Pathogenesis and treatment modalities of localized scleroderma

pathogenesis, and treatment modalities of this disease.


Introduction
Localized scleroderma (morphea, sclerodermia loca lisata, sclerodermia circumscripta) is a chronic infl ammatory skin disease, which manifests as a disorder of cellular immunity, microcirculation and abnormal collagen synthesis. This triad of components slowly causes sclerosis of the skin and sometimes even movement disorders.
There are only few data about the epidemiology of localized scleroderma. During the period from 1960 to 1993, the incidence rate of localized scleroderma in Olmsted County, Minnesota, was 27 per million inhabitants (1). The prevalence increases with age, being approximately 500 per million at the age of 18 years and 2200 at the age of 80 years (2). However, usually disease onset occurs at young age (at the age of 20-40 years), and about 15% of patients are children up to the age of 10 years (3). The disease is rare in blacks (3). Localized scleroderma is more prevalent in women than men, with a femaleto-male ratio of 2-3:1 (3,4).
Localized scleroderma is usually a relatively harmless disease. However, in about 10% of patients, scar formation may lead not only to cosmetic defect, but also to signifi cant disfi gurement or growth retardation and handicap of the affected individuals for their entire life (1). Appropriate treatment with topical or systemic drugs and phototherapy may be helpful for about 60% of patients with localized scleroderma (4). In this article, we will discuss the clinical and morphological characteristics, etiology, and pathogenesis and treatment modalities of localized scleroderma.

Etiology and pathogenesis
The pathogenesis of localized scleroderma has not been completely delineated. There is increasing evidence that sclerosis represents the end stage of the disease and results from an increased synthesis of collagen types I and III. According to literature data, three major components are involved during the development of sclerosis: damage of small vessels, activation of T lymphocytes, and production of altered connective tissue. The morphological changes affect principally capillaries and small arterioles 50-500 μm in diameter (4). The initial changes include expression of adhesion molecules and endothelial swelling, followed by thickening of the basement membrane and hyperplasia of the intima. Activated T cells that release cytokines -interleukin 4 (IL-4) and transforming growth factor β (TGF-β) -accumulate around affected vessels (5).
B. burgdorferi infection has been showed to be a cause of erythema chronicum migrans, acrodermatitis chronica atrophicans, and lymphadenosis cutis benigna and has been implicated in the development of localized scleroderma. In 1987, Aberer et al. were the fi rst to hypothesize about association between B. burgdorferi infection and localized scleroderma (7). Many techniques of analysis have been used to show the relationship between B. burgdorferi and localized scleroderma: indirect immunofl uorescence assay and enzyme-linked immunosorbent assay (ELISA), histological investigations with special staining methods, cultivation of spirochetes, or their detection from lesions of patients with morphea using polymerase chain reaction (PCR). The research results have been contradictory. Researchers distributed into two groups: supporting and denying the signifi cance of B. burgdorferi in the etiopathogenesis of localized scleroderma (Table 1).
Many reports relate localized scleroderma to B.

Clinical findings
The characteristic lesion of localized scleroderma is a circumscribed sclerotic plaque with an ivory-colored center and, if the disease is in an active infl ammatory stage, blue-pink or violaceous border. The lesion often begins as a peripherally expanding erythema. The center gradually becomes yellow or white and more or less hardened, but not bound to the deeper structures. After lesions persist for a fairly long time, atrophic skin changes may develop with loss of hairs and sweat glands, as well as hypopigmentation and hyperpigmentation. Many clini-cal variants of localized scleroderma are described ( Table 2).

Diagnostics
Histological evaluation is the most important in the diagnosis of local scleroderma: at the beginning, features of infl ammation (infl ammation phase) and later features of sclerosis (sclerosis phase) can be assessed. Early on, there is a dense superfi cial and deep perivascular infl ammatory infi ltrate primarily composed of lymphocytes with a few plasma cells and eosinophils. Typically a much more pronounced infl ammatory infi ltrate can be observed at the junction between the dermis and the subcutaneous fat around the deep vascular plexus that often involves the subcutaneous fat and causes panniculitis and extends upward toward the eccrine glands. During infl ammation phase, slight edema may be seen with swollen or thickened bundles of collagen. Later on, the infl ammatory infi ltrate disappears almost completely and collagen bundles become thickened, sometimes closely packed and arranged parallel to the epidermal surface. Elastic bundles usually lose their sinuosity and are outstretched. In this stage, the atrophy of adnexal structures and reduction in number usually can be observed.
Usually no specifi c changes are found in laboratory fi ndings of patients with localized scleroderma. Sometimes peripheral blood analysis may show eosinophilia. Immunological testing is not specifi c as well. According to the literature, antinuclear antibodies (ANAs) are found in 47-76% of patients (31). Antibodies against deoxyribonucleic acid (anti-DNA) are found in isolated cases and more often in   (37). Different imaging techniques may be used in the diagnosis of localized scleroderma. The activity of scleroderma lesion is often assessed by thermography, laser Doppler fl owmetry, or laser Doppler imaging: in active areas and areas of new lesions, the temperature and blood fl ow are increased (38,39). Localized scleroderma on high-frequency (20-40 MHz) ultrasonographic evaluation usually presents as a regular increase of dermis echogenicity as a result of the accumulation of collagen fi bers in this region and increase of the skin thickness (38,40). Imaging techniques are of particular importance when assessing the effi cacy of treatment of localized scleroderma (41).

