Morphea and Lichen Sclerosus

Vascular Changes

A prominent feature of advanced sclerosis is a reduction in the number of capillaries. Studies performed in SSc suggest that hypoxia resulting from microvascular injury is a very early, or even the primary, event. Endothelial cells respond to various stimuli, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) (see Ch. 102 ). In the sera of patients with SSc, markers indicative of endothelial cell activation (e.g. soluble adhesion molecules, VEGF) are elevated. Morphologic changes principally affect capillaries and small arterioles, and the initial changes in SSc include expression of adhesion molecules and endothelial swelling, followed by thickening of the basement membrane and intimal hyperplasia. An extrapolation is that similar changes may occur early on in morphea.

Control of Fibroblast Function by T-Cell-Derived Cytokines

Pioneering work by E Carwile Leroy showed that in vitro cultured fibroblasts isolated from sclerotic tissue produce increased amounts of collagen (types I, II and III) and other extracellular matrix proteins. These fibroblasts can maintain this phenotype for weeks over several passages. This raised the question as to whether scleroderma results from an inborn or acquired error in collagen metabolism within fibroblasts. Today, most data favor the concept that abnormal collagen production is directed by surrounding cells. T cells in particular have the capacity to modify collagen synthesis by fibroblasts, and T cells are regularly present, at least early on, in a perivascular location and especially at the leading edge of developing sclerosis (see Fig. 44.1 ).

Enhanced production of collagen and other extracellular matrix proteins is induced by T-cell-derived cytokines, especially interleukin (IL)-4, IL-13 and TGF-β. IL-4 is produced by CD4 ⁺ T helper type 2 (Th2) lymphocytes (see Ch. 4 ) and can directly enhance TGF-β production . In contrast, production of collagen and other extracellular matrix proteins can be significantly suppressed by interferons that are associated with Th1 lymphocytes . Th1 differentiation also implicates IL-12 signaling via the transcription factor STAT4. Of note, an association between STAT4 polymorphisms (e.g. rs7574865) and susceptibility to SSc, especially the limited subtype, has been reported . Additional susceptibility loci associated with SSc include immune-related genes (e.g. CD247 , IRF5, HLA region) and the promoter region of the gene that encodes connective-tissue growth factor (CTGF) .

More recently, circulating levels of the chemokine ligand CXCL4 (secreted by plasmacytoid dendritic cells) were found to be significantly elevated in SSc . Increased CXCL4 levels correlated with a higher prevalence of lung fibrosis and faster progression of skin fibrosis . Interestingly, CXCL4 promotes the Th2 cytokines IL-4 and IL-13 and has anti-angiogenic properties.

IL-4 is the most potent force in driving Th2-cell differentiation (see Fig. 4.10 ) . Because IL-4 enhances pathologic collagen production by fibroblasts and induces recruitment of eosinophils, it is believed that immune responses dominated by IL-4- as well as IL-13- and TGF-β-producing cells are critical in the initiation of skin sclerosis. This concept is supported by clinical and experimental data:

• In situ analysis of the advancing inflammatory margins of skin sclerosis revealed predominantly IL-4 expression.

• Th2-associated IL-13 and IL-33 have been shown to promote skin fibrosis in mice, and early treatment of scleroderma-developing mice with anti-IL-4 antibodies prevented scleroderma.

• Systemic retinoids (which interact with TGF-β signaling) appear to reduce pathologic collagen synthesis by fibroblasts and may improve skin sclerosis in patients with chronic GVHD .

• Th2-promoting CXCL4 is so closely associated with SSc that it has been suggested as a biomarker for SSc .

One therapeutic approach for morphea would be to redirect Th2 responses into Th1 responses. Unfortunately, placebo-controlled clinical trials using the Th1-inducing cytokines IFN-γ or IFN-α in morphea had negative results . In the future, perhaps more effective inhibitors of Th2 responses may help to prevent or improve skin sclerosis.

Lastly, when scleroderma fibroblasts are compared to control fibroblasts, there are differences in intracellular signaling proteins. Examples include activation of p38 mitogen-activated protein kinase and higher levels of Ha-Ras protein and reactive oxygen species. These findings plus data from animal studies demonstrating a link between skin fibrosis and pro-oxidative agents support hypoxia and oxidative stress as key factors in the pathogenesis of skin sclerosis.

Animal Model and Genetics

Currently, the best animal model for studying pathogenic events in scleroderma is the tight skin (TSK) mouse ( Fig. 44.2 ). A partial duplication of the fibrillin-1 gene may be responsible for the increased synthesis and accumulation of collagen in the skin and internal organs of TSK mice. TSK mice not only have increased collagen deposits, but also the collagen fibers are reduced in length and the quantity of hydroxyproline is increased in the dermis. Moreover, the mice have high antibody titers against topoisomerase I and fibrillin-1, similar to patients with SSc and morphea, respectively. One major difference is that blood vessels remain uninvolved in TSK mice, demonstrating that sclerosis of the skin can develop in the presence of apparently normal vessels . The phenotype can be transferred from diseased animals to healthy syngeneic mice via bone marrow cells (see Fig. 44.2 ).

