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Hindawi Publishing CorporationAutoimmune DiseasesVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleUpdates on Morphea: Role of Vascular Injury and

Advances in Treatment

Julio C. Sartori-Valinotti,1 Megha M. Tollefson,1 and Ann M. Reed2

Te Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN , USA Te Department of Pediatrics, Mayo Clinic College of Medicine, Rochester, MN , USA

Correspondence should be addressed to Ann M. Reed; reed.ann@mayo.edu

Received April ; Accepted September

Academic Editor: Paulo Ricardo Criado

Copyright Julio C. Sartori-Valinotti et al. Tis is an openaccess article distributed under the Creative Commons AttributionLicense, whichpermits unrestricted use, distribution, andreproduction in anymedium, providedthe original workis properlycited.

Morphea and systemic sclerosis are brosing disorders o the skin that share common inammatory and immunologic pathwaysthat are responsible or the vascular changes, increased collagen production, and extracellular matrix prolieration seen in bothconditions. Recent advances in molecular biology techniques have urthered our knowledge o the potential underlying pathogenicmechanismsand offer new and provocative areas o research or novel diagnostic and therapeutic interventions. Tis review ocuseson the role o vascular injury in the development o morphea, the use o ultrasonography as a diagnostic modality, and well-established and newly proposed treatments.

1. Introduction

Morphea is an inammatory, brosing skin disorder thatleads to sclerosis o the dermis and subcutaneous tissue butin some cases may also extend to the ascia, muscle, andunderlying bone. Clinically, morphea has an asymmetricdistribution and is usually conned to one body area; hence itis also reerred to as localized scleroderma. Systemic sclerosis(SSc), however, in addition to symmetric skin changes ischaracterized by internal organ involvement, sclerodactyly,presence o Raynauds phenomenon, and nailold capillary

abnormalities. Despite these differences, both entities sharecommon inammatory and immunologic pathways that areultimately responsible or the vascular changes, increasedcollagen production, and extracellular matrix prolierationseen in both conditions. Although the etiology and precisemechanisms that trigger the cascade o molecular eventsthat culminate in skin brosis are not ully understood,advances in molecular biology techniques have urtheredour knowledge o the potential culprits and offer new andprovocative areas o research or novel diagnostic and thera-peutic interventions. Tisbrie review willocus on the role o

vascular injury in the developmento morphea with emphasison recent basic research data as well as use o ultrasonography

as a diagnostic method. Lastly, well-established and newlyproposed treatments will be discussed.

2. Clinical Features

Several classication systems have been developed in attemptto grasp the breath o the various orms o presentation omorphea [, ]. Tey are largely based on clinical ndings andinclude, with minor differences, at least our major variants:plaque-type, linear, generalized and a miscellaneous group o

morphologically distinct phenotypes.Plaque-ype Morphea (Morphea en Plaque or Circumscribed).It is the most common subtype overalland themost common

variant in adults. Most ofen located on the trunk, it begins asan erythematous-to-violaceous, edematous plaque o severalcentimeters that extends peripherally over a period o to years beore it reaches a plateau phase. Tis is ollowed by aninvolution phase that leaves behind atrophic skin (Figure).

Linear Morphea (Including Morphea en Coup de Sabre(Figure) and Progressive Hemifacial Atrophy or Parry-Romberg Syndrome). Most common in children and ado-lescents, it presents as a linear induration on the scalp,

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F : Plaque-type morphea.

F : Morphea en coup de sabre.

orehead, trunk, or extremities (Figuresand), sometimeswith involvement o the eye (in the case o acial lesions),underlying ascia, muscle, and bone. Te latter may lead tolimb atrophy and joint immobilization. Patients with Parry-Romberg syndrome anden coup de sabremorphea may also

have seizures, headaches, and abnormal intracranial ndingson magnetic resonance imaging (MRI) []. Linear morpheaaffecting the mouth has also been described (Figure ).Antinuclear antibodies, ssDNA, and antihistones antibodiesare usually positive.

