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Expert Review of Clinical Immunology

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The contemporary management of systemicsclerosis

Maysoon Eldoma & Janet Pope

To cite this article: Maysoon Eldoma & Janet Pope (2018) The contemporary managementof systemic sclerosis, Expert Review of Clinical Immunology, 14:7, 573-582, DOI:10.1080/1744666X.2018.1485490

To link to this article: https://doi.org/10.1080/1744666X.2018.1485490

Accepted author version posted online: 06Jun 2018.Published online: 20 Jun 2018.

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REVIEW

The contemporary management of systemic sclerosisMaysoon Eldomaa,b,c and Janet Popea,d

aDivision of Rheumatology, St. Joseph’s Health Care, Department of Medicine, University of Western Ontario, Ontario, Canada; bRheumatologist,Connective Tissue Disease Fellow, University of Western Ontario, Ontario, Canada; cDivision of Rheumatology, Department of Medicine, Universityof Calgary, Calgary, Alberta, Canada; dDivision Head Rheumatology and Professor of Medicine, University of Western Ontario, Ontario, Canada

ABSTRACTIntroduction: Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized byvascular dysfunction, fibrosis, inflammation and autoantibodies. The pathophysiology of SSc is notcompletely understood, and many patients acquire organ or tissue damage despite advances intreatment. Current treatments target affected organs with modest improvements.Areas covered: This review evaluates several treatment strategies for SSc based on involved organsincluding skin, pulmonary, cardiac, renal, musculoskeletal, and gastrointestinal. Currently, pulmonaryhypertension and interstitial lung disease are the primary causes of increased mortality. We will outlinean approach to treatment of SSc based on disease manifestations and current evidence.Expert commentary: This complex disease is currently treated with therapies developed for similarindications such as for vascular manifestations of SSc using idiopathic pulmonary arterial hypertensiontreatments. Future directions in this field may include combination and maintenance therapy that iscurrently used in other autoimmune diseases, and tailoring these treatments according to the patients’phenotype. This will hopefully increase the efficacy of available treatments and decrease mortality fromSSc.

ARTICLE HISTORYReceived 2 April 2018Accepted 4 June 2018

KEYWORDSAutoimmunity; Connectivetissue disease; Scleroderma;Systemic sclerosis;Treatment

1. Introduction

Systemic sclerosis (SSc), also known as Scleroderma, is a chronicconnective tissue disease (CTD) with multisystem involvement. Ithas a low incidence of 10–20/1000,000 with a higher prevalencein females [1–3]. SSc pathogenesis consists of fibrosis, vasculo-pathy, inflammation, and autoantibodies. However, pathophy-siology of the disease is not completely elucidated [1,4–7]. Theusual natural history begins with autoimmunity followed byinflammation, vascular dysfunction, and sclerosis with occasionalregression in disease [8]. Organ systems involved include skin,respiratory (lung parenchyma and pulmonary arteries), renal,musculoskeletal, gastrointestinal (GI) tract, and cardiovascularsystem [5]. SSc is classified into two subtypes, limited and diffusecutaneous SSc (lcSSc and dcSSc) based on extent of skin involve-ment [1,9,10]. LcSSc is defined by thickened skin distal to elbowsand knees but may involve the face and neck. DcSSc extends toinvolve the trunk and proximal arms and legs. It is important toidentify the patient’s subtype due to differences in prognosis andorgan involvement [9,11].

LcSSc is more likely to be associated with anti-centromereautoantibodies (ACA), longer Raynaud’s phenomenon (RP)prior to disease onset and a better prognosis [9,11]. DcSSc ismore likely to have internal organ involvement and a worseprognosis with a 5-year survival rate of 20–81% [12,13]. Theannual mortality in lcSSc is 1–4% per year compared to 5–10%per year in dcSSc [14]. Poor prognostic factors include pul-monary arterial hypertension (PAH), interstitial lung disease

(ILD) with decreased diffusing capacity of the lungs for carbonmonoxide (DLCO), higher modified Rodnan Skin score (mRSS),and male sex [4,9].

Treatment guidelines are organ based including screeningfor early recognition of potential complications [5]. The mostrecent guidelines for SSc include 2016 European Leagueagainst Rheumatism (EULAR) recommendations and BritishSociety for Rheumatology and British Health Professionals inRheumatology (BSR and BHPR) guidelines [5,15]. Both guide-lines have similar recommendations with minor differences.However, there is a need to tailor treatment according to thepatient’s phenotype, and to consider new therapies from trialsafter publication of these guidelines. This review aims toprovide a treatment approach to this complex disease utilizingknown and emerging treatments.

2. Approach to treatment

2.1. Cutaneous fibrosis

Skin fibrosis is the one of the key features of SSc characterizedby thickened skin with restricted movement that is quantifiedusing the mRSS in 17 anatomic sites [4]. Microvasculaturedysfunction, altered T-helper 1 immune response, andincreased activity of dermal fibroblasts leads to upregulationof protein synthesis and deposition of collagen in skin [8].Several immunosuppressive treatments have been used andinvestigated that have yielded some improvement.

CONTACT Janet Pope janet.pope@sjhc.london.on.ca Professor of Medicine, Division of Rheumatology, St. Joseph’s Health Care, 268 Grosvenor St., London,ON N6A 4V2, Canada.

EXPERT REVIEW OF CLINICAL IMMUNOLOGY2018, VOL. 14, NO. 7, 573–582https://doi.org/10.1080/1744666X.2018.1485490

© 2018 Informa UK Limited, trading as Taylor & Francis Group

Methotrexate (MTX) is considered first-line in early dcSSc [5].Other immunosuppressive options include cyclophosphamide(CYC) and mycophenolate mofetil (MMF) [5,15].

The earliest randomized controlled trials (RCTs) for MTXwere two small trials that included patients with early diseaseusing 15 mg of MTX per week with the earliest trial usingintramuscular and the later used oral MTX [5,16]. Both trialsshowed more improvement in skin softening versus placebobut the results were not significant [9]. However, it can beargued that higher doses of MTX which are commonly used inother rheumatic diseases (such as 25 mg/week) may improveefficacy. Also, some patients with SSc may have poor GIabsorption which could make it difficult to reach therapeuticlevels of MTX so subcutaneous administration could optimizeabsorption. However, self-injection may be difficult due tosclerodactyly with reduced hand function, and difficultly topierce the skin due to sclerosis.

