1.2.2 Systemic scleroderma (SSc)

Diffuse systemic sclerosis.

Incidence varies between 0.1-4.3/100000; F:M = 4:1, the onset is typically from 35 to 50 years old.

Systemic scleroderma, also called systemic sclerosis (SS c), is an autoimmune, chronic and progressive multisystemic disease leading to aberrant deposition of collagen and extracellular matrix involving the skin, vessels and internal organs (lung, heart, gastrointestinal tract, kidney).

SSc is a multifactorial disease, characterized by an immunogenetic predisposition (HLA association), an alteration of the vascular regulation, humoral and cellular immune activation with antibody production, and of tissue sclerosis with altered collagen and extracellular matrix proteins synthesis and deposition.

Early events in vascular dysregulation include impaired angiogenesis and endothelial cell injury with perivascular leak and edema. Activation of endothelial cells leads to an increased expression of adhesion molecules and binding of circulating inflammatory cells, with an elevation of vascular endothelial growth factor and the receptors. Impairment of perivascular smooth muscle cells with dysregulation in vasoconstriction and vasodilatation. The result of this process is an intimal proliferation that conducts to a luminal occlusion, hypoxia and an augmented synthesis of profibrotic cytokines, fibroblast activation, and collagen production. Sclerosis is the final process in the tissue damage. The clinical presentation includes Raynaud’s phenomenon and digital ulcers, caused by a reversible vasospasm and an irreversible arterial damage secondary to intimal proliferation and luminal obstruction. The immune dysregulation involves some specific autoantibodies (anti-centromere, anti-topoisomerase I, and anti-RNA polymerase III), which bind tissues involved in SSc. Lymphocytic infiltrates are composed of T and B cells. Oligoclonal T-cell expansion has been seen in lesional skin, indicating an antigen-driven response, and T-cells demonstrate a Th2 predominance with an augmented production of IL-4 and IL-13. Th17 and IL-17 are also implicated in the immune response and interferons type I and II have been observed in blood and skin. Extracellular matrix dysregulation has also been observed in SSc, in particular, sclerosis is the final process in the tissue damage. An excessive deposition of collagen, proteoglycans, fibronectin, fibrillins and adhesion molecules are the players of this process. Transforming growth factors β (TGF-β) and connective tissue growth factor are also involved, in particular TGF-β is responsible for maintenance of collagen synthesis.

Characteristic of SSc is the presence in the serum of auto-antibodies. These include anti-nuclear antibodies (ANA) with the nucleolar or speckled patterns, that are positive in 90-95% of cases.

• The anti-centromere antibodies are present in the limited SSc type, with a discrete speckled pattern (20-38%).

• Among the extractable nuclear antibodies (ENA), the anti-topoisomerase I antibodies (Scl70) in the diffuse type, with speckled pattern (15-42%). The anti-RNA polymerase III antibodies are present in the rapidly progressive, diffuse skin disease (5-31%), and are associated with renal involvement. The U3-RNP (fibrillarin) with a nucleolar pattern, are present in 4-10% of the diffuse form.

The Th/T0 and the U1-RNP with a speckled pattern in the localized form (4-10%). The anti-PM/Scl with a nucleolar pattern in the localized and overlap form (4-11%). The Ku and U11/U12 RNP antibodies with a speckled pattern with a positivity of less than 4%.

The early lesions are characterized by a dense superficial and deep perivascular and periadnexal lymphocytic infiltrate with plasma cells.

The late lesions show an increased collagen (sclerosis), generally in the absence of or with limited. Systemic scleroderma is histologically indistinguishable from morphea.

Inflammation, with loss of adnexal structures (alopecia, decreased sweating). Indurated lesions are histologically characterized by an augmented deposition of collagen, atrophic eccrine and pilosebaceous glands, loss of subcutaneous fat, and a sparse dermal lymphocytic infiltrate. The adnexal glands are atrophic, trapped by the deposition of collagen.

Direct immunofluorescence is usually negative.

SSc has a chronic and progressive evolution. Patient with a diffuse form tend to have a more rapidly progressive course and worse prognosis than those with the localized form. In patients with diffuse SSc, 5- and 10-year survival rates are 70% and 55%, respectively, whereas in patients with the localized form, survival rates are 90% and 75%, respectively. The prognosis correlates with the extent of skin involvement, which itself is a surrogate for visceral organ involvement.

The complications are joint contractures, trophic ulcers, esophageal stenosis, Barrett esophagus, pulmonary fibrosis with pulmonary hypertension, renal failure with renal hypertension and renal crisis, cardiac failure, cardiac rhythm disorders and right heart overload. Major causes of death are pulmonary arterial hypertension, pulmonary fibrosis, gastrointestinal and cardiac disease, and scleroderma renal crisis.

he diagnosis is based on the clinical features, the histology, and on the immune serology.

• The provocation testing for Raynaud’s phenomenon consists in the immersion of the hands in ice water and measuring skin temperature normalization.