Generalized Morphea.It is dened by the presence o our ormore plaque-type lesions affecting two or more body sitesor by the insidious onset o a slowly progressing plaque-type morphea on the trunk with eventual involvement o theentire trunk leading to progressive dyspnea due to mechan-ical restriction o chest cage expansion. Similar to linearmorphea, patients in this subgroup have positive serology orantinuclear antibodies, ssDNA, and antihistones antibodies

and are more likely to have constitutional symptoms.

Miscellaneous Group. Encompasses a variety o phenotypi-cally different lesions including nodular, mixed (combinationo two or more variants), guttate, bullous morphea andatrophoderma o Pasini and Pierini.

Irrespective o the clinical subgroup, morphea can be dis-tinguished rom SSc by the absence o internal organ involve-ment, Raynauds phenomenon and nailold capillary changes.On the other hand, SSc can be urther subdivided into limitedSSc (lSSc) and diffuse SSc (dSSC) on the basis o the extentand distribution pattern o skin disease. Sclerodermatousskin changes distal to the elbows or knees are reerred to

F : Linear morphea affecting the leg.

F : Linear morphea o the upper extremity.

as lSSC whereas skin thickening proximal to these anatomiclandmarks are characteristic o dSSC. A subset o patientswith lSSc and calcinosis, Raynauds phenomenon, esophagealdysmotility, sclerodactyly, and telangiectasias comprised theso-called CRES syndrome.

3. Pathogenesis

Vascular Injury as the Crucial Event. It has been proposedthat endothelial cell damage may represent the initial andpivotal step in the development o sof tissue changes in mor-phea and systemic sclerosis. For example, using whole-elddigital microscopy and transmission electron microscopy,

Frech and coworkers demonstrated that patients with SSchad increased skin interstitial edema, brosis, basal laminalamellation, and endothelial swelling compared to normalcontrols, irrespective o disease duration, or appreciable clin-ical eatures []. Tis is consistent with the clinical ndings oRaynauds phenomenon and nail old capillary changes seenin the early stages o the disease prior to the development orank brosis. Inection, hypoxia, trauma, radiation, reactiveoxygen species, and antiendothelial cell autoantibodies con-tribute to vascular injury and subsequent recruitment andactivation o and B lymphocytes and mononuclear cells,secretion o proinammatory mediators and growth actors,endothelial cell apoptosis, and broblast activation which in

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F : Linear morphea o the mouth. Note subtle changes othe inner upper lip and gingival mucosa around the maxillary rightcentral incisor.

turn leads to vascular and tissue remodeling and brosis[].

Under physiologic and pathologic conditions, disruptiono the capillary network results in decreased blood ow andtissue ischemia. Te ability to withstand hypoxia varies bytissue type and is tightly regulated by hypoxia inducibleactors. One o the adaptive responses to diminished tissueoxygen delivery is the ormation o new vessels via eitherangiogenesis and/or vasculogenesis. Te ormer reers to theormation o new vessels rom preexisting vessels whereas

vasculogenesis represents de novo vessel ormation rombone marrow derived endothelial precursor cells (EPC).Cumulative evidence suggests that both processes are deec-tive in SSc despite strong proangiogenic stimuli [].

Viruses may trigger vascular damage via neointimalprolieration and apoptosis likely through overproduction oprobrotic cytokines including GF-beta, PDGF-alpha, andPDGF-beta []. Cytomegalovirus (CMV) RNA transcriptshave been ound in the endothelium o patients with scle-rodermoid changes []. Similarly, parvovirus B-inectedendothelial cells, broblasts, and perivascular inammatorycells o SSc patients have increased expression o NF-alpha[] which has been shown to participate in regulation obroblast unction and endothelial activation []. A roleor viral inection is urther supported by the observationthat molecular mimicry between human CMV late proteinUL and NAG-, a surace molecule present on endothelialcells and dermal broblasts, is responsible or cross-reactivityo human anti-CMV antibodies against the latter and maycontribute to chronic sclerodermoid graf versus host disease