Evidence for use of MMF is obtained from observationalstudies and the Scleroderma Lung Study (SLS) II [4,17,18]. SLSII showed more safety and comparable efficacy over 24 monthswith MMF given for 2 years compared to CYC given for 1 yearwith no maintenance. There was no significant difference inmRSS between CYC (−5.35) and MMF (−4.90) [2,17]. MMF hadbetter safety and tolerability than oral CYC [17,18]. MMF targetdose was 3 g/day but GI upset was a common side effect thatis dose limiting in some patients [19].

CYC also improved skin score in multiple RCTs [4,5]. The SLS Ievaluated 158 patients with both dcSSc and lcSSc in a multi-center, double-blind, randomized, placebo-controlled trial todetermine effects of oral CYC (2 mg/kg/day for 12 months) onlung function and health-related symptoms. The mRSS in 85dcSSc patients showed significant improvement with CYC(−3.06, 95% CI, −3.54 to −0.52, p = 0.008) [20]. Improvementwas maintained for 6 months after stopping CYC but it was lost12 months after stopping treatment [21]. Both SLS I and II notedtoxicity of CYC as a limitation to its use therefore CYC recom-mendations are in patients with progressive ILD [5,15,17,20].MMF is now considered first-line treatment for ILD in SSc.

Other therapies that have been investigated includeRituximab (RTX) due to the known role of B cells in modulatinginflammation and fibrosis [22]. One of the earliest studies was a24-week open-label study of eight patients with dcSSc. Theyreceived 1000 mg of RTX infusions 15 days apart with 1000 mgof methylprednisolone [23]. This study assessed patient’sresponse using skin scores among other indices with a uniquehistopathological assessment of the skin. Results demonstrated asignificant change in skin score at week 24 with histopathologi-cal evaluations showing decreased dermal hyalinized collagencontent and myofibroblast numbers [23]. In another case seriesof 10 patients with SSc (5 lcSSc and 5 dcSSc) with mean diseaseduration of 6.3 years were treated with one ormore cycles of RTX(4 weekly infusions of 375 mg/m2). RTX efficacy was assessedafter 6 months with a mean follow-up of 37 ± 21 months. RTXsignificantly improved skin score in the dcSSc subset at 6 months(25 ± 4.3 to 17.2 ± 4.6, p = 0.022) [22]. RTX showed improvementin articular symptoms and stabilization of SSc-related ILD [22].Similar results were also found by Bosello et al. in a case series (20dcSSc patients), RTX was evaluated for efficacy and safety usingsingle and multiple course of RTX in SSc with or without lung

disease. Skin score improved significantly after 12 months and atfinal follow-up. The mRSS was significantly better at 12 months(11.2 ± 7.5) versus baseline (22.4 ± 9.5) and at final follow-up [24].

The most recent multicenter, open-label study of 51patients, RTX (375 mg/m2 of body surface area weekly for4 weeks and then every 6 months) was compared to controlson traditional therapies (azathioprine, MTX, and MMF) [25].Patients in the RTX group had significant improvement intheir skin scores compared to their baseline from year 1 toyear 4 [25]. Furthermore, comparison between RTX and thecontrol group mRSS showed benefit of RTX compared tocontrols over 4 years [25]. Overall, favorable RTX results havebeen reported in several case reports, 11 open-label uncon-trolled trials, which usually demonstrate improvement in skinand improvement or stabilization of lung fibrosis [22–32].Consequently, RTX may be considered for treatment inpatients who have failed MTX, CYC, and MMF, but moreevidence is needed to confirm efficacy using controlled trials.RECOVER (Rituximab in Systemic Sclerosis) is a French rando-mized trial evaluating the efficacy of RTX for treatment ofassociated polyarthritis primarily as well as skin scores andlung fibrosis for secondary outcomes (NCT01748084).

Two RCT’s are currently awaiting completion comparing intra-venous (IV) CYC with RTX. One has been completed in Kolkata,India for treatment efficacy for lung and skin manifestations andhopefully the results will be promising (http://ctri.nic.in/Clinicaltrials/advsearch.php, Identifier CRTI/2017/07/009152).RECITAL is the second UK’s, multicenter RCT to evaluate efficacyof RTX for treatment of CTD-related ILD with inclusion of SScpatients (ClinicalTrials.gov: NCT01862926) [33] There have beensome negative studies with RTX in SSc, often publication biasoccurs where more positive reports are published compared tothe actual number of treated patients (some of whom have nobenefit), so large properly designed RCT’s will give a betteranswer to the relative benefit of RTX. Other biologics underinvestigation are discussed under emerging therapies.

Other treatments have been suggested with most of thedata from case reports such as phototherapy and intravenousimmunoglobulin (IVIG). These treatments are not consideredconventional. Phototherapy uses wavelengths of the electro-magnetic spectrum to alter the skin with anti-inflammatoryand anti-fibrotic effects [34]. There are different types ofphototherapeutic modalities that include ultraviolet B, ultra-violet A (UVA1), psoralen and UVA (PUVA), etc. [34]. UVA1increases collagenase, decrease hydroxyproline and collagenlevels based on doses [34]. UVA1 can have immunomodulat-ing effect on skin by reducing inflammation in the dermis byapoptosis of T-cells [34]. However, long-term effects are notknown and the optimal does of UVA1 for scleroderma is notknown [8,34]. UVA1 treatments are given 3–4 times per weekfor 30 treatments. There is one RCT (n = 9) that showed noimprovement in mRSS and four uncontrolled prospective stu-dies which showed improvement; however, more research isneeded in this area since most of these trials were smallranging from 4 to 18 patients [34–39].

