Scleroderma

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Scleroderma

  1. 1. 113*This chapter is dedicated to James N. Gilliam, MD, a loving husband and father, who inspired our careers and our mutual interests inautoimmunity.J. Varga et al. (eds.), Scleroderma: From Pathogenesis to Comprehensive Management,DOI 10.1007/978-1-4419-5774-0_12, © Springer Science+Business Media, LLC 2012A.E. Gilliam, MD ( )Department of Dermatology, Palo Alto Medical Foundation Group, Palo Alto, CA 94301, USAe-mail: gilliaa1@pamf.orgA.C. Gilliam, MD, PhDDepartment of Dermatology and Dermatopathology, Palo Alto Medical Foundation Group, Palo Alto, CA 94301, USAe-mail: gilliaa@pamf.orgKeywords Clinical features of morphea • Classification of morphea • Epidemiology of morphea • Localized forms ofscleroderma • Morbidity in morphea • MorpheaMorphea, also called localized scleroderma, is a fibrosing disorder that resembles scleroderma (systemic sclerosis)microscopically, but typically has a quite different clinical presentation, course and possible pathophysiology. The indi-vidual with morphea has single or multiple circumscribed indurated cutaneous plaques that can have variable appearances,depending on the subtype (see classification below and Table 12.1). The main variants are circumscribed or plaque-typemorphea (Fig. 12.1a), generalized morphea (Fig. 12.1b), linear morphea (Figs. 12.1c–f and 12.2a–d), and deep morphea ormorphea profunda. Unlike scleroderma, systemic disease and involvement of internal organs are uncommon in morphea.The classic appearance of the most common forms of morphea is indurated or sclerotic dyspigmented (i.e. hyper orhypopigmented) plaques sometimes with a violaceous border. The development of morphea can be insidious and subtle.Initial misdiagnosis as other skin disorders, particularly by non-dermatologists, occurs. Early morphea can mimic otherquite different cutaneous diseases. These include, among others, atrophic conditions such as lichen sclerosis, vascularlesions such as port wine stains (Fig. 12.1c), depigmenting disorders such as vitiligo [1], and even more common skinlesions such as bruises and scars. Because of this variable presentation, diagnosis and treatment of early morphea can bedelayed or inappropriate [1–3]. Skin biopsy is often helpful in differentiating morphea from these other disorders.There are several excellent recent reviews of morphea covering a large number of case reports and small case studies[4–15]. This review will concentrate on the English language literature for morphea from the 2000s to the present.Practical guidelines for assessment and management of morphea are presented at the end of this chapter.Classification of MorpheaThe subtypes include plaque-type morphea, generalized morphea, linear morphea, morphea profunda, pansclerotic dis-abling morphea (which may be a subtype of morphea profunda) and mixed types of morphea. Clinical images of themorphea subtypes are presented in Fig. 12.1. The classification scheme was developed by the Committee on ClassificationCriteria for Juvenile Systemic Sclerosis, composed of members of the Pediatric Rheumatology European society (PRES),the American College of Rheumatology (ACR), and the European League Against Rheumatism (ELAR) [8] (Table 12.1).Diagnosis is mainly by clinical features, as the histopathology is similar in all the forms except eosinophilic fasciitis andatrophoderma of Pasini and Pierini (Fig. 12.3a). Some believe that these last two disorders are separate entities.Chapter 12Localized Forms of Scleroderma*Amy E. Gilliam and Anita C. Gilliam
  2. 2. 114 A.E. Gilliam and A.C. GilliamWhen linear morphea occurs on the upper face most notably the paramedian forehead, it is often called en coup de sabre(ECDS)(Fig. 12.1c, d). When it involves the lower face or produces hemifacial atrophy of deeper tissues, it is often called Parry-Romberg syndrome (Fig. 12.1e, f). Whether these conditions are a spectrum of the same disorder or are two distinct entitieshas been a subject of considerable debate, but recent literature suggests that they are on the same spectrum of disease [16].Epidemiology of MorpheaMorphea is diagnosed more often in whites and females than in individuals of color or in males. The disorder occurs pre-dominantly in young individuals and children with an incidence of 0.4–1 per 100,000 individuals or 25 cases per 1 millionindividuals [13, 17–24]. There is a female: male ratio of 2–3.1 [19, 21]. Morphea is approximately 0.2% of the patientsreferred to a general pediatric dermatology clinic [21]. In general, guttate or plaque-type morphea is more common in adults,and linear morphea is more common in children, with the highest incidence in young white girls.Clinical features of morphea. The clinical appearance of morphea is a puzzle itself – plaques of indurated skin are foundimmediately adjacent to normal skin without induration. Genetic factors surely play a role in the clinical appearance ofmorphea, particularly the linear variants which often follow Blaschko’s lines [7, 25]. Blaschko’s lines are different fromdermatomal skin patterns and are thought to represent embryonic pathways of skin cell development. They reflect geneticTable 12.1 Classification of morpheaType Types of lesions Location IncidencePlaque types of morphea Trunk 37% of pediatric morpheapopulation [21]– Circumscribed PlaqueTypeOval or round circumscribed areas ofinduration sometimes with associateddyspigmentation or a violaceous (i.e.“lilac”) border (Fig. 12.1a)Trunk Most common type ofmorphea in adults [13]– Guttate Small (<1 cm) superficial pale plaques Neck and upper trunk [13]– Keloidal/Nodular Nodules of dense sclerosis, typicallyassociated with plaque-type morpheaTrunk Rare [168]– Atrophoderma of Pasiniand PieriniHyperpigmented depressed plaques, noobvious induration (Fig. 12.3a)Trunk, often lower back, innerthigh, axillaeRare [77]– Bullous – Tense subepidermal bullae develop overplaques of typical morpheaTrunk RareRare [71, 83, 169, 170]– Superficial – Involves superficial dermis onlyGeneralized Confluent plaques, hypo- andhyperpigmented (Fig. 12.1b)Three or more anatomicallocations, covering morethan 30% body surface area9% of pediatric morpheapopulation [21]Linear types of morphea Face and extremities 51.4% of pediatric morpheapopulation [21]– en coup de sabre(Frontoparietal linearmorphea)Linear depression with atrophy(Fig. 12.1c, d)Unilateral , scalp and upperface, paramedial lesionsmore common than median17% of pediatric morpheapopulation [21]– Parry-Rombergsyndrome (progressivehemifacial atrophy)Segmental linear deep plaques involvingsubcutaneous fat, muscle and bone; deepatrophy and sclerosis (Fig. 12.1e, f)Unilateral, face 2% of pediatric morpheapopulation [21]– Linear (nonfacial) Discrete, indurated linear bands ofsclerosis of skin often associated withdyspigmentation (Fig. 12.2a–d)Extremities>Trunk, can followBlaschko lines32% of pediatric morpheapopulation [21]Deep morphea/morpheaprofundaPoorly circumscribed bound down scleroticplaques involving fascia, “cobblestone”surface, often hyperpigmentedSymmetric 4% of pediatric morpheapopulation [12, 21,141, 171]– Eosinophilic fasciitis(Shulman syndrome)Deep indurated plaques, onset as localizedpain and edemaExtremities more common thantrunkRare [12, 13, 141, 172–174]– Pansclerotic disablingmorpheaGeneralized full thickness sclerosisextending from dermis to bone, withfixation to underlying structures(Fig. 12.3b)Extremities, progressing to restof body, sparing fingertipsand toes, “tank top sign”Rare [12, 141, 175]
