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Systemic sclerosis

             Systemic sclerosis (SSc) / scleroderma is a chronic, multisystem connective tissue disease, which is characterized by microangiopathy, fibrosis of the skin and internal organs, and immune activation. The term scleroderma from the Greek words „scleros“ and “derma” means thickened, hardened skin. SSc is divided into two major subsets defined by the extension of skin involvement: limited SSc, characterised by skin involvement at the face, neck and the skin distal to the elbows and knees, and diffuse SSc with skin thickening distal and proximal to the knees and elbows and thickening involving trunk. The prevalence and incidence of SSc vary in different populations, suggesting the involvement of genetic and/or environmental factors. It is a rare disease with estimated prevalence for Europe over 8 cases per 100 000 adults. SSc usually begins between 30 and 50 years of age and is three times more common in women than in men.


            Raynaud’s phenomenon (RP) is the initial symptom in the majority of patients with limited form of the disease, while in those with diffuse form of the disease the classic initial complaints are swelling of the hands, skin thickening, and sometimes arthritis. RP is one of the most frequent symptoms in SSc. It occurs in the course of SSc in more than 95% of patients. RP affects fingers, toes and less frequently – the tip of the nose, earlobes, tongue. It manifests usually in three phases: ischemia, asphyxia and reactive hyperemia with skin discolouration from pallor to cyanosis and finally redness when blood flow is recovered. Attacks of RP are characterized by sharp demarcation between affected and unaffected areas. Usually it is the initial symptom, that can precede the other features of the disease by years. RP in SSc is severe and often presents with digital ulcers. Small areas of ischemic necrosis or ulceration of the fingertip are a frequent finding, often leaving pitting scars. Development of digital ulcers and appearance of other non-Raynaud symptoms such as puffy fingers, skin thickening, sclerodactyly, dysphagia, heartburn (indicate gastroesophageal involvement) and dyspnea (pulmonary involvement) are signs for the beginning of SSc. Skin involvement is almost universal feature of SSc. The earliest skin changes in SSc are tight, puffy fingers, especially in the morning. Edema is followed by skin thickening and tightening. Finally, the skin tends to soften, in many cases reverts to normal and become thinner than normal. Telangiactasiae at the face and extremities may be observed. Patients with limited SSc or in late-stage of the diffuse form of the disease commonly develop intra- or subcutaneous calcifications. Pulmonary involvement occurs in more than 70% of patients and is the leading cause of morbidity and mortality in patients with SSc. As a consequence of pulmonary parenchymal or lung blood vessels’ involvement pulmonary arterial hypertension (PAH) may develop. PAH occurs in about 10–12% of the SSc patients. In SSc two pathogenetic pathways for the development of the syndrome are recognized: PAH associated with pulmonary fibrosis and PAH without pulmonary fibrosis. Isolated PAH, in the absence of lung fibrosis, was found to be more frequent in the limited form of SSc (45%) than in the diffuse form of the disease (26%). Currently, PAH is the most devastating complication of SSc. Thus, nowadays in SSc patients with established diagnosis, a regular screening for development of PAH is recommended. The fibrosis of myocardium and the conducting system may lead clinically to rhythm disturbances. Gastrointestinal abnormalities in SSc involve motility dysfunction and mucosal damage in different segments of the alimentary tract. Myogenic and neurogenic factors are involved in the pathogenesis of these abnormalities. Although any part of the gastrointestinal tract may be involved, esophageal disease occurs in nearly all patients with SSc. Common esophageal manifestations in SSc include esophageal dysmotility that occurs in 75-90% of SSc patients, gastroesophageal reflux, etc. Joint symptoms have been noted in a high proportion of SSc patients during the disease varing between 24 to 97% of the patients. Arthralgias (joint pain without presence of joint inflammation) have been considered to occur more frequently, but in up to 66 % of synovial biopsies of SSc patients a histological evidence of synovitis has been found. Scleroderma renal crisis is the most acute and life-threatening manifestation of SSc, which occurs most often in patients with SSc with diffuse cutaneous involvement. After the administration of angiotensin converting enzyme (ACE) inhibitors in 1979 for the treatment of scleroderma renal crisis their prognosis approved substantially.


Laboratory and instrumental methods

            Capillaroscopic examination of the capillaries at the area of fingers’  nailfold reveals specific microvascular changes in SSc early in the disease course, which are diagnostic (the so-called “scleroderma” type capillaroscopic pattern). Chest radiographs has a low sensitivity for detection interstitial lung disease especially in the early stages. At present, chest high-resolution computed tomography is the preferred non-invasive standard technique for its diagnosis. If PAH is suspected, a transthoracic Doppler echocardiography and right heart catherization has to be performed. Additional laboratory and instrumental tests are ordered by the consulting rheumatologis if indicated.


            ACR (American College of Rheumatology) classification criteria (1980) are used for a long period of time in clinical practice (they require presence of one major criterion (skin thickening proximal of the metacarpophalangeal joints of the hands) or two minor criteria among the following e. g., sclerodactyly, digital pitting scars, bibasilar pulmonary fibrosis). ACR classification criteria for SSc are specific, but not sensitive. To improve the early diagnosis of SSc, Le Roy and Medsger proposed new criteria for early diagnosis of the disease that include the SSc-specific capillaroscopic changes and SSc-specific  autoantibodies together with signs for RP. For validation of new criteria for SSc an international multicenter project was sterted (project VEDOSS (Very Early Diagnosis of Systemic Sclerosis), organized by EUSTAR. The project is based on the notion, that the very early diagnosis of the disease provides the opportunity to delay the development of organ involvement via appropriate treatment. As red flags, which are indicators for referral of the patient to a VEDOSS center, are considered presence of RP, puffy fingers or sclerodactyly, and positive antinuclear antibodies. In 2013, new validated classification criteria for SSc have been proposed by ACR and EULAR (European League Against Rheumatism) that include new criteria for the disease such as presence of “scleroderma” type capillaroscopic pattern, SSc-specific autoantibodies, RP, telangiactasiae, PAH.


            In differential diagnosis, localised scleroderma should be taken into account. It is defined as a fibrosing disorder, which usually involves the skin and/or the underlying tissue of the same area. Depending on its subtype and localization, it can be associated with manifestation in fat tissue, muscles, joints and bones. It is distinguished from SSc by the absence of sclerodactyly, RP, typical scleroderma changes in the nailfold capillaries and internal organ manifestations.


            The therapy of SSc includes a number of different medication classes according to the disease presentations e. g., calcium channel blockers, ACE inhibitors, angiotensin receptor blockers, cyclophosphamide, methotrexate, endothelin-receptor antagonists, phospho-diesterase inhibitors, prostaglandins, nitrates, etc. Patient education for appropriate hygienic-dietary regimen and physiotherapeutic procedures should be considered. The therapeutic regimen should be defined and tailored by rheumatologist according to the form of the disease and the disease activity. A therapeutic effect of different medications in very early SSc or “prescleroderma” will be observed and reported in the future.


                                                                                  Dr Sevdalina Lambova, MD, PhD