Extracorpeal photochemotherapy (photophresis) is anotherexperimental treatment for SSc that has been used in conditionssuch as graft versus host disease. It is a cell-based immunomo-dulatory therapy, which requires extraction of leukocytes from

574 M. ELDOMA AND J. POPE

peripheral blood and exposing them to a photosensitizing agentfollowed by UVA then infusing them back into the patient. It iscurrently approved in the United States for use in refractoryacute cardiac allograft rejection, and treatment resistant graftversus host disease among others. It is thought to induce apop-tosis in cells and produce anti-inflammatory cytokines; however,its mechanism is not fully understood [40].

In terms of IVIG, improvement was reported in skin fibrosisin uncontrolled studies [41,42]. Belimumab was also recentlytested in early dcSSc in a single center double-blind RCT whichcompared Belimumab to placebo where all patients receivedMMF (1000 mg twice daily). There was significant improve-ment for mRSS in both groups and more improvement in thebelimumab group that was not significant. This was possiblydue to the small sample size [43]. This study interestingly usedgene expression analysis which was significant in the belimu-mab group [43]. Larger studies are needed before efficacy canbe fully assessed. Recommendations for these therapies can-not be made until definitive trials demonstrate significantbenefit.

2.2. Interstitial lung disease

SSc-related ILD is one of the leading causes of mortality [7]. It ispresent in approximately 25–30% of patients and likely clinicallyrelevant in 15%. The most common pattern of ILD in SSc is non-specific interstitial pneumonia whereas usual interstitial pneumo-nia occurs far less often [4,20]. Other patterns such as organizingpneumonia have been described [44]. Early disease can be asymp-tomatic but common symptoms include non-productive cough,shortness of breath on exertion, and fatigue [44]. ILD is morefrequent in dcSSc than lcSSc but occurs in both subtypes. Risk fordeveloping ILD is increased in thosewith anti-Scl70 antibody (anti-topoisomerase I antibodies) [4]. Some of the poor prognosticfactors include male sex, early onset of ILD from SSc diagnosis,and evidence of honeycombing [4], Mortality in patients withsevere ventilatory restriction (forced vital capacity (FVC) <50% ofpredicted) from SSc-related ILD is 42% within 10 years [20].

The most commonly used treatments for ILD in SSc are MMFand CYC. The main trials evaluating efficacy of these drugs arefrom the SLS I and II [17,20,45]. SLS I evaluated oral CYC (≤2 mg/kg/day) versus placebo for 1 year and were followed for anotheryear. Mean absolute difference in 12 months for FVC% pre-dicted between CYC and placebo group was 2.53% (p < 0.03)showing significant improvement with CYC in terms of FVC,functional ability, and dyspnea but no change for DLCO. TheCYC group had higher adverse events with leukopenia andneutropenia but no differences between the two groups inthe number of serious adverse events [5,20]. SLS I showedthat lung function did not decline as much with CYC as in theplacebo group over 12 months but the advantage was lost 1year after stopping CYC [20]. If using CYC for induction, thequestion of maintenance therapy is important and agents suchas MMF or azathioprine might be considered but there are nostudies comparing maintenance therapies [44].

SLS II compared oral CYC for 1 year and MMF for 2 years withno difference between treatments for FVC% over 24months [17].Both drugs showed improvement in FVC% at 6–24 months and12–24 months in the MMF (2.17, 95% CI, 0.53–3.84) and CYC

(2.86, 95%CI 1.19–4.58), respectively [17]. Both treatment groupsshowed improvement in dyspnea scores in 78% and 84% in CYCandMMF, respectively. Therewas no change in DLCO in theMMFgroup and a decrease in the CYC group [17]. CYC had a highernumber of adverse events and deaths which may explain thepreference for MMF and if CYC is used, there is more considera-tion for IV CYC. Hence, CYC may be considered first-line treat-ment for SSc-related ILD particularly in rapidly progressing ILD[5,17]. Currently, SLS III is recruiting patients to evaluate efficacyof combining Pirfenidone with mycophenolate for treatment ofSSc-related ILD as the primary outcome with skin scores evalu-ated as a secondary outcome (ClinicalTrials.gov Identifier:NCT03221257).

Azathioprine has been used for maintenance treatment inILD; however, there is little evidence to support its use [21]. ARCT of 45 patients with SSc-related ILD for IV CYC (six treat-ments) followed by azathioprine (2.5 mg/kg/day) versus pla-cebo for 6 months. Results showed no significant difference inFVC, DLCO, appearance of High resolution computed tomo-graphy (HRCT), and dyspnea scores. However, there was animprovement in treatment versus placebo in FVC suggestingthat azathioprine may stabilize lung function (p = 0.08) [46].Azathioprine may provide an alternative as maintenance ther-apy for patients intolerant to MMF or with contraindicationssuch as pregnancy.

RTX has been suggested as second- or third-line for SSc-related ILD [22]. Bosello et al. demonstrated efficacy of RTXafter 12 months of treatment. Statistically, there were increasesin the FVC and TLC compared to baseline; however, DLCO didnot change. Different regimens for RTX have been used such asinduction with 500–1000 mg and repeated for 2 weeks or375 mg/m2 once a week for 4 weeks and retreatment every6 months or only when clinically needed [24]. Similar resultswere also seen by Daoussis et al. with an increase in FVC at2 years of treatment, which was superior to the control grouptreated with conventional treatment [25]. See emerging thera-pies for other ILD drugs that are under study.

Lung transplant is another option for patients withadvanced SSc-related ILD with survival rates after transplantcomparable to patients with lung disease secondary to othercauses if other manifestations related to SSc are mild [47,48].Survival rates in one of the largest single center trial compar-ing SSc patients with non-SSc ILD (96% idiopathic pulmonaryfibrosis (IPF) patients) showed survival rate of 83% at 1 yearand 76% at 5 years for SSc patients compared to 91% at 1 yearand 64% at 5 years for non-SSc patients [49]. Similar outcomeswere found in other studies with no difference in long-termoutcome [50]. Consequently, SSc should not be a contraindi-cation for the evaluation of a lung transplant [48,51].

