Systemic Sclerosis - Scleroderma

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Systemic sclerosis - scleroderma

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Systemic sclerosis - scleroderma U.-F. Haustein, MD Dermatology Online Journal 8(1): 3Department of Dermatology, University of Leipzig, Germany

AbstractSystemic sclerosis is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. This review discusses epidemiology and survival, clinical features including subsets and internal organ involvement, pathophysiology and genetics, microvasculature, immunobiology, fibroblasts and connective tissue metabolism and environmental factors. Early diagnosis and individually tailored therapy help to manage this disorder, which is treatable, but not curable. Therapy involves immunomodulation as well as the targeting of blood vessel mechanics and fibrosis. Physical therapy and psychotherapy are also important adjunctive therapies in this multifactorial disease.

IntroductionSystemic sclerosis (SSc) is a clinically heterogeneous generalized disorder which affects the connective tissue of the skin and internal organs such as gastrointestinal tract, lungs, heart and kidneys. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen. The first detailed description of a scleroderma-like disease was published by Curzio in Naples in 1753.[1] The patient, a young woman suffered from excessive tension and hardness of the skin. Nearly 100 years later, in 1847 Gintrac introduced the term scleroderma, as the skin was the most obvious organ involved.[2] The extensive involvement of internal organs has only been realized in the second half of the 20th century.[3,4,5]

The spectrum of sclerodermatous diseases comprises a wide variety of clinical entities such as morphea (patchy, linear, generalized), pseudo-scleroderma and the overlap-syndromes with

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Systemic sclerosis - scleroderma

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Figure 1 Figure 1. The clinical spectrum of scleroderma similar cutaneous and histopathologic manifestations. [7](Fig 1) However, these variants will not be discussed further. For the differential diagnosis see Table 1. Due to the complexity of the internal organ involvement SSc has attracted much attention from several disciplines (e. g. rheumatologists, pulmonologists,nephrologists) and therefore, a close cooperation with them is recommended, concerning diagnostic procedures and therapeutic regimens. In addition, the complex pathophysiology of SSc, involving genetic factors, environmental factors, vascular and immune system functions, as well as fibroblasts and matrix substances made SSc attractive to study events leading to autoimmune diseases or connective tissue diseases, in general. Basic functions of various cell types (endothelial cells, T-lymphocytes, monocytes, fibroblasts, mast cells) as well as the production and effects of cytokines, growth factors, and adhesion molecules have been studied and animal models have been developed to give closer insights into the pathophysiology of this disease. Table 1: Differential diagnoses of SSc Morphea (generalised, linear) Scleroedema generalised Buschke Scleromyxoedema Mixed connective tissue disease Shulman syndrome Shoulder-hand syndrome Pseudoscleroderma, e. g. porphyria cutanea tarda, polyvinyl chloride disease toxic oil syndrome drug induced pseudoscleroderma organic solvents syndrome Werner's syndrome

Definition, CriteriaDefinition, Criteria The American College of Rheumatology (former American Rheumatism Association - ARA) has defined criteria, that are 97 % sensitive and 98 % specific for SSc as follows[8]:

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Systemic sclerosis - scleroderma

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Major criterion: proximal diffuse (truncal) sclerosis (skin tightness, thickening, non-pitting induration)

Minor criteria: sclerodactyly (only fingers and/or toes) digital pitting scars or loss of substance of the digital finger pads (pulp loss) bibasilar pulmonary fibrosis The patient should fulfill the major criterion or two of the three minor criteria. Raynaud's phenomenon is observed in 90-98 % of SSc patients.[9] It may precede SSc for years and its presence may have predictive value for the subsequent development of SSc, in particular in association with abnormal nailfold capillaries and the occurrence of antinuclear antibodies (ANA).[9,10] In our experience, the American College of Rheumatology criteria from 1980 urgently need revision, particularly to more adequately incorporate patients with limited SSc. We support arguments that new advances in medical technology provide the opportunity to detect disease in patients who do not meet criteria established in 1980. In accordance with Poormoghin et al. and Lonzeti et al. we support the addition of simple clinical variables such as nail capillary microscopy and anticentromere antibody (ACA) positivity as novel minor criteria. [11,12] With these two new criteria the sensitivity of ARA preliminary criteria was improved from 33 to 97 %.[12,13]

