4 Scleroderma 4.1 Localized Scleroderma Catherine H. Orteu and Jan P. Dutz Introduction Localized scleroderma (LS) or morphea encompasses a group of disorders char- acterized by delimited and localized inflammatory sclerosis (thickening) and fibrosis of the skin, subcutaneous tissue, fascia and/or adjacent muscle. In contrast to systemic sclerosis, Raynaud’s phenomenon, acrosclerosis and in- ternal organ involvement do not usually occur. Morphea may be divided into 5 subtypes: plaque, generalized, bullous, linear and deep, based on the ex- tent, form and depth of cutaneous sclerosis (Peterson et al. 1995). These sub- types frequently occur together in the same patient. Although morphea is rarely life threatening, significant morbidity and disability occur, particularly in the linear and deep forms. Epidemiology Most studies suggest that morphea is commoner in women, with female to male ratios of between 6 and 2.6:1 (Christianson et al. 1956; Jablonska 1975b; Peterson et al. 1997; Silman et al. 1988). This female preponderance may be less marked in the linear group, in which ratios of 1:1 (Peterson et al. 1997) to 4:1 (Falanga et al. 1986) have been documented. The prevalence of morphea is not absolutely clear. A UK population based study in 1986, suggested prevalence rates of 13 and 48 per million in adult males and females respec- tively, with annual incidence rates of 1 and 6 per million (Silman et al. 1988). A second study, conducted over a 30 year period (1960–1993) by Peterson et al (1997) in Olmsted County, USA, revealed 82 cases, an overall incidence of 2.7/100 000/year. Prevalence was estimated at 0.05% at age 18 years and at 134 Catherine H. Orteu and Jan P. Dutz 0.22% at age 80 years. Interestingly, a progressive increase in the incidence of plaque morphea was noted over the 30year period. In this study, plaque morphea was the commonest subtype (56% of cases), followed in order of fre- quency by linear (20%), generalized (13%), and deep (11%). Of the 11 pa- tients with generalized morphea, 5 initially presented with morphea en plaque and progressed over 5 months to 3 years. Coexisting morphea subtypes oc- curred in 11% of patients. In a large European referral-based series, Jablonska (1975b) found that plaque morphea was commoner in adults (28.5% of adult cases versus 15% for the linear group), and that linear forms were commoner in children (31.5% and 21.3% of childhood cases respectively). These data are corroborated by those of Peterson et al (1997): the mean age at onset of disease was 12.2 years in the linear group, 31.5 years in the plaque group, 39.9 years in the general- ized group, and 45.1years in the deep group. A recent retrospective analysis of 239 cases seen at an Italian referral center further confirmed these results: Children more commonly had linear or “mixed” linear and plaque-type forms of morphea (54/126 cases) than adults (16/113 cases) (Marzano et al. 2003). The duration of disease activity can vary from a few months up to 20–30 years, but is usually 3–5 years (Christianson et al. 1956). Plaque lesions gen- erally resolve earlier than other subtypes. In the Olmsted county series, 50% of the patients had 50% softening (or more), or resolution by 3.8years after diagnosis. There was 50% resolution at 2.7 years in the plaque group, at 5 years in generalized and linear groups and at 5.5 years in the deep group (Pe- terson et al. 1997). Relapse can occur and may be more frequent with gener- alized, deep and “mixed” forms (Marzano et al. 2003). The exact relationship between LS and systemic sclerosis (SSc) remains unclear, however, it has been compared to that between discoid and systemic lupus erythematosus (Jablonska and Rodnan 1979). LS in the absence of Raynaud’s phenomenon and acral sclerosis rarely if ever evolves into SSc. In larger series, transition from morphea to SSc, was reported in 2/235 (Christi- anson et al. 1956) and 4/253 (Jablonska 1975b) patients. Plaques of morphea can be seen in association with true SSc, and occurred in 9/135 patients in a Japanese study (Soma et al. 1993). Histopathology Scleroderma derives from the Greek terms skleros, hard, and derma, skin and means hard skin. The different types of morphea do not differ in the elements of the histopathologic findings but rather with regards to severity and depth of involvement. Both early inflammatory and late sclerotic changes have been described. Most biopsies will show an intermediate picture (Figure 1). In the early inflammatory phase, a moderately dense infiltrate of lympho- cytes, plasma cells and histiocytes, and occasionally, mast cells has been de- scribed (O’Leary et al. 1957; Fleischmajer and Nedwich 1972). This infiltrate Localized Scleroderma 135 Fig. 1. Biopsy specimen showing normal epidermis, sclerosis of the papillary dermis, thickened sclerotic collagen bundles and periadnexal inflammation (Original magnification x40) may be found in the lower dermis, the subcutaneous fat and around eccrine glands. The reticular dermis