2.3. Pulmonary arterial hypertension (PAH)

PAH occurs secondary to vascular remodeling from SSc orpulmonary fibrosis [4]. There are several other etiologies toPAH according to the European Society of Cardiology (ESC)and European Respiratory Society (ERS) including idio-pathic, heritable causes, drugs, CTD, HIV, portal hyperten-sion, etc. [52]. This leads to elevation in the pulmonaryvascular resistance resulting in right heart failure and

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high mortality [53]. Prevalence of PAH in SSc is 10–15%with median survival at 2–3 years from diagnosis [51].Screening for PAH is important for early detection andinitiation of treatment that can slow progression of PAH.Predictors of worse outcome with SSc-related PAH wereinvestigated in the DETECT study cohort over 3 years.These factors included male sex, low DLCO%, high ratioof FVC% predicted/DLCO% predicted, and high BorgDyspnea Index [54]. PAH has increased mortality if thereis right ventricular dysfunction at diagnosis, pericardialeffusion, and/or decreased ejection fraction [4]. SeveralRCTs have demonstrated efficacy of treatment for CTD-associated PAH where the majority of the CTD patientshave SSc [5]. Treatments include endothelial receptorantagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5inhibitors), parentral prostanoids, and riociguat (a solubleguanylate cyclase stimulator) [1,2,53]. Although therapiesthat have shown improvement in idiopathic PAH do notyield as beneficial results in SSc-related PAH, the effect oftreatment in SSc is important with symptom improvementand prolonged survival in many patients [4,55].

ERAs such as bosentan, ambrisentan, and macitentan showimprovement in exercise capacity and time to clinical progres-sion [5]. In one RCT, macitentan was found to decrease mor-tality overall in patients with PAH from many causes [53]. PDE-5 inhibitors include sildenafil and tadalafil with results inclinical trials similar to ERAs and riociguat [5]. Therefore, theyare considered for treatment of PAH-related to SSc accordingto guidelines [5].

IV epoprestenol improved exercise capacity, hemody-namic measures, and survival in SSc but it is difficult touse (due to continuous IV use and hence the need for IVaccess, severe rebound if it is stopped, and poor tolerabilitydue to vasodilatory effects such as headache, flushing, andnausea); therefore, it is recommended for severe PAH(classes III and IV) [5,56]. Combination therapy is recom-mended for severe and progressive SSc-related PAH, but isalso commonly being used as initial therapy for PAH inmany centers [5].

Treatment guidelines for PAH according to World HealthOrganization (WHO) functional class recommend supervisedexercise training, diuretics where there is right heart failure,oxygen (if hypoxia), influenza, and pneumococcal immuniza-tions [57]. WHO class II patients have been recommended toreceive ERAs, PDE-5 inhibitors, or riociguat [57]. WHO classes IIIand IV may initiate combination therapy including ERAs, PDE-5inhibitors, and IV epoprostenol. WHO class IV require IV epo-prostenol as first-line [4,57]. Lung transplant should be recom-mended in patients that fail treatment in class WHO III or IVwho meet transplantation inclusion criteria, with 5-year survi-val for PAH following transplant at 45–50% [57]. SSc-relatedmortality is comparable after transplant to other age-matchedPAH patients; therefore, SSc should not be a contraindicationto consideration of lung transplant [51]. Most transplant cen-ters have historically excluded SSc patients due to esophagealdysmotility or acid reflux but this should not be an absoluteexclusion [51]. However, careful selection to exclude patientswithout severe extra-pulmonary disease is needed when con-sidering transplantation in SSc [47].

2.4. Cutaneous vascular manifestations

RP is caused by vasospasm of arteries leading to a color changefrom pallor to cyanosis or erythema [5,58]. This can be primary orsecondary with the latter caused by SSc, which tends to be moresevere than primary RP with associated abnormal nailfold capil-laries [2,59]. RP is the predominant feature found in >90% of SScpatients [60]. Complications from RP include digital ulcerations(DUs), ischemia, gangrene, bone, or soft tissue infection resultingin significant painful episodes and disability [5,58]. DUs are morecommon in dcSSc compared to lcSSc [4].

Management of RP requires counselling of patients to keeptheir extremities warm, smoking cessation, and discontinua-tion of vasoconstrictive agents [4]. RP treatments include oraldihydropyridine-type calcium channel blockers (CCBs), withnifedipine being the most commonly studied. There are sev-eral meta-analyses studies showing a decrease in the numberof RP episodes with nifedipine use [5,59]. An oral dihydropyr-idine-type CCB is usually first-line therapy [1,4]. Other treat-ment options include PDE5 inhibitors, IV iloprost, and lessfrequently losartan, fluoxetine, and occasionally topicalnitrates [1,5,15]. Prostanoids are usually reserved for severeRP. IV iloprost (0.5–3 ng/kg/min for 3–5 consecutive days)has demonstrated improvement [1,4,61].

Complications of severe RP attacks such as active SSc-related DUs are treated with CCBs but often require escalationof therapy to PDE-5 inhibitors or IV prostanoids [1,62].Bosentan has been shown to decrease new DU but does notheal ulcers and side effects may occur such as peripheraledema and elevated liver enzymes [60,63,]. PDE-5 inhibitorsmay improve healing and prevent DUs [4,60,63]. Iloprost wasshown to reduce the number of new DUs [60]. Other agentsfound beneficial in PAH are currently under investigation.Riociguat is approved for PAH and is currently being investi-gated for its efficacy in treatment and prevention of DU; theScleroderma Associated Digital Ulcers (RESCUE), phase 2 trial(ClinicalTrials.gov Identifier: NCT02915835).

2.5. Gastrointestinal manifestations

GI symptoms are present in almost 90% of SSc patients involvingany of the upper and lower GI tract due to impaired motilitysecondary to fibrosis of the muscles and around the nerves thatinnervate the GI tract with resulting muscle atrophy [64].Symptoms and signs include gastric esophageal reflux disease(GERD), lower esophageal dysphagia, gastric antral vascular ecta-sia (GAVE), constipation, diarrhea, small intestinal bowel over-growth (SIBO), malnutrition, and fecal incontinence [4,6,64]. SScis associated with an increased risk of primary biliary cirrhosis(PBC) in patients with lcSSc who have both an ACA and anti-mitochondrial antibody. It has a prevalence of 2% or more andmay have a better prognosis than PBC alone with slower pro-gression to end-stage liver disease [65].