ClassificationOver the years several attempts have been made to establish a classification system. Such classifications differentiate either different degrees of skin involvement,[14,15] distinct clinical manifestations such as CREST-syndrome (calcinosis, Raynaud's phenomenon, esophagus dysmotility, sclerodactyly, teleangiectasia),[16,17] SSc sine scleroderma,[18] vascular and inflammatory forms,[19] or associations with different autoantibodies. In the past, acroscleroderma and diffuse scleroderma were distinguished. Acroscleroderma was mainly defined by vascular alterations and by skin sclerosis, limited to acral areas (fingers), while diffuse scleroderma involved both the trunk and the extremities with pronounced inflammation and more rapid progression. On the other hand Barnett et al.[14] and the working group of the German Dermatological Research Community

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(Arbeitsgemeinschaft Dermatologische Forschung)[15] differentiated three types: Type I Involvement of the fingers and hands to wrist (acrosclerosis) and face Type II Proximal (extremity) ascending sclerosis including the forearm Type III Beginning of development of sclerosis at the trunk. During the last 10 years the majority of researchers have used the classification into limited versus diffuse cutaneous SSc according to Le Roy et al.[20] These categories are described as follows (Table 2): Table 2. SSc subsets according to LeRoy at al. J Rheumatol 1988;15:202-05 Limited Cutaneous SSc Raynauds phenomenon for years at presentation Skin sclerosis limited to hands, feet, face, and forearms, or absent Significant late incidence of pulmonary hypertension, trigeminal neuralgia, calcinosis, and teleangiectasia Dilated nailfold capillary loops, usually without capillary dropouts Detected by widefield nailfold capillaroscopy Diffuse cutaneous SSc Onset of Raynaud's phenomenon within 1 year of onset of skin changes Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Presence of anti-DNA topoisomerasi I (anti-Scl-70) antibodies Absence of anticentromere antibodies Nailfold capillary dilatation and destruction detected by widefield nailfold capillaroscopy

SSc subsets according to LeRoy at al[20] Limited Cutaneous SSc Raynaud's phenomenon for years at presentation Skin sclerosis limited to hands, feet, face, and forearms, or absent Significant late incidence of pulmonary hypertension, trigeminal neuralgia, calcinosis, and teleangiectasia Dilated nailfold capillary loops, usually without capillary dropouts Diffuse cutaneous SSc Onset of Raynaud's phenomenon within 1 year of onset of

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Systemic sclerosis - scleroderma

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skin changes Truncal and acral skin involvement Presence of tendon friction rubs Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement Presence of anti-DNA topoisomerase I (anti-Scl-70) antibodies Absence of anticentromere antibodies Nailfold capillary dilatation and destruction Detected by widefield nailfold capillaroscopy More than 50 % of SSc patients belong to the limited SSc. They have a more insidious onset of illness, a long history of Raynaud's phenomenon and swelling of digits, a more benign course, and a lower incidence of renal involvement and restrictive pulmonary disease with a much better prognosis. [21] Some cases are associated with anticentromere antibodies (ACA). Patients with diffuse cutaneous SSc have a short history. These patients often have acral sclerosis, arthritis, Raynaud's phenomenon, and rapid progression of skin involvement including arms and trunk. In addition, they have a higher incidence of renal, [21,22] cardiac, [23] pulmonary disease, [24] and tendon friction rub. [21] Antitopoisomerase antibodies (ATA) or antifibrillarin antibodies (against U3 RNA associated protein) may be present. When associated with anti-RNA polymerase, patients with diffuse SSc have the shortest surviv