shows thickened collagen bundles. Large areas of subcutaneous fat may be replaced by wavy fibers of newly formed colla- gen. Elastic fibers are preserved. The epidermis may be normal or slightly acanthotic (Morley et al. 1985). Electron microscopy shows the deposition of collagen fibrils with decreased diameter when compared to mature collagen (Fleischmajer and Perlish 1972). This is due, in part, to an increase in type III collagen (Perlish et al. 1988). Vascular changes are mild in the dermis and subdermis and consist of endothelial swelling and edema of vessel walls (O’Leary et al. 1957). In the sclerotic stage, there is little inflammation. Collagen bundles in the reticular dermis are thickened, eosinophilic and oriented horizontally. Eccrine glands are entrapped by collagen, and thus appear higher in the dermis. Fewer blood vessels are seen within the thickened collagen. The fascia and striated 136 Catherine H. Orteu and Jan P. Dutz muscles underlying the lesions may likewise show fibrosis and sclerosis (Jaworsky 1997). Although the histology of involved skin is almost identical in LS and SSc (Young and Barr 1985), a recent report has suggested that inflammatory changes are more prominent in morphea (Torres and Sanchez 1998). Sclero- sis of the papillary dermis was noted in 10/32 morphea cases, but not in any of the 19 patients with SSc. Thus, simultaneous involvement of the superfi- cial dermis with deep dermal changes may help differentiate localized from systemic scleroderma. Cases of morphea in which the sclerosis is limited to the superficial reticular dermis have also been described (McNiff et al. 1999). These changes were noted without any of the epidermal features of lichen sclerosus: epidermal thinning with vacuolar degeneration, lichenoid infiltrate or follicular plugging. Etiopathogenesis The cause of morphea is unknown. Proposed triggers for the development of morphea have included infectious and other environmental factors. Localised scleroderma has been reported after trauma (Falanga et al. 1986; Yamanaka and Gibbs 1999), vaccination (Mork 1981; Drago et al. 1998), ischemic injury (McColl and Buchanan 1994) and radiation (Bleasel et al. 1999, Schaffer et al. 2000). Such triggers may have in common the generation of inflammatory and molecular “danger” signals that can activate the immune system and ini- tiate fibrosis. There are rare cases of familial clustering suggesting a genetic component (Wuthrich et al. 1975). A possible association with Lyme borreliosis was proposed in 1985 (Aberer et al. 1985) but was not borne out by polymer- ase chain reaction analysis of affected tissues in North American patients (Dillon et al. 1995). Two possible explanations for the contradictory findings obtained in patients from Europe and Asia, and the USA have been offered (Weide et al. 2000): Either that Borrelia burgdorferi is not a causative agent for morphea, or that a subspecies present only in Europe and Asia, could cause morphea in a subset of patients. Most studies on the pathophysiology of scleroderma focus on changes in patients with SSc. Here, we will focus on abnormalities detected in patients with LS. In both diseases three main themes have been pursued: vascular al- terations, immune system activation and dysregulation, and changes in col- lagen metabolism and fibroblast biology. Abnormalities in these three areas are likely interrelated and contribute to the generation of the clinical phenotype. Vascular Activation in Morphea Endothelial swelling in early morphea lesions was first described by O’Leary et al (1957). Comparing biopsies from sclerotic centers, inflamed borders (lilac Localized Scleroderma 137 rings) and adjacent, clinically normal skin, Kobayasi and Serup (1985) described three patterns of vascular changes. Uninvolved skin as well as thickened skin showed vascular wall thickening and basal lamina duplication with associ- ated mast cell and histiocyte infiltration. In clinically inflamed lesions, the outer surfaces of pericytes were thickened, and lymphocytes and plasma cells were present. Pericyte hypertrophy was noted in clinically inflamed as well as in sclerotic lesions. There is evidence for generalized vascular activation: Jones et al (1996) noted low but increased levels of expression of the vascular adhe- sion molecules vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on endothelium of uninvolved skin of morphea patients. More recently, in- creased serum levels of soluble VCAM-1 and E-selectin were found in a third of patients with generalized morphea and in approximately 10% of patients with linear and plaque type morphea (Yamane et al. 2000). In addition to activation, the endothelium may be a primary site of dam- age in morphea: Endothelial cell apoptosis was noted in deep dermal vessels of 9/9 patients examined (Sgonc et al. 1996). Anti-endothelial cell antibody mediated antibody-dependent cytotoxicity has been suggested as a mecha- nism for the induction of endothelial cell death (Sgonc et al.