The lower esophageal sphincter in SSc is hypotonic due tofibrosis causing GERD [12]. GERD treatment is required toprevent complications such as strictures, erosive esophagitis,Barrett’s esophagus, or aspiration [6]. Counseling of patientssuch as avoiding foods that predispose to symptoms andraising the head of the bed is adjunctive therapy. Most

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patients with SSc and GERD require pharmacologic therapywhere proton pump inhibitors (PPI) are the standard of careincluding very high doses and sometimes addition of H2blockers [6,12]. Prokinetic agents can be helpful for GERDsymptoms such as domperidone (10 mg three times daily),metoclopramide, or prucalopride. One study showed thatalginic acid (anionic polysaccharide) (one chewing tabletthree times daily) neutralizes the acid in the esophaguswhich can help alleviate symptoms [12].

Dysmotility symptoms occur in 25% of patients leadingcomplications such as pseudo-obstruction, SIBO, constipation,intermittent diarrhea, and fecal incontinence [4]. Promotilityagents such as domperidone, erythromycin or metoclopra-mide, and laxatives may be prescribed [4,6]. Dysmotility occursdue to myopathy and neurogenic abnormalities involving theentire tract including anorectal dysfunction [66].

Constipation is one of the difficult symptoms to treat despiteuse of stool softeners, laxatives and prokinetic agents. Newtreatment options include prucalopride (at 2 mg/day), a seroto-nin (5-HT4) receptor agonist. A RCT of 29 patients with mild tomoderate GI symptoms showed pruclopride improved constipa-tion after failure of laxatives [64]. It was well tolerated andeffective for mild to moderate constipation and improved bloat-ing and GERD [64].

Ghrelin, a gut hormone produced by the stomach thatstimulates gastric emptying was recently investigated in asmall RCT in SSc. Ghrelin infusions (5 μg/kg) accelerated gas-tric emptying with no serious adverse effects [67]. SIBO isoften managed by rotating antibiotics (i.e. amoxicillin, erythro-mycin, tetracycline, metronidazole, ciprofloxacin) [5]. Rifaximinis used in traveler’s diarrhea and could be used in SIBO [11].GAVE is another manifestation that requires endoscopic inter-vention for treatment via argon plasma coagulation as it canresult in significant microscopic chronic bleeding with irondeficiency anemia [11].

2.6. Cardiovascular

Cardiac involvement occurs in 15% of SSc patients potentiallyleading to cardiomyopathy, pericardial effusion, ischemia,myocar-dial fibrosis, and conduction anomalies that are likely under-detected [4,6,68]. Screening may be achieved using echocardio-graphy and ECGs and in some centers cardiac MRI [6]. There islimited evidence for treatment in SSc; however, guidelines recom-mend symptomatic treatment for manifestations such as cardio-myopathy that include ACEI, beta-blockers, diuretics, and forarrhythmias insertion of a pacemaker or implantable cardioverterdefibrillator when indicated [15].

2.7. Renal

Scleroderma renal crisis (SRC) presents with severe hypertension,50% have worsening renal function and microangiopathic hemo-lytic anemia [69]. SRC is more common in dcSSc with a far higherprevalence if positive for anti-RNApolymerase 3 antibodies but it isoverall uncommon (in approximately 10% of dcSSc) [4]. Other riskfactors for SRC include rapidly progressive dcSSc, prednisone use(especially >15 mg/day), new onset SSc (<4 years after diagnosis),male, and presence of pericardial effusions [4]. Hence, SRC is

unlikely to occur after 5 years of disease duration if it has notalready occurred [6]. Angiotensin-converting enzyme inhibitors(ACEI) do not prevent SRC; therefore, their use is not recom-mended as they can mask symptoms of SRC [6]. There are nocontrolled trials for ACEI use; however, there are case controlstudies to support the use of ACEI even if patients are normoten-sive or on dialysis [4]. Mortality secondary to SRC after use of ACEIhas decreased from approximately 80% to 10–20% [69]. Rapidcontrol of blood pressure is necessary so adding other antihyper-tensives to maximum doses of ACEI is how SRC is treated.

2.8. Musculoskeletal

Musculoskeletal manifestations are commonwith findings such ascontractures, tendon friction rubs, acro-osteolysis, inflammatoryarthritis, and arthralgia [4,70,71]. Typically, patients present withnon-erosive arthritis; however, somepatientswith SSchaveerosivedisease andmayhave an overlapwith rheumatoid arthritis (RA) (1–5%) [4,71]. If there is inflammatory arthritis, treatment may includedisease modifying anti-rheumatic drugs (DMARDs) and biologics[6,71]. However, non-erosive arthritis can be approached withsymptomatic treatments such as use of NSAIDs, antimalarials,and/or low-dose corticosteroids as initial treatment [71].

Occupational therapy shows conflicting and limited evi-dence for benefit [72]. A multicenter RCT comparing usualcare to a supervised and personalized physical therapy pro-gram for SSc patient did not decrease disability at 12 monthsfor patients with SSc but had short-term benefits on handdisability, pain, and hand mobility [72].

2.9. Autologous hematopoietic stem cell transplantation(HSCT)

There have been three large studies evaluating autologous HSCT;these include: American systemic sclerosis Immunosuppressiveversus stem cell transplant (ASSIST), autologous stem cell trans-plantation international scleroderma (ASTIS), and myeloablativescleroderma cyclophosphamide versus transplant (SCOT) withover 250 patients that have undergone this procedure [14].There was improvement in skin and stabilization of lung functionfor up to 5 years and improvement in event-free survival [5,14].Non-myeloablative is safer than myeloablative regimens [14].