  3. 3. 11512 Localized Forms of Sclerodermamosaicism that is invisible in the normal individual and apparent in some of the genodermatoses such as epidermal nevus,incontinentia pigmenti and Goltz syndrome, and in acquired skin disorders such as linear lichen planus and lichen striatus.Cutaneous mosaicism can involve mutations in either keratinocytes (epidermal nevus, incontinentia pigmenti) and/or fibro-blasts (focal dermal hypoplasia or Goltz syndrome). In linear morphea, presumably the fibroblasts in the affected area haveFig. 12.1 (a) Plaque type morphea: Young adult man with an indurated flesh colored plaque with a faintly erythematous border on the right chest.(b) Generalized morphea: 9-year-old girl with numerous sclerotic pink and ivory colored plaques on the trunk. (c, d) En Coup De Sabre (linearmorphea of the face): 15-year-old girl with several year history of progressive linear depressions on her forehead (d). The appearance of the earlyinflammatory plaque without significant sclerosis in (c) demonstrates how morphea can be misdiagnosed as a vascular lesion. (d) shows thesclerosis after 4 years. (e, f) Parry-Romberg Syndrome (linear morphea of the face): 4-year-old girl with progressive linear depressions on herlower face (f) involving the chin, mandible, neck and tongue (e)
  4. 4. 116 A.E. Gilliam and A.C. Gilliama different genetic footprint than adjacent normal skin. The mutations are not known, but extensive molecular evaluation ofscleroderma fibroblast genes may ultimately provide clues to similar genetic alterations in affected skin in morphea.Clinical course of morphea. Disease activity of morphea, particularly plaque type, can resolve in 3–5 years, but reactivationmay occur [21]. The course is variable depending on the subtype. Linear morphea tends to be more chronic. Overall, thecourse is benign, with survival no different from the general population [13]. There is significant morbidity associated withthe linear forms however, including joint contractures, limb length and size discrepancy, arthritis/arthralgias, and neurologic/ophthalmologic consequences when morphea occurs on the scalp and face (see Morbidity below). Other symptoms includedysphagia and dyspnea [13]. The main complaints for the most common form, plaque-type morphea, are skin tightness,itching, and unfavorable cosmetic appearance.Fig. 12.2 (a) Linear morphea of the extremity: 12-year-old girl with sclerosis, dyspigmentation and asymmetric growth of the right lower extrem-ity after onset of linear morphea many years ago. (b–d) Linear morphea of the extremity associated with disabling contractures: Several examplesof contractures on foot and hands in children with longstanding linear morphea
  5. 5. 11712 Localized Forms of SclerodermaMorbidity in morphea. Quality of life assessments show that individuals with morphea have better outcomes than those withdisabling severe atopic dermatitis, with the exception of the more severe forms of morphea affecting face and limbs [26].A variety of morbidities are reported more frequently in the linear [27] and generalized or mixed subtypes [11] of mor-phea. The more commonly associated complications include musculoskeletal and deep soft tissue abnormalities, neurologic/ophthalmologic problems, and other extracutaneous complications including gastrointestinal, vascular, pulmonary, renal andcardiac problems. Malignancy is a rare associated morbidity. Few systematic studies have been performed because of therare frequency of morphea and even more rare co-existing morbidities [23].• Musculoskeletal and soft tissue complications. The most common extracutaneous finding in morphea patients is arthritis/arthralgias, which has been reported in 12% of pediatric patients with morphea [27]. Both articular and soft tissue/bonyabnormalities are typically associated with linear morphea. Other musculoskeletal complications include joint swelling,myalgia, and limb contractures [8, 11] (Figs. 12.2b–d and 12.3b). Spontaneous fractures [28], unexplained muscle atro-phy [29], hemiatrophy [30] and osteomyelitis [31] have also been reported. Morphea can be preceded by unexplainedskin edema [32, 33] or atrophy [29]. One case of linear morphea presented as a neuromuscular disorder with muscleatrophy, weakness and loss of arm function [34]. Individuals with facial linear morphea can have dental abnormalities[35] and even ipsilateral tongue hypoplasia (Fig. 12.1e).• Neurologic complications. Neurologic involvement was reported in 4% of pediatric patients with morphea [27]. It is morecommon in patients with linear morphea of the face. Complications include seizures, headache, and peripheral neuropa-thy among others. Intractable partial seizures [36], epileptic encephalopathy [37], and status migrainicus [38] have allbeen reported in association with morphea. Epilepsy can precede the development of en coup de sabre [39, 40]. Localizedepilepsy, often refractory to medications, is the most common complication of linear morphea of the face [41]. Kistgeret al. reviewed 54 patients with craniofacial scleroderma who also had neuroimaging (head CT or MRI) for neurologicalsymptoms. They found some common atypical features on imaging including atrophy, calcifications and T2 hyperintensi-ties. Others have described abnormal MRI results in patients with Parry–Romberg syndrome [42].• Ophthalmologic complications. Ocular involvement was reported in 2% of pediatric patients with morphea [27]. Ocularinvolvement in morphea is also more common in patients with linear morphea that affects the face although it has alsobeen reported to occur in patients without facial skin lesions [43]. Associated ophthalmologic abnormalities may includeanterior uveitis, episcleritis, glaucoma, xerophthalmia, keratitis and, strabismus.• Other extracutaneous complications. Gastrointestinal involvement, namely esophageal motor function abnormalitiescausing acid reflux and/or dysphagia, has been reported in approximately 2% of pediatric morphea patients [27]. Vascularcomplications including Raynaud’s phenomenon are also reported in about 2% of patients [27]. Pulmonary involvementcan present with dyspnea and is rare. Renal complications include nephritis [27], unilateral renal artery stenosis andimmunoglobulin M nephropathy [44]. Cardiac complications include pericarditis and arrhythmias due to supraventricularectopic beats and runs [45]. These systemic complications of morphea indicate that disease is not just “skin deep.”• Malignancy. Rare cases of malignancy are reported in morphea lesions, such as squamous cell carcinoma of the lip thatdeveloped in an individual with pansclerotic disabling morphea [35]. The etiology is likely similar to carcinoma develop-ing in chronic venous insufficiency ulcerations and burn scars.Autoimmunity in morphea. Individuals with the variants other than plaque-type morphea can have peripheral eosinophilia andabnormal serologies – the most common are positive antinuclear (ANA) and/or rheumatoid factor, and presence of anti-ssDNAFig. 12.3 (a) Atrophoderma of Pasini and Pierini: Preadolescent girl with several year history of a large plaque and small patches of atrophy onthe lumbar back. The lesions have a sharp drop-off with a “punched out” appearance and are not indurated clinically. (b) Pansclerotic disablingmorphea: Rapid onset of diffuse sclerosis and hyperpigmentation of the hands and arms resulted in contractures of the fingers reminiscent ofsystemic scleroderma in this 13-year-old girl
