL-17 (such as ixekizumab) or its receptor (for example,brodalumab) are underway in psoriasis arthritis,91 andevaluation in SSc could be considered.

TNF

Biologic therapies with demonstrated efficacy in otherinflammatory rheumatic diseases target proinflammatory

cytokines that are also implicated in the initiation of fibro-sis. Indeed, anti-TNF treatment has been demonstrated toameliorate fibrosis in animal models that involve inflam-mation, such as the bleomycin skin or lung models of SScpathology.92 An open-label study of the anti-TNF agentinfliximab in patients with dcSSc suggested transientbenefit for skin sclerosis but was not powered to demon-strate efficacy.93 Evidence of its safety nevertheless adds tothe general experience of TNF-blocking strategies in SSc;review of the EUSTAR (EULAR Scleroderma Trials AndResearch) database suggests that anti-TNF treatmentssuch as etanercept might be effective in treating arthritisoccurring in the context of SSc.94

IL-1 and IL-6

Few studies of IL-1 axis blockade have been conductedin SSc, although IL-1 is implicated in the pathogenesis inthe form of upregulated IL-1-dependent signallingin fibroblasts95 and skin samples96 from patients withSSc. Evidence from animal models suggests that tar-geting IL-1β might ameliorate fibrosis.97 Similarly, IL-6is upregulated in people with dcSSc, and especially ina subset of patients with poor long-term outcomes. 28 These observations provided the rationale to trial IL-6R-blocking antibodies such as tocilizumab in SSc. Skinsoftening was reported in a small case series,98 and theresults of ongoing clinical studies in patients with dcSSc(Table 2) are eagerly awaited.

Epigenetic pathways

Epigenetic regulation of gene expression occurs throughmechanisms that modify histones—especially histoneacetylation status—or DNA methylation, which hasan inhibitory effect on gene transcription. In addition,microRNA species regulate gene expression and mRNA

transcript stability, and these mechanisms are emerg-ing as important regulators in a number of disease pro-cesses.99 Epigenetic mechanisms provide an additionallevel of regulation, besides genetically encoded andshort-term environmental influences, that can be trans-mitted in cell division and can be important in regulatingprocesses in health and disease states. A potential thera-peutic approach in SSc is the use of inhibitors of histonedeacetylases; these agents reduced TGFβ-induced andPDGF-induced fibrosis in experimental models of SSc.100

Potentially, microRNA species could also be targetedor used therapeutically to modulate the expression ofprogrammes of genes relevant to fibrosis, but this is

a more distant clinical prospect than that of histonedeacetylase inhibition.

Morphogenic regulators

As we have mentioned, advances in the understand-ing of developmental biology have identified roles formediators of tissue development in disease. Tissue-forming pathways are especially relevant to fibrosis andscarring, which represents a defective repair process.Relevant mediators include molecules of the Wnt,101,102 Hedgehog 103 and Notch104–106 signalling pathways. Thesepathways, defined in studies of Drosophila genetics, havecritical roles in normal growth and development.

Dysregulated Wnt signalling, involving stabilizationand subsequent nuclear translocation of β-catenin toinitiate downstream gene expression, seems to be a relevant mechanism in lesional tissues in SSc.107 Resveratrolinhibits the transcriptional activity of β-catenin and hasbeen shown to reduce the upregulation of collagen andfibronectin in animal models of fibrosis.101,102 Notchsignalling involves several enzymatic processes, includ-ing cleavage of the Notch receptor by transmembraneγ-secretase to release the Notch intracellular domain;Notch activation is increased in SSc with accumulationof this domain in dermal fibroblasts.105 An inhibitor ofthis critical enzymatic step prevents the development

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of fibrosis in bleomycin-induced animal models offibrosis and in mice carrying the tight-skin mutation.108

Binding of ligands of the Hedgehog family, such assonic hedgehog, to their receptors alters the ability ofsmoothened (Smo) proteins to inhibit the degradation

of Gli1 proteins, which are major transcription factors.Experimental models suggest that targeting Smo inhibitsdermal fibrosis, as demonstrated in a bleomycin-inducedmodel and in tight-skin mutant mice.103 Vismodegib, aninhibitor of Hedgehog signalling, has been approved bythe US FDA for the treatment of adult patients with basalcell carcinoma who are not candidates for conventionalsurgical or radiotherapy treatment and do not havemetastatic disease (Table 1).109

TGFβ

TGFβ is a potential ‘master regulator’ of fibrosis and scar-ring and as such is a target of novel therapies (Figure 2).