(GVHD) [,].Endothelial cell apoptosis is a key eature o SSc and

arguably the earliest event []. IL- and the Fas-pathwayhave been implicated in endothelial cell apoptosis [, ]

via mechanisms dependent on the presence o neutrophilsand antibody-induced cell-mediated toxicity, respectively.Circulating angiogenic cells are also prone to and undergoapoptosis in SSc through phagocytosis o microparticles andstimulation o acid sphingomyelinase activity []. Plasmasamples o SSc patients have signicantly higher levels omicroparticles []. Tey are small, membrane-bound vesi-cles with altered surace lipids that participate in intercellularsignaling []. Conversely, dermal broblasts are resistant

to Fas-mediated apoptosis, perhaps due to deciency inacid sphingomyelinase, and increased levels o anti-apoptoticproteins cFLIPs and cIAP, partially explaining their survivaland contribution to increased extracellular matrix depositionin SSc [,].

Antiendothelial cell autoantibodies (AECAs) likely pro-

mote vascular injury, endothelial cell apoptosis, generationo reactive oxygen species, and expression o adhesionmolecules on endothelial cells in patients with SSc. Tey area heterogeneous group o antibodies against endothelial cell-specic proteins and are present in % o patients withSSc []. Upon interaction with these antibodies, endothe-lial cells augment the expression o vascular cell adhe-sion molecule- (VCAM-), intercellular adhesion molecule- (ICAM-), and E-selectin resulting in increased leucocyteadhesion. Moreover, they stimulate platelet-derived growthactor (PDGF) pathway and oxidative stress []. Beyondtheir pathogenic role in dermal brosis, AECAs have alsobeen linked to complications o SSs, including pulmonarybrosis andhypertension, andapoptosis o bone marrow EPC[,].

Microarray analyses o EPC rom patients with SScreveal a differential protein expression prole under bothbasal and hypoxic conditions, with differentiation towardsa proinammatory state. Furthermore, immunohistochem-istry o SSc skin samples shows downregulation o NFS,NFAIP, and HOX-A and overexpression o PGS-[]. Most recently, genomic DNA analysis o eight pairso monozygotic twins with SSc identied sites that werepreerentially hypermethylated or hypomethylated on the Xchromosome and corresponded to target genes governing,among other cellular pathways, apoptosis (MM), inam-mation (ARAF), and oxidative stress (ENOX) []. Teselatter ndings provide some insight into the molecular alter-ations behind the higher prevalence o morphea and SSc inwomen.

Vascular abnormalities seem not to be limited to the skin.Patients with SSc have reduced bone marrow vascularity, inspite o normal cell morphology, as measured by microvesseldensity. Notoriously, peripheral blood mononuclear cells(PMBC) rom individuals with SSc release greater amountso VEGF [], and its expression is much higher in SScpatients [,] thus suggesting a diminished responsivenessto angiogenic stimuli. Impaired production o NF-likeweak inducer o apoptosis (WEAK), a newly characterizedcytokine, by PMBC may be accountable or aberrant angio-

genesis and tissue remodeling in SSc[]. Lastly, broblastsand autoimmunity are also important pathogenic players inmorphea and SSc, but in-depth discussion o these topics isbeyond the scope o this review.

4. Evaluation

Based on the increasing evidence that vascular changesdominate the early stages o disease development, it is notsurprising that there is emerging research looking into waysto rapidly and accurately recognize them. Ultrasonographyhas gained particular attention as a noninvasive, harmless,and inexpensive diagnostic tool.