ASTIS compared HSCT with IV CYC pulse therapy (IV750 mg/m2/month for 12 months) in 156 patients with earlydcSSc. Patients had mRSS ≥15 and internal organ involvementor with mRSS >20 without organ involvement. HSCT hadincreased treatment-related mortality in the first year (8 vs. 0in CYC group, p = 0.007) but improved long-term event-freesurvival with significance at 3–10 years of follow-up. There wassignificant improvement in mRSS, function, FVC, and TLC at2 years. There was no effect DLCO and creatinine clearancewas worse in HSCT [5,73]. Results implied that better screeningof patients for cardiac disease was needed since three of eightdeaths were cardiac-related. [73].

ASSIST was a phase 2 trial with 19 patients using non-myeloa-blative autologous HSCT versus CYC. Patients needed to havemRSS >14 and organ involvement or a lower mRSS with pulmon-ary involvement. Follow-up was 1 year. Results showed improve-ment in all 10 HSCT patients, whereas none of the nine patients

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who received CYC improved. Seven of nine controls receivedtransplantation so it is difficult to compare groups for longer-term outcomes [74]. Overall, 24 months after HSCT, there wassignificant improvement in mRSS, FVC% predicted, and high-reso-lution chest CT [74]. TLC and DLCO did not differ between baselineand 2 years for all HSCT patients [74].

The SCOT trial testedmyeloablationusing total-body irradiationfollowed by reconstitution with a CD34+ selected autograft versusCYC [75]. This randomized, open-label, trial was conducted at 26sites [75].Myeloablative autologous hematopoietic stem cell trans-plantation showed long-term benefits in dcSSc patients, includingimproved event-free and overall survival [75]. These findings weresimilar to the ASTIS trial but with lower relapse rates at 24 months(SCOT trial, 9% compared to 22% ASTIS trial) [73,75].

Earlier studies did not exclude cardiac involvement despitecardiac involvement being a strong predictor for mortality[74]. To decrease the risks of treatment-related morbidityand death, HSCT needs to be considered early before cardiacinvolvement is present [74]. HSCT deaths were secondary toEBV re-activation, lymphoma, heart failure, myocardial infarc-tion, and acute respiratory distress syndrome (ARDS). Carefulpatient selection improves outcomes from HSCT, and usingexperienced centers [5]. Exclusion criteria for HSCT from thestudies consisted of: TLC <45% of predicted, left ventricularejection fraction <40%, cardiac symptoms, SSc >4 years sincediagnosis, HIV positive, pregnancy, creatinine >177 μmol/L,pulmonary artery systolic pressure >40 mm Hg, or mean pul-monary artery pressure >25 mm Hg [74]. Patients enteredmany trials with a high mRSS, and predicted mortality of50% in 5 years.

2.10. Emerging therapies

There are several ongoing trials currently investigating efficacyof previously approved agents used in other rheumatic dis-eases. These include Tofacitinib in early dcSSc (TOFA-SSc):phase I/II study in participants with dcSSc using same doseof tofacitinib used in adults with RA (5 mg twice per day).Patients will be randomized to tofacitinib versus placebo for24 weeks (ClinicalTrials.gov Identifier: NCT03274076).

Tocilizumab is an interleukin-6 receptor-alpha inhibitor andwas investigated for safety and efficacy via faSScinate phase 2trial. This included patients with early dcSSc. The mRSSimproved more in active treatment than placebo but theresults were not significant [76]. Also, less patients in thetreatment group had an absolute FVC decline more than10% [76]. A phase 3 trial is fully enrolled and is pendingcompletion (focuSSed) (ClinicalTrials.gov: NCT02453256) [76].

Abatacept is a fusion protein that acts as an inhibitor of T-cellactivation by binding to CD80/CD86 on antigen-presenting cellsinhibiting it from binding to CD28 on T-cells [77,78]. A study ofsubcutaneous abatacept to treat dcSSc (ASSET) is a fully enrolledRCT and will soon be completed (ClinicalTrials.gov Identifier:NCT02161406). Riociguat for patients with dcSSc (RISE-SSc) is arandomized, double-blind, placebo-controlled phase 2 studyinvestigating the efficacy and safety of this drug and the resultswill be available in 2018 [79] (Clinicaltrials.gov, identifier:NCT02283762). Anabasum (JBT-101) is a synthetic, oral, non-immunosuppressive, CB2 agonist. There were favorable results

for skin scores in a phase 2 trial. This requires further validation ina phase 3 trial anticipated to commence this year [80]. Othertreatments currently under investigations for SSc-related ILDspecifically include Nintedanib (SENSCIS) (ClinicalTrials.govIdentifier: NCT02597933), Pirfenidone (LOTUSS) (ClinicalTrials.gov Identifier: NCT01933334), and Imatinib (ClinicalTrials.govIdentifier: NCT00573326) [81–83].

3. Conclusion

Treatment guidelines for SSc provide therapy options for diseasemanifestations based on affected organ systems. However, treat-ments from more recent RCTs in SSc will need to be added toenhance the guidelines. There is often a lack of data when usualfirst- and second-line therapies have failed, so the treatment thenbecomes more eminence based. New treatment options for skinand lung disease may include biologics and anti-fibrotic therapiesbut results of RCTs are pending. Lung transplantation in patientswith ILD and PAH is not commonly seen as an option for SSc;hence, increased awareness is needed to decrease the rejection ofSSc patients for these procedures as they have 5-year survival thatis comparable to other age-matched transplant patients. Finally,HSCT transplantation shows event-free and overall survival butpatients need to be carefully screened for cardiac involvementand the procedure is only for the minority of early dcSSc patientswho would meet strict inclusion criteria.

4. Expert commentary

SSc is the most lethal CTD with several treatment options thathave been shown to provide only mild to moderate benefit. Thelimited efficacy of available therapies can be explained by severalfactors including heterogeneity of the disease, lack of completeunderstanding of pathophysiology, limited use of combination, ormaintenance therapy. Also, the low incidence of the diseasemakes it difficult to conduct clinical trials to demonstrate benefit.Nonetheless, many advances in the field have been made by useof immunosuppressive therapies that have at least stopped pro-gression of the disease, and more recently shown survival benefitas in autologous HSCT if used in the appropriate subset ofpatients. Guidelines for treatment of SSc provide a limitedapproach to treatment of SSc with no options further than sec-ond-line therapy inmost cases. Therefore, we aimed to provide anupdate to the current research in the field to present other optionsin addition to recommended treatment (see Table 1).