Treatment
Various therapeutic modalities are being used for the treatment of localized scleroderma. There is no precise treatment scheme for this disease. A majority of patients can be successfully treated with topical therapy and phototherapy, but the progressive forms of the disease with intensely expressed skin sclerosis sometimes may need even systemic treatment (3). Most of data about the effi cacy of treatment of localized scleroderma are based on single case reports or clinical trials without controls (Table 3).
Phototherapy. Phototherapy is the treatment with nature-identical ultraviolet radiation sources. The wavelength of the sun radiation ranges from 280 to 3000 nm. This is sectioned into ultraviolet radiation (UV), visible light, and infrared irradiation. Ultraviolet radiation is divided into UVC (200-280 nm, most of it is suspended in the ozone layer and it does not reach the surface of earth), UVB (280-320 nm), and UVA (320-400 nm) according to the wavelength. The effect of UV on the skin depends on the wavelength. The UVB radiation affects only in the upper layers of the skin and infl uences only keratinocytes and Langerhans cells. The UVA radiation penetrates more deeply into the skin and affects fi broblasts, dendritic cells, vascular epithelium, and infl ammatory cells (mast cells, granulocytes). The UVA radiation also stimulates the production of infl ammatory mediators, protein synthesis, and cell apoptosis.
In the medical literature, phototherapy for localized scleroderma was fi rst described in 1994 (42). The effi cacy of this treatment has been confi rmed by various clinical trials. Phototherapy with psoralen (PUVA) activates metalloproteinase 1 (collagenase 1), which is important in collagen renewal (4). Accord-ing to literature data, both bath PUVA and UVA1 phototherapy are effective treatments in most variants of localized scleroderma (43)(44)(45). It is safer and more effective than systemic treatment. Bath PUVA is more recommended for the late stage of localized scleroderma, when sclerotic changes predominate over infl ammation. Satisfactory treatment results are achieved when 25-35 procedures over 3 months are performed (total UVA irradiation dose, 40-50 J/cm 2 ) (4). In view of the recent reports, UVA1 (340-400 nm) phototherapy can be more effective in early cases of localized scleroderma, when infl ammatory changes predominate and progression of the disease is diagnosed (45,46). The recommended total irradiation dose is 10-50 J/cm 2 (45). When the total UVA1 irradiation dose is 20 J/cm 2 or 50 J/cm 2 , remission is achieved in 80% of cases or even more (45,46). According to the results from study by Kreuter et al., narrowband UVB phototherapy also can be an effective therapeutic option in localized scleroderma, with a favorable risk/benefi t ratio (45). However, according to their data, medium-dose UVA1 phototherapy was signifi cantly more effective than narrowband UVB phototherapy (45).
Isolated lesions of localized scleroderma can be successfully treated using photodynamic therapy.  Marked reduction of sclerosis is seen after photodynamic therapy 1-2 times per week for 3-6 months using 3% 5-aminolevulinic acid gel and irradiation dose of 10 J/cm 2 (47). Topical treatment. The disease is generally selflimited; most cases require little or no treatment and many patients do well with simple emollients. The benefi t of corticosteroids in the treatment of localized scleroderma is questionable. Mostly ultrapotent topical corticosteroids may be useful in superfi cial active lesions for reducing infl ammation. Sometimes even corticosteroids of weak (1% hydrocortisone) or medium (0.1% mometasone, 0.1% betamethasone, etc.) potency 1-2 times per day may be rather effective for the treatment of isolated lesions of localized scleroderma (3,4,46,48). Intralesional corticosteroids may also be effective, but usually are used if only a small number of lesions are present (3,4). Triamcinolone (0.1-0.3 mL) diluted with local anesthetic at a ratio of 1:2 and injected to the margin of the lesion may suppress infl ammation and stop progression of the disease (3,4). Injections can be repeated once a week for 3 weeks (3,4). Corticosteroids are ineffective in resolving sclerosis.
Derivatives of vitamin D and vitamin A are under study in localized scleroderma. In vitro, calcipotriol inhibits the proliferation of fi broblasts (4). A study by Cunningham et al. showed an improvement of localized scleroderma after treatment with topical calcipotriene (0.005%) twice a day for three months (49). However, placebo-controlled studies are needed to confi rm the effi cacy of calcipotriol for the treatment of localized scleroderma (50).