• Nail fold capillary microscopy is useful to document characteristic capillary abnormalities. In early stages shows ectasia of capillaries; in active stages, mega-capillaries and haemorrhages, whereas a reduced density and tufting of capillaries are observed in later stages.

• In the case of pulmonary involvement, it is important to perform pulmonary function tests, high-resolution CT scan, electrocardiography, echocardiogram, and a 6-minute walking test to assess right heart overload.

• In the case of gastrointestinal problems, a scintigraphy or high-resolution manometry of esophagus and pH testing, a gastroscopy for the diagnosis of dysphagia and reflux esophagitis should be performed.

• In the case of renal involvement, blood pressure monitoring, renal function tests, 24-hour urine collection analysis, kidney ultrasound; kidney biopsy is performed in selected cases.

• In the case of musculoskeletal symptoms, creatinine kinase (CK) and myositis-specific antibodies measurement, electromyography (EMG), magnetic resonance imaging (MRI), and in some cases a muscle biopsy may be necessary (overlap with dermatomyositis).

• Joint evaluation may rely on x-ray and ultrasounds, and is important to exclude overlapping with rheumatoid arthritis (rheumatoid factor, anti-citrullinated protein antibodies).

Differential diagnosis should be established with sclerodermoid disorders, particularly mucinoses such as scleredema and scleromyxedema. A full-thickness biopsy of the skin is required for establishing the differential diagnosis. Other disorders to be considered include eosinophilic fasciitis, chronic graft-vs-host-disease, generalized morphea, fibroblastic rheumatism, and overlap syndromes. Toxin-mediated sclerodermoid disease which may enter in differential diagnosis with SSc include nephrogenic systemic fibrosis, eosinophilia-myalgia syndrome, toxic oil syndrome, and silicosis. Drug- induced sclerosis has been associated with exposure to bleomycin, pentazocine, or L-tryptophan. Some genetic skin disorders may also present with SSc-like features including Werner syndrome, restrictive dermopathy, Hutchinson-Gilford progeria, Stiff skin syndrome, phenylketonuria, Weill-Marchesani syndrome, multicentric osteolysis-nodulosis-arthropathy, primary hypertrophic osteoarthropathy, ataxia-teleangiectasia, Huriez syndrome and H syndrome.

Therapy in SSc is focused to treat the organ involvement and may require a multidisciplinary approach. Multiple interventions are highly effective to minimize symptoms and to slow the progression on organ damage.

Treatment is primarily supportive, and based on protection from cold, physical therapy (to retain motility and circulation), skin protection and care.

When progressive and inflammatory, the treatment is based also on systemic immunosuppression. Glucocorticoids alleviate stiffness and aching in early inflammatory-stages, but their use is associated with an increased risk of scleroderma renal crisis. Cyclophosphamide reduces the progression of SSc associated with lung disease, with stabilization and, rarely, modest improvement of pulmonary function, high resolution computed tomography (HRCT) findings, respiratory symptoms, and skin induration. Methotrexate is useful for the skin involvement. Mycophenolate mofetil for the skin and lung involvement. Tocilizumab (monoclonal antibody directed against the IL-6 receptor that blocks IL-6 signaling, rituximab (monoclonal antibody directed against the mature B cell marker CD20), abatacept (fusion protein that inhibits T-cell co-stimulation and function) and intravenous immunoglobulin are used in selected cases.

There is no effective anti-fibrotic treatment. Pirfenidone and nintedanib are used in patients with idiopathic pulmonary fibrosis.

Calcium antagonist (amlodipine, nifedipine and diltiazem), angiotensin II receptor blockers (losartan), α1-adrenergic receptor blockers (prazosin), 5-phosphodiesterase inhibitors (sildenafil), topical nitroglycerine, and intermittent IV infusions of prostaglandins are useful for Raynaud’s phenomenon, to control episodes, and prevent and enhance the healing of ischemic complications, and slow the progression of obliterative vasculopathy. Patients with Raynaud’s phenomenon unresponsive to these therapies may require the addition of low-dose aspirin and dipyridamole to reduce platelet aggregation. In patients with ischemic digital tip ulcerations, the endothelin-1 receptor antagonist bosentan reduces the risk of new ulcers. Long-term therapy with statins and antioxidants may retard the progression of vascular damage and obliteration. Pulmonary arterial hypertension benefits from bosentan and sildenafil.

There is limited evidence-based information for the treatment of cardiac complications of SSc, which should be guided by specialists experienced in their diagnosis and management. While selective beta blockers such as metoprolol can precipitate vasospasm, non-dihydropyridine calcium channel blockers can be used for rate control in atrial arrhythmias, and non-selective alpha/beta blockers such as carvedilol for improving myocardial perfusion and left ventricular systolic function.

Monitoring: all patients require screening at routine intervals for the possibility of major organ involvement including interstitial lung disease, pulmonary hypertension, cardiac and kidney complications.