  6. 6. 118 A.E. Gilliam and A.C. Gilliamand antihistone antibodies – which suggest autoimmune disease, but do not reliably correlate with disease activity [21, 46, 47].There are no laboratory tests that confirm the diagnosis of morphea, which is made on clinical and histopathologic criteria.Like other autoimmune diseases such as scleroderma, the autoantibodies are not directly pathogenic, and are likely epiphe-nomena reflecting immune dysfunction.The presence of a positive ANA and serum autoantibodies was studied in a cohort of 72 adult and pediatric patients withlinear morphea [48]. The authors found no differences in ANA-positivity or type of autoantibody between children andadults. Antihistone and anti-dsDNA antibodies tended to be associated with more severe disease in children. Autoantibodytiters do not appear to correlate with disease activity but can reflect the burden of disease.In another study, positive autoantibodies occurred in individuals with morphea with an incidence of 46–80% (ANA), 50%(anti-ssDNA), 47% (anti-histone antibodies),and 26% (rheumatoid factor) [49]. Sato [50] reported that 46% of individualswith morphea have anti-cardiolipin antibodies and 24% have positive lupus anticoagulant tests. Approximately 16% ofpatients in a small study (n=41) had increased serum antibodies to matrix metalloprotease-1 by ELISA [51]. Elevated serumB-cell activity factor (BAFF) in individuals with morphea is higher compared with normal controls, particular in generalizedmorphea [52].Positive ANA and body surface area of involvement had prognostic value in a retrospective study of 35 adults and chil-dren with plaque-type (n=15), generalized [15], linear morphea [4] and eosinophilic fasciitis. The majority of patients ontreatment improved clinically and by morphometric measurements of skin induration (53%). Failure to improve or stabilizeafter a mean follow-up of 29 months was associated with generalized morphea and/or positive ANA [53].An interesting but unexplained feature of autoantibodies found in morphea patients is that they are mainly those of lupus,not scleroderma, which morphea resembles clinically and microscopically. Rare cases of morphea with scleroderma autoan-tibodies such as anti-centromere antibodies are described [54].In a larger study of 245 individuals with morphea that included 123 adults and 122 children, there was a high prevalenceof concomitant autoimmune disease (18%) and familial autoimmune disease (16%). These authors found a strong associa-tion between the generalized and mixed morphea subtypes and markers of a “systemic autoimmune process” which includedhigh frequency of concomitant autoimmune disease, extracutaneous complications, and abnormal serologies (i.e. ANA).They suggested that patients with these subtypes of morphea (generalized and mixed) should be monitored closely for thepresence of systemic and autoimmune disorders and treated with immunosuppressive therapy when appropriate [11].Similarities and differences between morphea and scleroderma. Scleroderma (systemic sclerosis) occurs mainly in adultwomen and is characterized by not only skin sclerosis, but also visceral sclerosis (lungs, kidneys, and esophagus). Thepresentation of scleroderma is different from morphea. Scleroderma typically begins in acral skin and progresses proxi-mally, often involving the trunk. Patchy involvement as seen in morphea is uncommon. Extensive cutaneous and visceraldisease in scleroderma has significant morbidity and increased mortality.Molecular genetic studies in morphea. Milano et al. [55] used gene array analysis to establish a genetic “fingerprints” forscleroderma subsets, including morphea, compared with normal controls. They identified 5 significantly different geneexpression change clusters: diffuse-proliferation, inflammatory, limited, and normal-like. Gene expression profiles from3 biopsies of morphea skin fell into the inflammatory category which was characterized by markers for increase in immuneresponse, response to pathogen, humoral defense, lymphocyte proliferation, chemokine binding, chemokine receptor activ-ity, and response to virus. The gene array results overall confirm and further refine the distinct subsets of scleroderma, anddemonstrate that morphea can potentially be differentiated from those subsets at a molecular level.Overlap autoimmune disorders and other skin disorders in morphea. The role of genetics in autoimmune diseases is impor-tant yet incompletely understood, particularly in morphea. There are no specific mutations that are associated with morpheabut familial morphea and morphea in association with other autoimmune disorders occurs, suggesting a genetic predisposi-tion [11, 46, 56, 57]. Some clues to an “autoimmune phenotype” – a genetic predisposition to autoimmune disease – areseen in these familial and overlap forms of connective tissue disease. For instance, of 47,361 individuals with rheumatoidarthritis in a Swedish study, there was a significant risk (SIR2.4) of morphea in their offspring [58]. Morphea can also coex-ist rarely with other autoimmune diseases, most often reported as case studies. These unusual overlap disorders includemorphea variants with other connective tissue and autoimmune diseases such as scleroderma [59], systemic lupus erythe-matosus [60, 61], rheumatoid arthritis [58], inflammatory bowel disease [62], autoimmune thyroid disease [63, 64], vitiligo[63, 65, 66], alopecia areata, Type I diabetes mellitus [62], antiphospholipid syndrome [67], necrotizing vasculitis [68], aswell as mixed types of morphea [16, 69, 70]. Other types of inflammatory skin disorders can also be associated rarely withmorphea such as psoriasis [71], lichen planopilaris [72], lichen sclerosis [73], and lichen striatus [74]. A case of morpheain association with Rosai-Dorfman disease is reported [75].Histopathology of morphea. Classic morphea can have a different histopathology depending on the stage of development.The histopathologic changes have been divided into indeterminate (early), inflammatory, mixed inflammatory and sclerotic,
  7. 7. 11912 Localized Forms of Sclerodermaand sclerotic (late) stage morphea [76]. As expected by definition, increased T-cells are present in the inflammatory stagecompared with normal skin.Like scleroderma, the inflammatory stage of morphea is characterized by dermal edema, and by lymphocytic and histio-•cytic inflammatory cell infiltrates with plasma cells.The later sclerotic stage is characterized by thickened acellular homogenized-appearing collagen bundles at all levels of•dermis, typically seen first in the deep reticular dermis near interface of dermis and fat. The adnexal structures (hair, eccrineglands) are surrounded by dense fibrosis with loss of fat around the eccrine glands in chronic disease (Fig. 12.4a–e).The atrophic stage is characterized by dermal atrophy and eventual disappearance of adnexal structures.•Eosinophilic fasciitis is considered by some to be a deep version of morphea with the fibrotic changes in the deep dermisand fascia, which are thickened and contain hypertrophied collagen bundles. There is typically a dense perivascular inflam-matory cell infiltrate composed of lymphocytes, histiocytes, plasma cells and eosinophils in the fascia.Fig. 12.4 (a) Skin biopsies of morphea have a characteristic “squared off” shape because of the dense dermal sclerosis. There are patchy perivas-cular mononuclear cell infiltrates of lymphocytes, histiocytes and occasional plasma cells, but otherwise the dermis is acellular compared withnormal skin. Flattening and atrophy of the epidermis is associated with underlying sclerosis. Hair follicles and sebaceous glands normally seenin a skin biopsy of hair-bearing skin are absent. (Magnification=2.5×). (b) This specimen shows the characteristic “bottom up” sclerosis that canbe seen in morphea before entire dermis is involved. The sclerotic collagen is in the lower half of dermis, while normal collagen is in the upperhalf. Dense collagen has replaced normal collagen from the arrow down. The left upper corner of the image also shows the edge of an atrophichair follicle. (Magnification=5×). (c, d) Higher power views of the non-sclerotic (c) and sclerotic (d) dermal areas show that the collagen in thesclerotic area has lost the fine fibrillar texture of normal collagen seen in non-sclerotic areas (Magnification=40×). (e) Encasement of adnexalstructures by dense collagen with loss of the fat around eccrine glands is shown. Eventually, atrophy of hair follicles, sebaceous glands, andeccrine glands (arrow) occurs in long-standing morphea. (Magnification=20×)