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Morphea and SSc are characterized by three distinctphases o skin disease: active or edematous; inactive, sclerotic,or brosis; and atrophic lesions. Early recognition o theactivephase may have both therapeutic andprognostic impli-cations. In a study o morphea lesions, ultrasonographywas not inerior to dermatopathologic examination in eval-

uating active disease. Indeed, when compared to histology,increased cutaneous (dermal or subcutaneous) blood owand hyperechogenicity o the subcutaneous tissue had both% specicity and % sensitivity[]. In keeping withthese observations, using ourteen MHz ultrasonography o morphea lesions, hyperechogenicity correlated with thepresence o moderate or severe sclerosis on histology. Moreimportantly, ultrasonographic ndings were more reliablethan clinical-based scores such as the Modied Rodnan SkinScore (mRSS) [] and have acceptable and reproducibleinter- and intraobserver reliability. Te inactive and atrophicphases o the disease also exhibit unique sonographic eatures[,].

Ultrasound can additionally be used to determine theseverity o musculoskeletal involvement [] and endothelialunction [] in SSc and in sclerodermoid GVHD []. It hasalso been shown to be useul in monitoring the response totreatment. For instance, in pediatric patients, the hyperemiaand increased echogenicity o active lesions disappeared afersuccessul treatment []. In a different series, dermal thick-ness as measured by ultrasound was decreased in patientstreated with phototherapy [] and topical imiquimod[].Due to its depth o penetration, which is a unction orequency, the useulness o ultrasonography is somewhatlimited to the skin and subcutaneous tissue. In this regardMRI is more advantageous and allows or better assessmento deeper structures such as the ascia and underlying muscle[, ]. As with ultrasonography, MRI can be resourceulin monitoring disease activity and response to treatment[].

5. Treatment

Te treatment o morphea and skin disease in SSc is chal-lenging, and its efficacy is difficult to assess owing to theabsence o validated and standardized outcome measures.Nonetheless, numerous treatment modalities both systemicandtopical have been investigated, the majority o which havebeen abandoned due to lack o response or have not beeninvestigated in larger populations. However, among these

interventions, methotrexate (MX) alone or in combinationwith systemic steroids and phototherapy have been provento be benecial with stronger evidence to support theiruse.

.. Methotrexate. Te effectiveness o methotrexate, primar-ily in conjunction with systemic steroids, has been validatedby several retrospective studies. In the recent past, at leastsix prospective, including double-blind, randomized trialshave conrmed the efficacy and saety o this therapeuticregimen. For example, in patients with juvenile morphea,clinical remission or a mean duration o months wasachieved with simultaneoususe o MX andprednisone[].

In another study o pediatric patients with moderate to severemorphea, this combination strategy quickly resulted in clini-cal improvement, as determinedby Modied LS Skin SeverityIndex, within two months o treatment []. Improvementin musculoskeletal involvement has also been observed in aprospective study o adults with deep morphea (mean age

years) []. When added to MX and prednisone, imatinib,which inhibits broblast activity, halted the progression oskin disease and joint deormity in a -year-old patient [].MX likely exerts its antibrotic effects via inhibition oinammatory cytokines such as IL-, IL-, IL-, IL-, andNF-alpha and adhesion molecules such as ICAM- [,,].

With regard to the use o MX in SSc, in theEuropean League Against Rheumatism/EULAR Sclerodermarails and Research published recommendations or themanagement o the multiple maniestations o SSc, includingcutaneous involvement. Based on two randomized con-trolled trials on patients with early diffuse SSc or limitedSSc [, ], methotrexate was recommended as a rst-line treatment or early diffuse SSc (Class A recommen-dation). Notwithstanding, MX was superior to placeboin one o these studies [], whereas the other showedonly a trend avoring MX, but it did not reach statisticalsignicance. wo important considerations can be drawnrom these conicting observations. First, it is conceivableto hypothesize that, relative to morphea, the modest or lacko response to treatment with MX in SSc is due to the actthat most studies or management o morphea included acombination o MX and steroids. Second, with widespreadinvolvement, the efficacy o MX may be reduced or difficultto quantiy. Placebo controlled trials assessing the benetso combined MX and systemic steroids or diffuse SSc arelacking.