Support for this approach is based on increased expres-sion of TGFβ and its receptor in skin and lung tissue frompatients with SSc, in comparison with controls, and alsofrom studies that have defined a ltered TGFβ receptorexpression and signalling in explanted fibroblasts frompatients with SSc.7 The results of specific studies, however,have often been conflicting; for example, fibroblasts frompatients with SSc have been shown in vitro to expressequivalent amounts of TGFβ to control fibroblasts, withno differences in the production of total TGFβ1 or activeTGFβ1.110 A study published in 2010 found clear evi-dence of a TGFβ-activated gene expression signature inthe skin of a subset of patients with SSc; this apparentsubtype-specificity provides a potential explanation forthe observed variation in the results of previous studies.111

The potential importance of TGFβ in many physio-logical processes, however, suggests that toxicity mightprevent the use of TGFβ antagonism in fibrosis. Thus, tar-geting co-stimulators or downstream mediators insteadmight be a more feasible approach, and such possibili-ties are being actively pursued.112,113 A single RCT in 45

patients with SSc has tested topical use of the recombi-nant antibody CAT-192, which blocks TGFβ1; no safetyconcerns were raised but the study did not provide anyclear signal of efficacy.114 This result could reflect therelatively weak neutralizing activity of CAT-192 and/or its monospecificity for TGFβ1. Overexpression ofboth TGFβ1 and TGFβ2 in the skin of patients in thetrial was confirmed;114 thus, an antagonist with broaderspecificity might be needed. The potential risk of pan-neutralization of all three isoforms of TGFβ is, however,unknown and will require careful evaluation in clinicaltrials. Pan-neutralization could be achieved using recom-binant receptors or with a broader specificity antibody.

One such agent, the human monoclonal antibody fre-solimumab (GC1008, which targets all three isoforms ofTGFβ), is available and being evaluated in SSc in a smalldose-finding safety study.115

CTGF

CTGF contributes to TGFβ-mediated fibrosis leadingto myofibroblastic differentiation but is not consideredto be a potent fibrogenic factor on its own. A specificmonoclonal antibody to CTGF, known as FG3019, hasshown potential in reducing lung fibrosis and scarring.Indeed, preclinical data and a small safety study in idio-pathic lung fibrosis have been promising,116,117 but no

formal clinical trials have been conducted in SSc. Theprecise role of CTGF as a mediator or marker of fibrosisremains unclear; clinical trials in relevant patient groupswith appropriate end points, accompanied by functionalstudies, are likely to shed light not only on the poten-tial of CTGF as a therapeutic target, but also on how itcontributes to fibrosis.

Integrin signalling

A critical component of matricellular function, integ-rins have important mechanical and signalling activ-ity. Integrins provide cells with the ability to sense theirmicroenvironment and are constitutively expressed on

Canonical and

non-canonical signalling

Receptor specificand non-specifickinase cascades

Gene regulation

TGFβ familyTGF β1BMP4Activin

MatricellularproteinsThrombospondinCTGF

GPCRsignalling

Feedback andfeedforwardregulation

Extracellular regulationof ligand availabilitye.g. TGF β, lipids,morphogens

MechanicalfactorsIntegrin-mediatedsignalling

CytokinesIL-6IL-1IL-13IL-17

ChemokinesCCL2CCL7CXCL12

Growth factorsFGF PDGF

Peptide mediatorsEndothelin 1

Neuropeptides

Lipid mediatorsPGI2LPA

Non-peptidemediatorsSerotoninCannabinoid

MorphogensWntHedgehogNotchOthers

Anti-fibroblastor anti-receptor

agonistantibodies

Figure 2 | Targeting multiple pathways of fibroblast activation in SSc. Many factorsregulate fibroblast differentiation and proliferation, including components of multiplepathways that are fundamental to growth, development and tissue repair.Furthermore, each pathway has multiple positive and negative regulatorymechanisms, and reciprocal crosstalk occurs between mediators and theirdownstream signalling intermediates. This interconnectedness constitutes acomplex network of control that incorporates much redundancy. Some key factorsseem to be master regulators with the ability to influence multiple relevant targetsand pathways. The TGF β family are good examples of pleiotropic mediators in thiscontext; targeting these factors, together with key downstream gene products, offersperhaps the most promising strategy for affecting multiple relevant mechanisms.Experimental investigation will address the ways in which TGF β drives SSc pathology,and will identify key pathways that are perturbed as a result of its modulation.

Conceptually, whether partial attenuation of multiple pathways or more completeinhibition of a specific mediator will prove to have the most advantageous balance ofsafety and efficacy should be considered. These questions are probably best testedin biological ‘proof-of-mechanism’ trials. Abbreviations: BMP4, bone morphogeneticprotein 4; CCL, CC-chemokine ligand; CTGF, connective tissue growth factor; CXCL,CXC-chemokine ligand; GPCR, G-protein-coupled receptor; FGF, fibroblast growthfactor; LPA, lysophosphatidic acid; PGI2, prostaglandin I2; SSc, systemic sclerosis;TGF β, transforming growth factor β; VEGF, vascular endothelial growth factor.