Traditionally, patients have been classified as either lcSSc ordcSSc. However, this classification appears to be an over simplifica-tion of this complex disease, which needs to be re-examined as ourknowledge has grownwith newer cytokines, antibodies, and geneexpression. For example, type 2 innate lymphoid cells were foundto be increased in patients with diffuse involvement of skin andpulmonary fibrosis [18]. Other studies have shownover-expressionof genes that could be used as biomarkers [18]. Currently, guide-lines dictate treatment based on organ involvement; however, itmay be more advantageous in the future to tailor treatment ofpatients based on their disease phenotype to improve outcomes.Trials of autologous HSCT demonstrated the importance of select-ing the appropriate clinical cohort for the treatment to decrease

578 M. ELDOMA AND J. POPE

Table1.

Summaryof

treatm

entrecommendatio

ns.

Disease

manifestation

Skin

ILD

PAH

RP

DU

SRC

GI

Healing

Preventio

n

Recommendedtreatm

ents

accordingto

guidelines

MTX

[5,16]

MMF[17]

Indu

ction:

MMF[17]

CYC[20]

Mainten

ance:M

MF

[17]

AZA[46]

WHOclasses

II–III:ERA

s[57]

PDE-5i

[57]

Prostano

ids[57]

Riociguat[57]

WHOclasses

III–IV:IV

epop

rostenol

[57]

Combinatio

ntherapya

[57]

CCB[59]

PDE-5i

[58,62]

IVprostacyclin

[61]

CCB[59]

IVprostacyclin

[61]

PDE5i

[60,62,63]

CCB[59]

PDE-5i

[60,62,63]

Bosentan

[63]

Statins

IVprostacyclin

[60,61]

ACEI

[5]

GER

D:P

PIat

high

doses,H2blockers[6]

Dysmotility:p

rokinetic

agents

(dom

perid

one,

metaclopram

ide,

erythrom

ycin),

pruclopride[64]

SIBO

:rotating

antib

iotics[5,11]

GAVE:

APC[11]

Others

CYC[21]

RTX[22–32]

Belim

umab

[43]

Phototherapy

[34–39]

Photop

hresis[40]

IVIG

[41,42]

Tofacitin

ib(NCT03274076)

Abatacept

(NCT02161406)

Anabasum

(JBT-101)

RTX[24,25]

Belim

umab

[43]

Lung

transplant

[49–

51]

Tocilizum

ab(NCT02453256)

Abatacept

(NCT02161406)

Nintedanib

(NCT02597933)

Pirfenidon

e(NCT03221257,

NCT01933334)

Imatinib

(NCT00573326)

Lung

transplant

[51]

Supp

ortive

therapyfor

heartfailure

andhypo

xia

Fluo

xetin

eNitrates

ARB

Riociguat

(NCT02915835)

Riociguat

(NCT02915835)

Addantih

ypertensives

tomanage

BPto

norm

otension

(CCB

,ARB

,alph

a-blockers,p

razasin,

labetalol,hydralazine,

minoxidil,etc.)

GER

D:p

romotility

agents,alginicacid

[12]

Dysmotility:G

hrelin

ILD:interstitiallung

disease;

PAH:pu

lmon

aryarterialhypertension

;RP:Raynaud’sph

enom

enon

;DU:digitalulcers;SRC:

scleroderm

arenalcrisis;GI:gastrointestinal;MTX

=metho

trexate;

PDE-5i

=ph

osph

odiesterase-5

inhibitors;MMF=mycop

heno

late

mofetil;

CYC=cyclop

hosphamide;

AZA=azathiop

rine;

ERA=endo

thelin

receptor

antago

nist;WHO

=World

Health

Organization;

CCB=calcium

channelblocker(dihydropyrid

ine);

PPI=proton

pumpinhibitors;R

TX=Rituximab;IVIG=intravenou

simmun

oglobu

lins;AR

B=angiotensinIIreceptor

blocker;GAV

E=gastric

antral

vascular

ectasia;

APC=argo

nplasmacoagulation;

ACEI:a

ngiotensin-

convertin

g-enzymeinhibitor;GERD:g

astroesoph

agealrefluxdisease;SIBO

:smallintestin

albacterialo

vergrowth.

aCo

mbinatio

nof

PDE-5inhibitors,ERA

,orprostano

ids.

EXPERT REVIEW OF CLINICAL IMMUNOLOGY 579

mortality and demonstrate benefit. Classificationmay be based onantibodies, clinical subtypes, cytokines, genetics, or proteomics.

Efficacy of treatments may be further increased if combinationtreatment is used in patients. This is already used in other diseasesin rheumatology to provide better efficacy such as in rheumatoidarthritis treatment, and we can see that this model has beenadopted for treatment of PAH. SSc has underlying autoimmunityleading to fibrosis; therefore, combination of treatments that tar-get bothmechanismsmay yield better results. This is alreadybeinginvestigated in SLS III with use of MMF and Pirfenidone. The sameargument canbe used to advocate formaintenance therapy that islikely required to sustain benefit of treatment that is lost aftertreatment discontinuation such as in SLS I. However, research islacking in this aspect of the fieldwithuseofMMFor azathioprine asthe main agents with little evidence. A treatment approach thataims for initial induction thanmaintenance therapy is likely neededfor better efficacy as currently used in SSc-related ILD (see Table 1).

There are several new treatments being explored for possibleefficacy with promising results, which will allow for a treatmentalgorithm to be developed and included in updated guidelines.Also, safety data from trials should inform experts’ choices fortreatment. For example, CYC would not be considered as first-line in SSc-related ILD. However, MMF can be utilized as first-linetreatment due to its comparable efficacy and better safety profilefollowed by CYC as a second-line agent. Given that RTX has thelargest new evidence at this time with encouraging results, RTXcan be considered a third-line alternative. We believe lung trans-plant should be reserved for the subset of patients who arecompatible with the selection criteria of the large clinical trialsand it can be used as a fourth-line option. Similarly, managementof skin fibrosis utilizes MMF and CYC which can be consideredsecond- and third-line therapies, respectively. MTX has a bettersafety profile than MMF; therefore, it can be used as a first-linetherapy in mild to moderate skin involvement. RTX may be con-sidered fourth-line therapy due to its favorable results thus far.