Mycophenolate moetil is reserved as a second line agentthat could be used or treatment o localized and generalizedmorphea afer ailed response to MX and/or phototherapy[, ]. Over the past decade, B-cell depletion therapyhas gained special attention as a successul intervention or

various immune-mediated diseases. Pertaining to its useor sclerodermoid conditions, there are conicting resultsin patients with reractory sclerodermoid GVHD eithershowing improvement [] or lack o response []. Arecent case report showed resolution o localized sclerodermawith rituximab []. Larger case series and prospectivestudies will help elucidate its potential use as a standard

treatment.

.. Phototherapy. First documented in [], pho-totherapy or treatment o morphea has since been widelyused and studied. By virtue o their longer wavelength andthus deeper penetration, PUVA therapy and UVA are thecornerstone o light treatment or localized scleroderma.Its mechanism o action likely involves the combination o

various effects such as alteration in cytokine and growthactors expression, modulation o endothelial dysunction,induction o matrix metalloproteinases thatdegrade collagen,apoptosis o Langerhans cells and cells, and inhibitiono collagen synthesis []. Te treatment course varies

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among clinical protocols, but it typically requires approx-imately sessions beore clinical, histological, and ultra-sonographic improvement can be appreciated. Furthermore,clinical improvement continues beyond cessation o therapy;thus prolonged treatment is neither needed nor indicated.Phototherapyis effective in all Fitzpatrick skin prototypes and

is generally well tolerated, with no serious side effects. Temain caveats to the use o UVA are the need or prolongedexposure times, diminished effectives afer repetitive treat-ment owing to increased pigmentation, and its availability atspecialized centers only. Alternatively, narrowband UVB andbroadband UVA can be used with satisactory results [].

Tere is a paucity o data on the use o phototherapy ormanagement o diffuse skin involvement in SSc, but PUVAand UVA have been reported to be effective. In a studyo patients with acrosclerosis, low dose UVA resulted inreduction o clinical score rom . to .; this was accom-panied by elevation o dermal collagenase []. In a largerseries o patients with different skin conditions amenableto treatment with UVA, patients with SSc/CRES hada moderate response (% improvement) as determinedby clinical assessment by the same physician beore andafer treatment []. Another study involving patientswith systemic scleroderma also reported improvement in themRSS afer UVA treatment []. Due to the small number ostudy subjects, evaluation o limited disease with involvemento the hands only, and the subjective (clinical) assessment oresponse to treatment, the results o these studies cannot begeneralized.

On the other hand, provocative data rom the basicresearch literature may be key in providing the ounda-tion or the development o new therapeutic interventionsor morphea and SSc. For instance, the tight-skin (sk(/+)) model o SSc shows abnormal brillin- expressionand chronic oxidative damage that may be responsible orimpaired angiogenesis []. Circulating endothelial cells andEPCs rom patients with SSc treated with iloprost, a syn-thetic analogue o the vasodilatory prostacyclin PGI, exhibitupregulation o antiapoptotic genes and genes involved inwound healing []. reatment with recombinant humanerythropoietin resulted in resolution o a nonhealing digitalulcer and reduction in apoptotic rates o bone marrowendothelial cells [] in a patient with SSc. In conclusion, theadvent o new technology has urthered our understandingo the imbricated mechanisms behind the development o

these debilitating and disguring conditions. Nonetheless,placebo-controlled trials exploring these newly discoveredpathways are much needed to expand our treatment reper-toire. Tis task is rather challenging because, by virtue oits heterogenous presentation, better measures o diseaseactivity and outcomes are necessary to accurately evaluateevidence-based therapies. Fortunately, research in this area isunderway.

Conflict of Interests

Te authors declare that they have no conict o interests.

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