  8. 8. 120 A.E. Gilliam and A.C. GilliamA clinical and pathologic study of 17 patients with atrophoderma of Pasini and Pierini showed similar histopathology inall cases, some of which were compared with unaffected skin in the same individual [77]. There was no atrophy, sclerosis,or entrapment of adnexal structures. The only abnormal finding in elastic tissue stained sections was reduced total numbersof elastic fibers, many of which were fragmented.Elastic fibers in the skin in morphea. [76, 78] Morphea can resemble a scar microscopically; elastic fiber staining withelastic van Gieson histochemistry can be helpful in distinguishing the two entities because elastic fibers are lost in scars butnot in morphea. Walters [78] describes preservation of elastic fibers in all biopsies of morphea by histochemistry (n=28).There were straightened compressed fibers with parallel orientation between sclerotic collagen bundles in both sclerodermaand morphea which are indistinguishable microscopically.Therefore, histochemistry and immunohistochemistry (see below) are helpful in distinguishing morphea from otherclinical mimics such as scars, hemangiomas, and vitiligo.Immunohistochemical studies of morphea. Investigators have evaluated matrix molecules, dendritic cells and immune cellsin morphea by immunohistochemistry. Not all of these studies used uninvolved skin of the same individual for comparisonunfortunately.CD34 and Factor XIIIa (FXIIIa) in normal skin. CD34 and Factor XIIIa (FXIIIa) immunostaining identifies two differentpopulations of dermal dendritic cells. Both are found in embryonic mesenchyme and persist in adult tissue. CD34 (hematopoi-etic progenitor cell antigen) is a membrane marker for many types of cells including hematopoietic stem cells, endothelialcells, embryonic fibroblasts, and fibrocytes [79, 80]. In normal skin, there are numerous dendritic CD34+ cells with fine pro-cesses scattered among collagen bundles of reticular dermis in a diffuse pattern. These cells are likely fibrocytes, a normalcomponent of skin that function in wound repair [80]. FXIIIa+cells include platelets, megakaryocytes, bone marrow cells,tissue monocyte/macrophages, and dermal dendrocytes, which are found mainly in papillary but not reticular dermis in normalskin. FXIIIa is a protransglutaminase component of the coagulation cascade that is activated by thrombin and calcium to cross-link fibrin in clot formation (“fibrin stabilizing factor”). It also functions to cross-link matrix proteins, including collagen.CD34+ and FXIIIa+cells in the skin in morphea. In scleroderma and morphea, the immunostaining pattern is reversedwhen compared with normal skin. CD34 immunostaining is lost and FXIIIa is gained in the areas of sclerosis [1, 76, 81–83].When fibrocytes become activated, they become CD34-negative smooth muscle actin–positive myofibroblasts and secretecollagen. It is a plausible hypothesis that FXIIIa+tissue macrophages appear in active areas of sclerosis and cross-link thenew collagen synthesized by the now CD34-negative fibrocytes [1].UVA1 phototherapy for morphea may act by changing the cytokine and stromal microenvironment to favor persistenceand not loss of the CD34 dermal dendritic cells and return to normal collagen synthesis and degradation [84]. In one studyin which CD34 and FXIIIa immunostaining was evaluated after UVA1 phototherapy, the UVA1 was less effective in restor-ing CD34+ dermal dendrocytes in linear (n=2) than in plaque type morphea (n=5). UVA1 also decreases inhibitory Smad7expression in morphea, another possible effect on fibrosis [85].T-cells and antigen-presenting cells in the skin in morphea. Immunostaining for various immune markers on biopsy speci-mens from morphea patients shows increased numbers of T-cells (CD3+, CD4+, CD8+) and dendritic cells (CD1a+, CD25+,CD57+) compared with normal controls (p<0.05). CD30+ cells were approximately the same in that study [86]. The findingis not surprising — no effort was made to compare with other similar skin diseases such as scar and comparable inflamma-tory disorders, or with uninvolved skin from the same individual to establish specificity of the findings for morphea.Macrophages in the skin in morphea. CD68, CD163 (hemoglobin scavenger receptor), and CD204 (Class A scavenger recep-tor molecule) have high expression on alternatively activated M2 macrophages in morphea [87]. M2 macrophages are impor-tant in the early stages of fibrosis—they have an IL-10 low, IL-23 low, IL10-high phenotype and influence wound repair andsclerosis by releasing TGF-beta. Similar increases in activated macrophages have been reported in systemic sclerosis [87].Melanocytes in the skin in morphea. Sung et al. demonstrated with immunoperoxidase and immunohistochemical stainingthat there were reduced numbers of melanocytes in the epidermis in 2/3 cases of hypopigmented morphea and 2/4 cases ofnon-hypopigmented morphea compared with 7 matched biopsies of normal skin [1]. The data suggest a complex immuno-phenotype in children with morphea that involves more than dermal changes. These data help to explain the hypopigmenta-tion often seen in morphea clinically (approximately 54%) in a set of 35 children with morphea in a pediatric dermatologyclinic at UCSF [1].Cytokines and growth factors in the skin in morphea. Most of the in vivo and in vitro work on fibrosis has been done inscleroderma and in cell cultures of scleroderma fibroblasts. Some information is published on morphea from which we canextrapolate a hypothesis for pathophysiology. There are serum and tissue cytokine alterations similar to scleroderma which
  9. 9. 12112 Localized Forms of Sclerodermaare associated with morphea that suggest a mechanism for initiation and perpetuation of the fibrotic phenotype. Immunostainingon skin biopsies of the inflammatory phase of morphea shows increased transforming growth factor (TGF)-beta [88] andinsulin-like growth factor, a mediator of extracellular matrix homeostasis [89]. Increased circulating TGF-beta1, intercellularadhesion molecule −1 (ICAM-1), interleukin-2 (IL-2) IL-4 and IL-6 in patients with morphea may promote increased col-lagen synthesis and fibroblast proliferation [90–92]. These profibrotic Th2 cytokines along with TGF-beta, PDGF, CTGF andmetalloprotease-3 promote the stromal changes of morphea. The immune mediator pathways are complex and not completelyworked out. Cytokine therapy has been proposed and tested in a few clinical trials for morphea but as in scleroderma, obtain-ing appropriate controls and demonstrating efficacy is difficult in a disease which can resolve on its own.Morphea induced by environmental triggers (Table 12.2). The emergence of morphea following exposure to environmentalexposures is intriguing and may provide clues for the pathophysiology of morphea. The triggers fall into the categories ofradiation, drugs, trauma, and infection.Table 12.2 Morphea induced by environmental agentsInduced by Agent Action Clinical ReferencesRadiation X-ray therapy forbreast carcinoma;fluoroscopyRadiation may induceneoantigens that trigger theprofibrotic inflammatorycascadeLate onset erythema and induration,not dose-related, with dermalfibrosis extending beyond theradiation port[93–98, 100,104, 176]Drugs Anti-TNF-alpha agents Biologic immunomodulators,inhibit TNF-alpha[177]Balicatib Cathepsin K inhibitor forosteoporosisClassic morphea plaques in 58-year-old woman, resolved when drugdiscontinued[105]Bleomycin Antibiotic and chemotherapeuticagent that induces DNA strandbreaks, inhibiting DNA repairScleroderma-like skin changes in rareindividuals[105]Bromocryptine forpituitary microadenomaand Parkinson’s diseaseDopamine D2 and D3 agonist thatactivates post-synaptic signals.Inhibits