Further studies of biologic agents such as Abatacept,Tocilizumab, Tofacitinib, and Belimumab may provide otherchoices. Confirmatory results are pending from their studies andpreliminary data from some of them appear to show efficacy.Finally, in terms of research, clinical trials in SSc may begin to useinnovative ways to measure clinical response such as geneexpression similar to the design of the Belimumab trial [43]. Thistype of research will help to further our understanding of thedisease, provide objective methods to measure response, andinform the field of basic science of SSc [84].

5. Five-year view

There are several trials currently being conducted for treatment ofSSc with agents that include anti-fibrotic drugs, Tocilizumab,Tofacitinib, RTX, Abatacept, and Riociguat. Some of these studiesare close to completion with results that will hopefully facilitatetheir use as third- or fourth-line agents. Patient cohort from thesestudies may lead to better characterization of SSc phenotypes.Also, development of basic science research in this field will helpguide use of biomarkers or antibodies in this field. New guidelinesin the future will likely reflect these changes to patient classifica-tion in addition to a more systematic approach to treatment.

Key issues

● SSc is a multisystem complex disease characterized by vascu-lopathy, fibrosis, and inflammation with a heterogenouspatient population.

● Current guidelines provide limited treatment options withan approach aimed at affected organs.

● Current therapy shows mild improvement in disease withmostly loss of benefit after discontinuation of treatment.

● Autologous HSCT is the only treatment to show event-freeand overall survival benefit but only in a subset of patientsthat need careful selection.

● New treatment modalities are currently under investigationwith some initial results that show improvement but effi-cacy is yet to be proven.

● There is a need for a revised classification of patients basedon clinical subtype, genomics or autoantibodies to tailortreatment options and improve efficacy.

● Use of combination and maintenance therapy is likelyrequired to demonstrate and sustain benefit.

Funding

This paper is not funded.

Declaration of interest

J Pope has been a consultant for AbbVie, Amgen, BMS, Celtrion, GSK, Janssen,Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB The authors have noother relevant affiliations or financial involvement with any organization orentity with a financial interest in or financial conflict with the subject matteror materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or otherrelationships to disclose.

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69. Turk M, Pope JE. The frequency of scleroderma renal crisis overtime: a metaanalysis. J Rheumatol. 2016;43:1350–1355.

70. Baron M, Pope J, Robinson D, et al. Calcinosis is associated withdigital ischaemia in systemic sclerosis – a longitudinal study.Rheumatol (United Kingdom). 2016;55:2148–2155.

71. Young A, Namas R, Dodge C, et al. Hand impairment in systemicsclerosis: various manifestations and currently available treatment.Curr Treat Options Rheumatol. 2016;2:252–269.

72. Rannou F, Boutron I, Mouthon L, et al. Personalized physical therapyversus usual care for patients with systemic sclerosis: a randomizedcontrolled trial. Arthritis Care Res (Hoboken). 2017;69:1050–1059.

73. Van Laar JM, Farge D, Sont JK, et al. Autologous hematopoieticstem cell transplantation vs intravenous pulse cyclophospha-mide in diffuse cutaneous systemic sclerosis: a randomizedclinical trial. JAMA J Am Med Assoc. 2014;311:2490–2498.

• Important RCT examining Autologous HSCT versus cyclopho-sphamide (ASTIS).

74. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative hae-mopoietic stem-cell transplantation compared with pulse cyclo-phosphamide once per month for systemic sclerosis (ASSIST): anopen-label, randomised phase 2 trial. Lancet. 2011;378:498–506.

• ASSIST trial: autologous HSCT versus cyclophosphamide.75. Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative

autologous stem-cell transplantation for severe scleroderma. NEngl J Med. 2018;378:35–47.

• Important SCOT trial: autologous HSCT for treatment of SScshowing event-free and overall survival.

76. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcuta-neous tocilizumab in adults with systemic sclerosis (faSScinate): a phase2, randomised, controlled trial. Lancet. 2016;387:2630–2640.

77. De Paoli FV, Nielsen BD, Rasmussen F, et al. Abatacept inducesclinical improvement in patients with severe systemic sclerosis.Scand J Rheumatol. 2014;43:342–345.

78. Wehner Fage S, Arvesen K, Olesen A. Abatacept improves skin-score and reduces lesions in patients with localized scleroderma:a case series. Acta Derm Venereol. 2018;98:465–466.

79. Distler O, Pope J, Denton C, et al. RISE-SSc: riociguat in diffusecutaneous systemic sclerosis. Respir Med. 2017;122:S14–S17.

80. Spiera R, Hummers L, Chung L, et al. Oral Presentations. In: OP0126:a phase 2 study of safety and efficacy of anabasum (JBT-101) insystemic sclerosis. BMJ Publishing Group Ltd and European LeagueAgainst Rheumatism. 2017. Available from: http://dx.doi.org/10.1136/annrheumdis-2017-eular.2712.

81. Distler O, Brown KK, Distler JHW, et al. Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS™). Clin Exp Rheumatol.2017;35:75–81.

82. Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of thesafety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol.2016;43(9):1672–1679.

83. Fraticelli P, Gabrielli B, Pomponio G, et al. Low-dose oral imatinib inthe treatment of systemic sclerosis interstitial lung disease unre-sponsive to cyclophosphamide: a phase II pilot study. Arthritis ResTher. 2014;16(4):R144.

84. Pope JE, Lee JJ, Denton CP. Editorial: bench to bedside-andback again: finding the goldilocks zone within the sclerodermauniverse. Arthritis Rheumatol. 2018;70:155–156.

582 M. ELDOMA AND J. POPE

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