Fibroblasts from TSK mice have elevated IL-4 receptor α expression and back-crossing the TSK mice onto a genetic background that either cannot respond to IL-4 or is deficient in producing TGF-β prevents skin sclerosis. Moreover, this back-cross normalizes collagen length, skin thickness and hydroxyproline content and prevents antibody formation to topoisomerase I (see Fig. 44.2 ) . In this murine model of SSc, interventions that promoted Th1 responses or targeted PDGF receptor activity (e.g. imatinib) reduced dermal thickening and fibrosis . More recent strategies for improving experimental skin fibrosis have focused on the role of platelet-derived serotonin , β integrins, TGF-β , and Janus kinases .

Besides the phenotypic similarities, the genetic locus associated with the TSK phenotype appears to be related to the risk of developing scleroderma. In humans, this susceptibility locus is on chromosome 15q in a region that contains the fibrillin-1 gene, which is implicated in stiff skin syndrome .

Triggering Events

Most immunologic and metabolic studies have been directed toward understanding SSc, and the question remains as to whether they can also explain focal, asymmetric inflammation and sclerosis of the skin. The major discriminating factor between morphea and SSc might be the triggering event, with morphea being caused by a local trigger within the skin and SSc initiated by a systemic insult. The putative local triggering events for morphea include mechanical trauma, injections, vaccinations , and X-irradiation.

These questions initiated the search for potential triggers and studies of diseases that share clinical features with morphea and scleroderma. One intensively investigated area was the potential role of infection with Borrelia burgdorferi . The isolation of B. burgdorferi from the skin of some selected patients with morphea originally supported this speculation. However, larger studies failed to confirm this initial observation . Thus, this theory has been abandoned.

Plaque-Type Morphea

Plaque-type morphea, the most frequent variant, is characterized by the insidious onset of a slightly elevated, erythematous or violaceous, slightly edematous plaque that undergoes centrifugal expansion ( Fig. 44.3 ). It is generally asymptomatic and therefore frequently goes unnoticed by the patient. The central portion of the progressing lesion starts to transform into sclerotic, scar-like tissue. Depending on the depth of the sclerosis, the skin becomes progressively indurated. Centrally, it can acquire a shiny white color, and peripherally, a violaceous or “lilac” ring ( Fig. 44.4A ). Postinflammatory hyperpigmentation often dominates over the white sclerosis as the lesions mature ( Fig. 44.4B ).

Skin structures such as hairs and sweat glands are frequently lost. Some patients complain of itch, perhaps due to associated xerosis. Once the “lilac” ring vanishes, the lesion's progression also halts. Although this inflammatory margin may be difficult to appreciate, especially in linear sclerosis, it is an important indicator of clinical activity.

The plaques of morphea most commonly develop on the trunk and in general are between 2 and 15 cm in diameter. They are usually multiple and asymmetric, but marked variation exists. Individual lesions may enlarge significantly or remain stable in size.

The course of morphea is also variable. In most patients, morphea progresses over 3–5 years, then arrests and eventually resolves spontaneously. However, residual atrophy and dyspigmentation are commonly observed. Patients rarely have relapsing disease for more than 5 years.

Linear Morphea and Parry–Romberg Syndrome

Linear morphea is different from plaque morphea, with respect to age of onset, distribution, clinical outcome and serologies. Morphea en coup de sabre (meaning stroke or blow with a single-edged sword) is a term used for linear morphea of the forehead and scalp. Hemifacial atrophy, or Parry–Romberg syndrome, is probably a very severe variant of linear morphea, but it may be a phenotype for more than one entity. There is a progressive loss of subcutaneous fat, but little or no sclerosis ( Fig. 44.7 ). The entire distribution of the trigeminal nerve, including the eye and the tongue, may be affected.

Linear morphea may present initially as a linear, erythematous (inflammatory) streak, but more frequently begins as a harmless-appearing lesion of plaque-type morphea that extends longitudinally as a series of plaques that then join to form a scar-like band ( Fig. 44.8 ). This band may severely impair the mobility of the affected limb. Linear morphea tends to involve the underlying fascia, muscle and tendons. This leads not only to muscle weakness but also to shortening of the muscles and fascia that impairs joint mobility. Linear morphea is especially problematic when it extends over joints, as this almost invariably results in a decrease in range of motion and functional impairment . In some patients, involvement is circular rather than linear and results in progressive atrophy of the limb similar to the Parry–Romberg variant of facial morphea. The linear variant can have prolonged periods of quiescence followed by reactivation.

The en coup de sabre type of morphea represents linear morphea of the head ( Fig. 44.9 ). It is typically unilateral and extends from the forehead into the frontal scalp. It may start either as a linear streak, which may initially mimic a port-wine stain, or as a row of small plaques that coalesce. A paramedian location is most common. Like plaque morphea, it may initially be surrounded by a discrete lilac ring that extends longitudinally and may reach the eyebrows, nose and even the cheeks. As inflammation wanes, a linear, hairless crevice develops that in some patients is sclerotic, while in others appears more atrophic.

En coup de sabre morphea can also involve the underlying muscles and osseous structures. Rarely, the inflammation and sclerosis progress to involve the meninges and even the brain, creating a potential focus for seizures .