prolactin release bypituitary gland57-year-old man with plaque-typemorphea[178]Docetaxel for breastcarcinomaMicrotubule-stabilizingchemotherapeutic agent, haltsmitosis and allows apoptosisof malignant cellsPlaque-type morphea, begins asedema, involves lower extremitiesand spares hands and feet[105, 179, 180]Ibuprofen Cyclooxygenase inhibitor, blocksprostaglandins which modulateinflammatory pathways20-year-old woman with linearmorphea and en coup de sabrehad positive lymphocyte IFN-gamma release activation test foribuprofen; clinical improvementafter ibuprofen discontinued[181]l- tryptophan;l-5-hydroxytryptophanplus carbidopa,bromocryptineand clobazam forParkinsons’s diseaseEssential amino acid used forinsomnia, sleep apnea,depression, anxiety; 5-OHtryptophan is a precursor forserotoninUse of l-tryptophan documented ineosinophilia-myalgia syndrome[182, 183]Trauma Vibration Unknown Unilateral generalized morphea in amarble cutter[184]Tattoo Trauma to skin known to producemorphea rarelyMorphea-like reaction in red pigmentarea of tattoo in 47-year-oldwoman[185]Injection sitemorpheaMepivacaine HCl,vitamin K, vitaminB12, pentoazocine,aluminum absorbantfor allergy shots;vaccination in infantsPossible vascular injury Several case reports of deep morphea-like sclerosis in injection sites[105, 186–188]Infection Hepatitis B and C Viral activation of immunesystem, including interferonsIndividuals with chronic hepatitisB and C[189–193]Borrelia Possible selective activation ofhyperaggressive autoimmuneT-cells; molecular mimicryAssociated with acrodermatitischronicum atrophicans andmorphea in Europe[115, 116]
  10. 10. 122 A.E. Gilliam and A.C. GilliamRadiation- and surgery-induced morphea [93–100]. Morphea at the site of supervoltage therapy for breast carcinoma iswell-described, occurring in approximately 0.2% of women treated for breast cancer from a few months to up to 20 yearsafter the radiation therapy [101]. Another name for the disorder is “radiation port scleroderma”. The association with tamox-ifen therapy in the cases involving the breast is questionable; the controlled studies and statistical analysis have not beendone. Cases of recurrent radiation-induced morphea after a second surgery but no radiation and following cosmetic surgeryalone suggest that the surgery itself may play a role in this variant of morphea [97, 102, 103].Other rare variants of radiation-induced morphea includeExtensive morphea on lower abdomen and upper extremities in a 74-year-old woman with extensive morphea after radio-•therapy to the pelvis for endometrial carcinoma [98].Morphea following fluoroscopy [• 104]Post-radiation morphea can mimic radiation dermatitis, infection and recurrent breast carcinoma. Differentiating mor-phea from radiation dermatitis depends on both clinical and histopathological features [93].Radiation injury has dose-related acute erythema and scaling, possibly desquamation, and deep fibrosis in subcutaneous•fat, fascia, and muscle that are confined to the radiation port. Bizarre atypical fibroblasts, hyperpigmentation, dermalatrophy, and telangiectasia are microscopic clues to radiation dermatitis, not morphea.Post-radiation morphea has later onset, erythema and induration that are not dose-related. There is rapidly progressive•predominantly dermal fibrosis that extends beyond the radiation port.The pathophysiology of post-radiation morphea is thought to be neoantigen production by ionizing radiation that triggersthe pro-fibrotic inflammatory cascade [93]. Tamoxifen may induce TGF-beta production and induce fibrosis, but the path-ways are complex and not completely understood.Drug-induced morphea. Drug-induced morphea is rare, and has been reported for a diverse group of medications from anti-epileptics to chemotherapeutic agents (Table 12.2). In these case reports, the proof of concept was the partial or completeresolution of morphea after stopping the medication [105]. Profibrotic agents associated with drug-induced morphea arebleomycin, peplomycin, dopaminergic drugs and beta-blocking agents [105]. Several agents (i.e. pentazocine) can causedirect vascular injury and dermal sclerosis, likely the etiology for the injection site type of morphea.Other common themes include interference with signaling pathways [anti-tumor necrosis factor (TNF) alpha agents andbalicatab]. Interferons have been used for therapy of morphea with paradoxical results. Intralesional interferon-gamma wasreported to be successful for linear morphea in case reports [106] and interferon-gamma was used successfully for ocularsymptoms of en coup de sabre [107], presumably because interferon inhibits fibroblast growth and collagen synthesis invitro. However, the systemic in vivo effects can be quite different from local effects. Interferon-beta therapy for multiplesclerosis may be a trigger for development of morphea in a subset of individuals, suggesting a genetic predisposition tofibrosing disease [108]. Interferon-alpha therapy for myeloproliferative disorders or chronic hepatitis in several case reportsresulted in worsening or new onset of scleroderma and morphea, rather than improvement [109–111]. These findingsemphasize the complex immunological networks in morphea and scleroderma. It is not always possible to translate in vitroexperiments to in vivo therapy with biologic agents which can have many different functions in vivo.Trauma. In a study of 26 patients with severe juvenile localized scleroderma, four (15% ) reported a history of trauma tothe area and one had a history of dental extraction ipsilateral to the area in which morphea developed [23]. Another possibletrigger is vibration, thought to be a factor in a case report of a marble cutter who held an electric tool in his left hand anddeveloped extensive sharply demarcated unilateral morphea on the ipsilateral side [112]. He had no lung disease to suggestsilica-induced scleroderma. Other instances of fibrosing disease, i.e. sclerodactyly, due to vibration in chainsaw users, metalworkers, forestry workers, miners, quarry drillers and stone-carvers have been reported. There are many examples in theliterature of injection site morphea, including onset of morphea at the site of vaccinations as well as at the site of an insulinpump placement (observed by these authors) (Table 12.2).Infection. Borrelia infection is a confounding factor in European studies of morphea because a small percentage (7%) ofindividuals with morphea has positive Borrelia titers [53]. It is not clear if Borrelia plays a role in pathophysiology of mor-phea or if this is a coincidental finding because Borrelia exposure is common in Europe [113–116]. Acrodermatitis chroni-cus atrophicans is thought to be an atrophic variant of morphea induced by Borrelia infection [117].Pathophysiology of morphea. The reason for the heterogeneity of the morphea variants is a fascinating puzzle yet to besolved. Also fascinating are the rare forms of morphea typically in adults associated with various environmental triggerssuch as radiation, drugs, trauma, and injected substances, among others (Table 12.2). The variety of disease forms and pos-sible etiologies in morphea suggests that there are many different pathways to skin fibrosis. Hypotheses include autoimmune
