Improved Topical Treatment in Localized Scleroderma and Systemic Sclerosis
Improved Topical Treatment in Localized Scleroderma and Systemic Sclerosis
SSc is a chronic progressive disorder of unknown aetiology characterized by excess synthesis and deposition of collagen and other extracellular matrix components in a variety of tissues and organs. Localized scleroderma (LS) differs from SSc in that with LS only skin and occasionally subcutaneous tissues are involved. Although rarely life threatening, LS can be disfiguring and disabling and, consequently, can adversely affect quality of life. There is no known effective treatment for LS, and various options, including, as examples, corticosteroids and other immunomodulatory agents, ultraviolet radiation and vitamin D analogues, are of unproven efficacy. Clinical trials evaluating combination therapy such as corticosteroids with MTX or UVA1 exposure with psoralens have not been established as consistently effective. New immunomodulators such as tacrolimus and thalidomide are also being evaluated. A better understanding of the molecular and cellular mechanisms of LS has led to evaluation of new treatments that modulate profibrotic cytokines such as TGF-β and IL-4, regulate assembly and deposition of extracellular matrix components, and restore Th1/Th2 immune balance by administering IL-12 or IFN-γ. IFN-γ acts by directly inhibiting collagen synthesis and by restoring immune balance. In this review, we evaluate current and future treatment options for LS and cutaneous involvement in SSc. Recent advances in therapy focus mainly on anti-fibrotic agents. Delivery of these drugs into the skin as the target tissue might be a key factor in developing more effective and safer therapy.
SSc is a chronic disorder manifested by excess synthesis and deposition of collagen (both Types I and III) in skin and connective tissue, vascular abnormalities and autoimmunity. Localized scleroderma (LS) differs from SSc in that LS does not involve the internal organs and patient prognosis is more favourable. Skin involvement in SSc presents clinical signs similar to that of LS, and the two conditions are histopathologically identical, thus treatment approaches for LS could also be applicable to sclerotic skin in SSc. Clinical signs of fibrosis are caused by sclerotic fibroblasts (myofibroblasts) in the dermis, which are capable of multiple passages, thus their accumulation might be responsible for the fibrosis characteristic of the disorder. These fibroblasts produce excessive collagen even without an immune stimulus, suggesting the dysfunction of some regulatory genes associated with phenotypic selection (i.e. the subpopulation of fibroblasts producing excessive collagen is amplified at the expense of the normal fibroblasts). Although generally not considered as serious a condition as SSc, LS still lowers a patient's quality of life. Those affected often develop lesions on their trunk, arms, face or legs. The number and size of lesions varies from person to person, with some showing limited involvement and others having more extensive pathology. The skin in affected areas, which may take the form of patches or linear bands, becomes thick, hard and discoloured (Fig. 1). In some cases, disfiguring and debilitating deformities can occur on the face and limbs, and mobility, as a result of the sclerotic lesions across joints, may become restricted. LS has an estimated prevalence of 50 per 100 000 before the age of 18 yrs and 220 per 100 000 by the age of 80 yrs.
(Enlarge Image)
Figure 1.
Clinical presentation of morphoea and linear scleroderma. The lesions can appear on any area of the body. Morphoea plaques are indurated, hyper- or hypopigmented with erythematous and/or violaceous halos (A). The size of the lesions can vary considerably. (B) Representation of linear scleroderma.
Treatment options for both LS and SSc are currently limited, thus there is a need to develop more rationally conceived, universally applicable and effective therapies. The clinical presentation of LS has multiple components, so researchers and clinicians are evaluating pathological markers as possible treatment targets. This review provides the latest information on the pathogenesis of LS, cutaneous involvement in SSc and the most widely used and effective treatments for the condition. We focus on novel treatment approaches in the context of the recently evaluated pathways, including signal transducers and activators of transcription (Stat) and Smad signalling pathways. In addition, improvement of drug delivery systems could have a major impact on the therapeutic outcome in LS and sclerotic skin in SSc.