Ointments containing heparin or heparinoids have been recommended for the treatment of localized scleroderma (51). Preliminary reports on new therapies for localized scleroderma are also available. These include the use of tacrolimus 0.1% ointment applied 2 times per day by occlusive dressing with a signifi cant clinical improvement of late sclerotic lesions and complete clearance of early infl ammatory skin lesions in 3 months (52,53). This medication is well tolerated and safe for the longterm treatment of localized scleroderma (52). Case reports are published about successful treatment of this disease using imiquimod (5% cream) (54,55). A few patients were successfully treated with topical tocoretinate for 6 months to 3 years, and clinical as well as histological improvement of lesions of localized scleroderma was observed (56).
Systemic treatment. A wide variety of systemic therapies have been recommended for the treatment of localized scleroderma. Systemic treatment is usable only for the progressive and destructive variants of the disease.
Penicillin and other antibiotics are often prescribed, but no controlled study, establishing their effi cacy, has been carried out. Regression of localized scleroderma during prolonged treatment with penicillin or penicillamine has been observed in adults and children (57). Penicillin in the range of 10-30 million IU per day for 2-4 weeks is helpful in about 5% of patients (4,51). Penicillamine seems to be similarly effective but is used less often because of its potential side effects.
In linear forms of scleroderma, phenytoin has been recommended (initially 100 mg 2 or 3 times per day, later 100 mg for 1-3 years) (51). Antimalarial drugs have been helpful in individual cases (200 mg of chloroquine per day for 3-6 months or 250 mg of hydroxychloroquine per day) (51).
Oral corticosteroids (1-2 mg of methylprednisolone per day) may be helpful in the infl ammatory stages of localized scleroderma, especially in some patients with either rapidly progressive linear or disabling types of the disease, but corticosteroids do not improve established sclerosis (4). Alternatively, 15-20 mg of methotrexate per week seems to be helpful in the acute phase of localized scleroderma (58,59). Based on experience with other autoimmune diseases, some authors favor the combination of methotrexate and corticosteroids, especially in rapidly progressive types of localized scleroderma (60). Immunosuppressive treatment is recommended for several months up to one year. Cyclosporine has not been shown to be effective and should not be combined with any phototherapy that currently is the most effective therapy for localized scleroderma.
Retinoids can inhibit TGF-β, one of the key cytokines that promote collagen synthesis by fi broblasts (61). Treatment with the vitamin A derivatives -etretinate or acitretin -at doses of 10-50 mg per day is effective in localized scleroderma (62)(63)(64). The only disadvantage of this method is that the response to the treatment is noticed only after a few months.
Despite promising case reports, a double-blind, placebo-controlled study has not confi rmed the clinical effi cacy of oral calcitriol (1.25-dihydroxyvitamin D 3 ) in localized scleroderma. This vitamin D derivative has a pronounced anti-infl ammatory effect and modulates fi broblast growth and TGF-β (65). Perhaps it would be useful to investigate more advanced derivatives that cause fewer side effects and test them for longer treatment periods.
In vitro both interferon γ and interferon α nor malize pathogenic collagen production by fi broblasts. However, the clinical effi cacy of these cytokines in localized scleroderma has not been con fi rmed (66).
Physiotherapy. Long-term physiotherapy is obligatory for patients in whom localized scleroderma threatens to impair mobility. Regular procedures 3-4 times per week are recommended: phonophoresis with corticosteroids, iontophoresis, regular massages, technique of vibration, etc. In later stages of localized scleroderma, drainage of lymph, tissue massage, and undercurrent massage may be helpful. Remedial exercises always are useful.
However, in the case of persistent contractures, especially in linear localized scleroderma, reconstructive surgery may be needed.

Conclusions
Localized scleroderma may last from a few months to many years. The severity of the disease varies and is unpredictable, but the prognosis is usually good. With time, the infl ammatory process diminishes, lesions soften, and sometimes even the sclerosis can lessen. The treatment of localized scleroderma is still controversial, and no specifi c treatment for the disease is available. Most of patients can be successfully treated topically with corticosteroids or other immunosuppressive agents, but occasionally systemic therapy is needed for disseminated, progressive, and destructive variants. Bath PUVA therapy is extremely effective for many forms of localized scleroderma and currently recommended as the treatment of choice, being safe and more effective than the systemic therapies discussed above. Further defi nition of the role of Borrelia burgdorferi in localized scleroderma is pivotal in making treatment recommendations.