  11. 11. 12312 Localized Forms of Sclerodermaactivation, vascular alterations and injury, and abnormal collagen metabolism. The pathophysiology of infection-inducedmorphea such as hepatitis and Borrelia infection may be due to activation of hyperaggressive T-cells in response to infection,release of interferons, and by molecular mimicry [115]. There are no hard data for these hypotheses however.Because of its uncommon incidence predominantly in children and generally benign course, basic laboratory investiga-tion into the pathophysiology of morphea has lagged behind that for scleroderma. We assume that because morphearesembles scleroderma microscopically, it has the same underlying pathophysiology – i.e. alterations in TGF-beta, plateletderived growth factor (PDGF) and other cytokine and growth factor microenvironments, and alterations in pathways ofmatrix production and collagen metabolism. A combination of these changes could lead to excessive production of normalcollagen. As in scleroderma, triggers for disease may include endothelial cell injury and activation of an inflammatorymediator cascade [118]. The experimental data to support these hypotheses for morphea are not available to date, however,and there is no animal model for morphea.Practical Guidelines for Assessment and Management of Morphea, OverviewClinical evaluation, although problematic, is still the gold standard for morphea diagnosis and assessment. The classic“active” lesion is a well-circumscribed indurated plaque with a violaceous border, which indicates ongoing inflammation.Disease activity can also be associated with increased warmth of skin lesions as well as increasing size of the plaque/s. Meantime to diagnosis was 1.2 years in a retrospective study of 136 children with morphea [21]. The delay was mainly due tolack of recognition of morphea by primary care physicians. Morphea can rarely present with fever, arthralgias, and lymph-adenopathy before the development of obvious sclerosis.Management of morphea can be challenging because reliable and widely accepted measures for monitoring diseaseactivity in morphea are not available. Clinical evaluation and laboratory testing are not reliable methods for detecting andfollowing disease activity in morphea. Making decisions about choice of initial therapies, intervening with more aggres-sive therapy, and monitoring effectiveness of therapy are problematic. Development of therapeutic clinical trials andoutcome studies depends on objective and validated measures to monitor disease activity, a challenge in the study ofmorphea.Assessment of morphea [48, 119, 120]. Unlike scleroderma, where a combination of accepted clinical indices based on skinthickening and sclerotic changes are used to score disease severity [121], scoring severity of disease in morphea with patchylocalized cutaneous involvement is more challenging. Many physicians use parameters such as degree of warmth and rela-tive “softness” of the skin to monitor disease course. These methods are subjective however, and quantifiable methods arepreferable. The following non-invasive methods do not expose the patient to the risk of poor healing, scarring and the poten-tial for wound infection after skin biopsy; they allow quantifiable and sequential assessment.Quantifiable Clinical Assessment• Skin scores. A modified skin score (MSS) has been used for morphea, but the MSS is only reliable for extensive skinlesions and is not designed to detect subtle increases in size of skin lesions [122, 123]. Another clinical tool to assessmorbidity in morphea, the Localized Scleroderma Skin Damage Index, involves calculation of scores for three parame-ters of cutaneous damage: dermal atrophy, subcutaneous atrophy and dyspigmentation measured at 19 anatomic sites[120]. These scores correlate well with the Physician Assessment of Global Disease Damage, a more general tool fordisease in general. However, the scoring system is not applicable to isolated localized lesions.• Dermoscopy shows accentuated fibrotic tracts crossed by spreading telangiectasia centrally with an obvious erythema-tous border peripherally in plaque type morphea [2, 124]. Like dermoscopy of pigmented cutaneous lesions, dermoscopyrequires a level of experience with the dermatoscope.Skin thickness can be measured and followed over time using a• durometer [123].A computerized method for measuring and following of circumscribed lesions of morphea over time consists of delineat-•ing the morphea plaque with transparent adhesive film, transferring to cardboard, and calculating the area of the plaquewith specific software [125]. This method includes body surface area (BSA) in its calculations of rate of change overtime. Although promising, this method for monitoring disease activity has not yet been evaluated prospectively and isnot widely available.
  12. 12. 124 A.E. Gilliam and A.C. GilliamImaging Methods• Ultrasound [126–129]. The most reliable assessment uses 20–25 MHz ultrasound (US). Ultrasound at 10–15 MHz –which is more readily available in the Unites States – is also useful [126, 127]. This modality appears more helpful inmaking the diagnosis of morphea, rather than for monitoring disease activity [126]. However, ultrasound assessment isoperator-dependent and lacks standardization.• Magnetic resonance imaging (MRI )[130]. Although the MRI findings in morphea can overlap with other soft tissueabnormalities such as fibromatoses and myofibromatoses, there are some pathognomic features of morphea which dis-tinguish it from those entities. MRI allows evaluation of depth of infiltration and sequential analysis of diseaseactivity.• Infrared thermography for detection of disease activity via blood flow changes in early morphea is also an exciting newarea of investigation [131]. Infrared thermography uses an infrared camera and Thermosoft software. It is comparablewith clinical assessment unless severe atrophy of skin and fat has occurred [23, 131, 132]. In these locations, there arerelatively high false positive rates for clinically inactive lesions, especially those located on the face and scalp. This isattributed to increased skin heat conduction because of the relatively thinner skin and decreased density of subcutaneousfat in these areas. Therefore, thermography is less appealing as a reliable tool for monitoring disease activity not onlybecause it appears to be useful only in certain clinical contexts but also because it is not widely available. The combina-tion of infrared thermography and laser Doppler flowmetry – which measures the cutaneous microcirculation – is moreeffective in these cases [7, 128, 133].All of these methods have not been prospectively evaluated to date, and most are not widely available.•TherapyTreatment of morphea. Morphea is difficult to treat ---and well-controlled clinical trials are difficult to carry out because ofthe low incidence of morphea, the lack of objective measures for monitoring disease activity, and the tendency for morpheato regress spontaneously. In children with morphea, clinicians are reluctant to treat aggressively with immune modulators.Because of the morbidities in morphea (see above), early treatment is recommended, particularly of the inflammatory stageof disease [134]. The goal is to limit damage and prevent the sequelae of cutaneous fibrosis.There are several different strategies for therapy that are based on hypotheses of triggers for morphea:Altering the inflammatory immune cascade: topical corticosteroids, topical calcineurin inhibitors, imiquimod, vitamin D•analogues (calcitriol and calcipotriol), methotrexate, mycophenolate mofetil and UVA1 phototherapy all alter thecytokine and growth factor microenvironment of skin. The new biologics also function to change the cutaneous immuneenvironment.Altering the vascular microenvironment: bosetan, an endothelin receptor antagonist, likely functions by altering vascular•resistance.Altering the extracellular matrix homeostasis:• d-penicillamine inhibits cross-linking of collagen.The most common topical and systemic therapies reported during the 1980s and 1990s are listed in Table 12.3 [15, 47, 129,135–139].Topical therapy. [139] (Table 12.3) The mainstay of morphea treatment is topical corticosteroids and more recently, topicalvitamin D analogues, calcineurin inhibitors and imiquimod.Phototherapy. Phototherapy has been a great advance in morphea therapy because it is tolerated well and does not put thepatient at risk for the potential side effects associated with systemic treatment with oral immunomodulators [140].Penetration of the skin by ultraviolet light depends on the wavelength. UVB is not as effective as UVA because it penetratesthrough only epidermis and superficial dermis. Long wavelength UVA (UVA-1) is not absorbed as effectively by melanin,and the longer wavelength allows the deepest penetration of skin. Thus UVA-1 phototherapy has been used successfully fordeep morphea and eosinophilic fasciitis [141, 142]. Other forms of phototherapy used for morphea include topical psoralenwith ultraviolet light (PUVA), narrow band ultraviolet B (NbUVB) therapy, and photodynamic therapy which uses light inthe visible range [143, 144]. Changes in the cytokine and growth factor microenvironment, induction of metalloproteases,and apoptosis of lymphocytes may all help to explain the beneficial effects of phototherapy in morphea. Side effects of