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fibroblasts in SSc.118 An important role for epithelialintegrins in the activation of latent (inactive) secretedcomplexes of TGFβ has raised the potential for integrintargeting as an antifibrotic therapy.119 Preclinical studieshave demonstrated that antibodies against αvβ6 integrinprevent fibrosis in mouse models.120,121 The relative bene-fits of integrin-targeted therapies (for example, inhibitorstargeting αvβ6, α1β1 or α2β1 integrin) over strategiesthat attenuate integrin-responsive signalling pathways(such as those directed at phosphoinositide 3-kinase andmitogen-activated protein kinase survival pathways) arelikely to be delineated through controlled clinical trials inother diseases before they might be considered in SSc.122

Tyrosine kinases

Small-molecule inhibitors of intracellular kinases, withdifferent degrees of specificity, have exciting potentialin rheumatic disease. Several agents in clinical develop-ment aim to reduce the activity of key signalling inter-mediates that are implicated in SSc pathogenesis, andmost of these agents have been developed or tested in

other clinical contexts. Nevertheless, discrepancy existsbetween encouraging preclinical results in animal modelsand disappointing clinical experience of several agents.Imatinib, for example, was developed for treatment ofchronic myelogenous leukaemia and has well-establishedclinical utility for that indication. Potential efficacy inSSc was supported by theoretical effects on PDGF andnon-canonical TGFβ signalling and by evidence ofbenefit in a number of animal models.123 Although onestudy reported improvement in mRSS by 6.6 points at a12-month time point,124 other studies have not replicatedthese findings, and several have indicated that imatinibhas unacceptable toxicity that might partly reflect effects

on underlying subclinical comorbidity in SSc.124,125 Othertyrosine kinase inhibitors, such as dasatinib and nilotinib,have also been evaluated in SSc but reported tolerabilityissues—including ECG findings of QTc prolongation—might limit further clinical development.126,127 Emergingdata show potential benefit of imatinib in PAH, includingcases of connective tissue disease-associated PAH.128

The angiokinase inhibitor BIBF 1120 (nintedanib) hasshown potential utility in a phase II study in idiopathicpulmonary fibrosis, with suggestions of clinical benefitand a dose–response relationship.129 This agent inhibitsthe activity of kinases that mediate downstream responsesto PDGF, bFGF and VEGF. Ongoing phase III clinical

trials in idiopathic pulmonary fibrosis130 will providebetter evidence of any benefit, which must be consideredin the context of potential toxicity. If the results arefavourable, it may be of interest to evaluate this strategyin patients with SSc and/or SSc-associated pulmonaryfibrosis. Dasatinib and nintedanib are less selective andinhibit a broader range of tyrosine kinases than imatinib;any greater toxicity of imatinib might thus reflectoff-target effects.

Targeting cellular subpopulations

Uncertainty about the relevance of various processesin SSc pathogenesis precludes a complete review of all

possible targeted therapies, but agents that target spe-cific cell types might yet prove useful. B-cell-directed andT-cell-targeting approaches have been used or are underclinical evaluation. In particular, the anti-CD20 antibodyrituximab has been reported to be of potential benefit forSSc-associated lung fibrosis.131 Another novel strategy isdirected therapy with recombinant serum amyloid P, amember of the pentraxin family of proteins that modu-late the profibrotic microenvironment by disruptingfibrocytic recruitment and macrophage activity.132

T-cell co-stimulatory molecules are involved in theactivation of adaptive immune responses and havetherapeutic potential in a number of autoimmune rheu-matic diseases. Abatacept, a recombinant fusion proteinthat selectively inhibits T-cell activation via competi-tive binding to CD80 or CD86, is a licensed therapyfor rheumatoid arthritis. A safety and efficacy study ofabatacept in SSc concluded in 2011 but results have notbeen published.133

Conclusions

Growing understanding of the pathogenesis of SSc anddevelopments in the treatment of related diseases areincreasing the potential for specific targeted SSc thera-pies. Studies of such strategies are, in turn, likely to revealdeeper insights into the pathogenesis of the disease. In anuncommon and heterogeneous connective tissue disease,however, particular challenges impede prioritization ofpotential treatment approaches. In addition, validatedoutcome measures in SSc overall and in organ-basedmanifestations are lacking; these limitations make inter-national collaboration in multicentre clinical trials criticalfor progress.

Despite justified excitement about the potential for

targeted therapies in SSc, therefore, delivering on thispromise will take time. Current, tested managementstrategies remain necessary, despite their limitations,and their ongoing use will provide a key benchmarkin the evaluation of new therapies. Among a multitudeof ongoing studies, competition between trials mightbecome an issue and it will be important to carefullyreview outcomes in terms of effects on disease biologyas well as clinical benefit. New strategies should be com-pared with pooled data analysis of drugs that have beenshown to be ineffective in randomized studies, to avoidmisinterpretation of changes that might not representtreatment effect.134

Review criteria

This article presents a literature review and accompanying

hypothesis, based on clinical trials and translationalmedicine studies in systemic sclerosis (scleroderma).

The authors selected articles to cite by searching the

PubMed database for publications over the past 40 years,

but emphasized recent publications. The search termsused were “scleroderma”, “systemic sclerosis”, together

with “targeted therapies”, “innovative treatment” and

“pathogenesis”. Some articles were also identified from

the reference lists of other publications.

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http://www.clinicaltrials.gov/ct2/show/NCT01629667?term=nct01629667&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01629667?term=nct01629667&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01695239?term=nct01695239&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01629667?term=nct01629667&rank=1http://www.clinicaltrials.gov/ct2/show/NCT01629667?term=nct01629667&rank=1


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