Abstract and Introduction
Abstract
SSc is a chronic progressive disorder of unknown aetiology characterized by excess synthesis and deposition of collagen and other extracellular matrix components in a variety of tissues and organs. Localized scleroderma (LS) differs from SSc in that with LS only skin and occasionally subcutaneous tissues are involved. Although rarely life threatening, LS can be disfiguring and disabling and, consequently, can adversely affect quality of life. There is no known effective treatment for LS, and various options, including, as examples, corticosteroids and other immunomodulatory agents, ultraviolet radiation and vitamin D analogues, are of unproven efficacy. Clinical trials evaluating combination therapy such as corticosteroids with MTX or UVA1 exposure with psoralens have not been established as consistently effective. New immunomodulators such as tacrolimus and thalidomide are also being evaluated. A better understanding of the molecular and cellular mechanisms of LS has led to evaluation of new treatments that modulate profibrotic cytokines such as TGF-β and IL-4, regulate assembly and deposition of extracellular matrix components, and restore Th1/Th2 immune balance by administering IL-12 or IFN-γ. IFN-γ acts by directly inhibiting collagen synthesis and by restoring immune balance. In this review, we evaluate current and future treatment options for LS and cutaneous involvement in SSc. Recent advances in therapy focus mainly on anti-fibrotic agents. Delivery of these drugs into the skin as the target tissue might be a key factor in developing more effective and safer therapy.
Introduction
SSc is a chronic disorder manifested by excess synthesis and deposition of collagen (both Types I and III) in skin and connective tissue, vascular abnormalities and autoimmunity. Localized scleroderma (LS) differs from SSc in that LS does not involve the internal organs and patient prognosis is more favourable. Skin involvement in SSc presents clinical signs similar to that of LS, and the two conditions are histopathologically identical, thus treatment approaches for LS could also be applicable to sclerotic skin in SSc. Clinical signs of fibrosis are caused by sclerotic fibroblasts (myofibroblasts) in the dermis, which are capable of multiple passages, thus their accumulation might be responsible for the fibrosis characteristic of the disorder. These fibroblasts produce excessive collagen even without an immune stimulus, suggesting the dysfunction of some regulatory genes associated with phenotypic selection (i.e. the subpopulation of fibroblasts producing excessive collagen is amplified at the expense of the normal fibroblasts). Although generally not considered as serious a condition as SSc, LS still lowers a patient's quality of life. Those affected often develop lesions on their trunk, arms, face or legs. The number and size of lesions varies from person to person, with some showing limited involvement and others having more extensive pathology. The skin in affected areas, which may take the form of patches or linear bands, becomes thick, hard and discoloured (Fig. 1). In some cases, disfiguring and debilitating deformities can occur on the face and limbs, and mobility, as a result of the sclerotic lesions across joints, may become restricted. LS has an estimated prevalence of 50 per 100 000 before the age of 18 yrs and 220 per 100 000 by the age of 80 yrs.
(Enlarge Image)
Figure 1.
Clinical presentation of morphoea and linear scleroderma. The lesions can appear on any area of the body. Morphoea plaques are indurated, hyper- or hypopigmented with erythematous and/or violaceous halos (A). The size of the lesions can vary considerably. (B) Representation of linear scleroderma.
Treatment options for both LS and SSc are currently limited, thus there is a need to develop more rationally conceived, universally applicable and effective therapies. The clinical presentation of LS has multiple components, so researchers and clinicians are evaluating pathological markers as possible treatment targets. This review provides the latest information on the pathogenesis of LS, cutaneous involvement in SSc and the most widely used and effective treatments for the condition. We focus on novel treatment approaches in the context of the recently evaluated pathways, including signal transducers and activators of transcription (Stat) and Smad signalling pathways. In addition, improvement of drug delivery systems could have a major impact on the therapeutic outcome in LS and sclerotic skin in SSc.