  13. 13. 12512 Localized Forms of SclerodermaTable 12.3 Therapies for morpheaTopical therapiesAgent Action Dose Adverse effects ReferencesTopical corticosteroids Changes cytokinemicroenvironment of skin,inhibits T cellsStrength and dose dependson location on body[194]Cutaneous atrophyand telangiectasia;potential skinirritation forsystemic absorption;occasionally contactdermatitis[13, 195]Topical calcipotrieneointment(1, 25-dihydroxyvitaminD3)Active metabolite of vitamin D3,affects fibroblast proliferationand function and inhibitsinflammatory mediators0.005% ointment underocclusion twice a dayPotential for systemicabsorption of drugand alteration ofcalcium homeostasisPotential skinirritation[4, 13, 149, 196]Topical calcipotriol– betamethasonedipropionate ointmentORCombination of superpotenttopical steroid andVitamin D3 analogueCombined mechanism of actionof topical corticosteroidsand Vitamin D3 analogues(as above)Applied one to two timesdailySame potential adverseeffects as topicalcorticosteroidsand Vitamin D3analogues (as above)[197]Topical tacrolimus Calcineurin inhibitor,immunomodulator that inhibitsT-cell activation and cytokineproduction0.1% ointment twice a day Increased risk ofcutaneous herpesinfection; potentialfor systemicabsorption[13, 198–201]Imiquimod Reduces TGF-beta and PDGFlevels, increases IFN-gamma,IFN-alpha and TNF-alpha toinhibit fibrosisTopical 5% cream dailyapplied 3 days perweekAllergic reaction; mildskin irritation[13, 124, 197,202, 203]PhototherapiesAgent Action Dose ReferencesPsoralen and UVA (PUVA) Alters cytokine environment ofskin, reduces cutaneous T-cellactivity, affects Langerhans’cells, cutaneous macrophagesand keratinocyte function.Induces metalloproteasescausing increased collagenbreakdownOral 8-methoxypsoralen(25 mg/m2bodysurface area) given2 h before exposure toUVA , given two timesa week[13, 204]Bath PUVA Alters cytokine environment ofskin, enhances gene expressionof collagenase, reducesexpression of collagen anddecreases collagen cross-links1 mg/L 8-methoxypsoralenin warm water bath for15 min, then 0.2–4 mJ/cm2daily for 10 days,followed by bathPUVA once a week[13, 205]UV-A1 phototherapy Alters cytokine environment ofskin; induces apoptosis ofT-cells; decreases collagen typeI and III mRNA and increasesmatrix metalloproteasesHigh dose protocol:starting dose of 40–60J/cm2increasing to100 J/cm2three timesper week for 40–60treatments (Personalcommunication; HeidiJacobe, MD)[13, 140, 151, 206–210]Narrow band UVB(Nb UVB)Similar to broad band UVB, butminimizes burning and otherside effectsStarting dose 0.1–0.2 J/cm2Maximum dose1.3–1.5 J/cm2, givenfive times a week[15, 85](continued)
  14. 14. 126 A.E. Gilliam and A.C. GilliamExtracorporealphotochemotherapyAlters leukocyte function, causesapoptosis of lymphocytes andactivation of dendritic cellsTwo consecutive therapiesper day at 2-weekintervals[155, 211]Photodynamic therapy(PDT) with visible lightAlters cytokine environment ofskin, induces MMP-1 andMMP-3 in dermal fibroblasts;induces keratinocyte cytokinealterations5-amino levulinic acid(ALA) 20% creamunder occlusion toone area of morpheafor 5 h. Treatedwith PhotoCureTMCureLight 1301;570–670 nm, 25 J⁄cm2at weekly intervals forsix treatments total[144]Systemic therapiesAgent Action Dose Adverse effects ReferencesCorticosteroids: Oraland IntravenousaReduces inflammation, usuallycombined with methotrexateOral prednisone:0.5–1 mg/kg/dayfor several weeks,followed by slow taperImmunosuppression,bruising,hypertension,hyperglycemia,avascular necrosisof bone[13, 85,212, 213]Intravenousmethylprednisolone:30 mg/kg/dose (up to1 g)×three consecutivedoses monthly for3–6 monthsMethotrexate, oralor subcutaneousaInhibits folate-dependent enzymesimportant to DNA, RNA andprotein synthesis; immunemodulation by altering serumcytokine levels15–25 mg/week or0.3–0.6 mg/kg/week;folic acid 1 mg/day isgiven concomitantlyElevated liver functiontests, stomatitis,fatigue, weight loss,nausea[85, 212–218]Oral calcitriol Inhibits growth of dermal fibroblasts,affects fibroblast differentiation,possible immunoregulatoryeffects on Th-cellsOral 0.50–1.25 mcg/day,adult doseHypercalcemia,cutaneoushypersensitivityreactions[13, 219, 220]Oral anti-malarial drugshydroxychloroquineDecreases Toll Like Receptorsignaling, limiting B cell anddendritic cell activation andmitigating inflammatory responses200 mg daily or twicedaily (adult)Gastrointestinaldiscomfort,headache, dizziness,ocular toxicity[13, 56]4–6 mg/kg/day (pediatric)Oral d-penicillamine Inhibits collagen cross-linking 125–250 mg/day or2–5 mg/kg/dayChanges in tastesensation, anemia,leukopenia, hyper-sensitivity reactions[221]Oral cyclosporine Immunomodulator; inhibits Th-cellfunction3 mg/kg/day Immunosuppression,renal toxicity,hypertension,malignancy risk[216, 222]Thalidomide Immunomodulation and anti-inflammatory, reduces TNF-alpha production, promoting aTh1 response, alters integrins,inhibits angiogenesisImmunosuppression,somnolence,leukopenia, allergicreaction, peripheralneuropathy, birthdefects[139]Mycophenolate mofetil Selective inhibitor of purine synthesisthat inhibits proliferation oflymphocytes, fibroblasts andsmooth muscle cellsOral 600–1,200 mg/m2/daytwice a dayGastrointestinaldiscomfort,immunosuppression,cytopenias[157]Plasmapheresis Causes T-cell apoptosis, altersT-cell and dendritic cellfunction, alters cytokine andgrowth factor environment[154, 223]aA common practice is to give monthly pulses of methylprednisolone intravenously in combination with oral or subcutaneously administeredmethotrexate followed by oral prednisone given in combination with methotrexatePhototherapiesAgent Action Dose ReferencesTable 12.3 (continued)
  15. 15. 12712 Localized Forms of Sclerodermaphototherapy include erythema, sunburn, cutaneous photodamage, increased risk of skin carcinoma and premature ageing.The psoralens can cause gastrointestinal discomfort when taken orally.The number of treatments per week varies from three to five treatments per week for 20–40 treatments. Although UVA1is the preferred wavelength, it is not widely available, especially in the US. Therefore, most physicians rely on NbUVBtherapy in lieu of UVA1. Encouraging results were reported by Kreuter et al. [145], who demonstrated that although UVA1was significantly more effective in softening skin lesions of localized scleroderma, NbUVB produced remarkable improve-ment in skin lesions as well.Systemic Therapy. The most commonly used systemic therapies include corticosteroids, methotrexate, d-penicillamine, oralcalcitriol, and hydroxychloroquine. Guidelines of care for morphea describe these modalities [146, 147]. In general, treatmentwith the systemic agents is based on type of morphea, extent and location of disease, and likelihood of complications suchas disfigurement or functional disability without treatment [9, 15, 136, 148].An algorithm for therapy of the various types of morphea acute and chronic is presented below.Initial therapy. First line therapy for morphea is most often topical corticosteroids. For non-facial, well-localized, plaque-type skin lesions, observation is appropriate with the possible addition of super-potent topical steroids and/or topical calci-potriene, which has been demonstrated to soften skin lesions, especially when used under occlusion [149]. Other treatmentmodalities include physical therapy techniques both for improving range of motion of affected limbs as well as stretchingexercises for contractures [21].Many other agents have been reported as successful in isolated case reports or small open label trials, but none haveproved to be uniformly efficacious in double-blind placebo-controlled trials if tested.Intermediate level treatment for morphea recalcitrant to first line therapies usually includes the use of oral minocy-cline, hydroxychloroquine, and/or phototherapy. Oral minocycline is not often used in the US to treat morphea but hasbeen used in Europe to treat Borrelia-associated disease [150]. Most dermatologists rely on phototherapy with ultravio-let light as the “next step” beyond topical therapy for more widespread, rapidly spreading, or potentially disfiguringdisease.Aggressive treatment of morphea usually includes the use of D-penicillamine, oral calcitriol, and/or methotrexate incombination with corticosteroids, which is now becoming the treatment of choice for patients with severe disease thatthreatens function or disfigurement [84, 139, 151–153].There are other experimental therapies for severe disease which have been tried in a few patients and in small clinicaltrials. Data from long term follow-up and controlled studies of large numbers of patients are not available to date(Table 12.4).Extracorporeal photochemotherapy and plasmapheresis have been reported in case studies [• 154, 155].Anti-thymocyte globulin was effective in an individual with rapidly progressive pansclerotic morphea and accompanying•pancytopenia due to bone marrow aplasia. The treatment of marrow failure with anti-thymocyte globulin was thought toreverse the abnormal immune process [156].Mycophenolate mofetil is being used more commonly in routine practice to treat morphea patients. Success was reported•in arresting disease activity with minimal side effects in a group of pediatric patients who failed methotrexate and corti-costeroids [157].Imatinib, a tyrosine kinase inhibitor which interferes with TGF-beta and platelet derived growth factor signaling path-•ways, has also been reported as successful for one adult patient with therapy-resistant morphea [158].Surgical TherapiesLinear morphea can be extremely disfiguring, and often fails medical treatment. In certain cases, surgical excision and repaircan be considered once the disease activity has “burned out”. Reconstructive surgery with tissue expansion, grafting andscalp reduction of en coup de sabre has been used for disfiguring disease [159]. Autologous fat and artificial bone grafts arealso used with some success [160–162]. Autologous fat transplantation using donor sites from the buttocks or abdomen wasstudied in a series of 20 individuals with stable linear morphea of the face (en coup de sabre). The authors found the pro-cedure more useful for atrophic scarring of morphea over the forehead than over the nose, cheeks or chin where fat survivalwas less [161]. Successful arthrodesis and flap surgery were described in a case of severe linear morphea over an extremity[163]. Other modalities include use of cosmetic fillers such as Alloderm [164], BoneSource [165], poly-l-Lactic acid andpolyethylene implants in facial asymmetry [166, 167].
  16. 16. Table12.4Newertherapeuticagentsformorphea–casereportsandsmallclinicaltrialsAgentActionDosePatientResultsReferencesImatinib(Glivec)Tyrosinasekinaseinhibitor;interfereswithTGF-betaandPDGFsignalingpathways200mg/dayfor6months74-year-oldmanwith1-yearhistoryofextensivemultiplesymmetricplaques;hadfailedUVA1,CSA,glucocorticoids,azathioprineResolutionwithin3monthsbyclinicalassessmentandultrasonography;lesionsreappearedwhentherapydiscontinuedat6months.[158,224]Infliximab(Remicade)MonoclonalantibodyagainstTNFalphamayinhibitvascularinjury5mg/kgpermonth66-year-oldwomanwith1-yearhistoryofextensivelargeplaquesofmorpheaontrunkandupperextremities,hadfailedmethotrexateandacitretinClinicalimprovementafterseconddoseofinfliximab,continuedtoimproveafterfourthdose[225]CeftriaxoneAntibiotic2g/dayfor20daysintravenous16-year-oldmanwith2-yearhistoryofmultiplesubcutaneousnodulesofdeepmorpheaonupperextremitiesResolutionwithinweeksaftertherapywithceftriaxone[226]BosentanEndothelin-1AandBreceptorantagonistdecreasesvascularresistance31.25mg/dayfor4weeks,then41.35mgtwiceaday4-year-oldgirlwithpanscleroticdisablingmorpheaClinicalimprovement[227]ZincNutritionalsupplement60–90mgzincgluconate/day17individualswithmorpheaClinicalimprovementinabouthalfofthepatients[228]MycophenolatemofetilSelectiveinhibitorofpurinesynthesisthatinhibitsproliferationoflymphocytes,fibroblastsandsmoothmusclecellsOral600–1,200mg/m2/daytwiceaday10individualswithseveremorpheaClinicalimprovementandarrestofdiseaseprogression[157]BotulinumtoxinBindstopre-synapticcholinergicnerveterminals,blockingneurotransmissionPeriodicbotulinuminjectionsover4–5monthperiod40-year-oldwomanwithlinearmorpheaandthoracicoutletsyndromeduetocompressionofbrachialplexusReliefofsymptomsofthoracicoutletsyndrome;nochangeinmorphealesions[229]Anti-thymocyteglobulinDepletionofT-cells,interferencewithlymphocytetrafficking,B-celldepletion,modificationofantigenpresentationbydendriticcells,andinductionofregulatoryT-cellfunction40mg/kgdailyfor4days,plus10mg/kgcyclosporineandmethylprednisolone1mg/kgperday50-year-oldmanwithrapidlyprogressivesclerosisofskinoftrunk,neckandupperarmsandbonemarrowaplasiaClinicalreversalofsclerosis[156]
  17. 17. 12912 Localized Forms of SclerodermaSummaryIn summary, morphea or localized scleroderma is a complex cutaneous disorder with multiple heterogeneous subtypes.There is no reduced mortality, but significant morbidity occurs mainly in the linear forms. Morphea is considered to be anautoimmune disorder because of the presence of autoantibodies; it can be associated with other autoimmune disorders andrarely is familial. The pathophysiology is unknown. The triggers may be similar to scleroderma (vascular injury, abnormalimmune regulation, extracellular matrix dysregulation) in genetically susceptible individuals. There are additional clues topathophysiology in the variants of morphea induced by triggers in the environment such as radiation, trauma, ingestion ofcertain drugs, injection of foreign materials and infection. Like scleroderma therapy, therapy of morphea is difficult to evalu-ate because disease tends to resolve spontaneously. The workhorses of therapy include topical corticosteroids, phototherapy,and methotrexate +/−systemic corticosteroids. There are some new immunomodulatory biologic agents for morphea alsobeing tested in small clinical trials.Acknowledgment We appreciate the expertise of Geralyn Bodeker, MS AHP in the Palo Alto Medical Foundation Group library and her helpwith obtaining reference material.References1. Sung JJ, Chen TS, Gilliam AC, McCalmont TH, Gilliam AE. Clinical-histopathological correlations in juvenile localized scleroderma (JLS);a subset of children with hypopigmented JLS due to loss of epidermal melanocytes. J Am Acad Dermatol. 2011;65(2):364–73.2. Kakimoto CV, Victor Ross E, Uebelhoer NS. En coup de sabre presenting as a port-wine stain previously treated with pulsed dye laser.Dermatol Surg. 2009;35(1):165–7.3. Nijhawan RI, Bard S, Blyumin M, Smidt AC, Chamlin SL, Connelly EA. Early localized morphea mimicking an acquired port-wine stain.J Am Acad Dermatol. 2011;64(4):779–82.4. 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