E
WAM
ORGIEL1, J
OANNAK
RYWEJKO1, P
IOTRW
ILAND2Immunological Aspects of Systemic Sclerosis
and New Strategies in Therapy
Immunologiczne aspekty twardziny układowej
i nowe możliwości terapeutyczne
1Department of Rheumatology and Internal Diseases Silesian Piasts University of Medicine in Wrocław, Poland 2Department of Balneology Silesian Piasts University of Medicine in Wrocław, Poland
Adv Clin Exp Med 2008, 17, 4, 441–446 ISSN 1230−025X
REVIEWS
© Copyright by Silesian Piasts University of Medicine in Wrocław
Abstract
Systemic sclerosis is a chronic autoimmune disease characterized by multiorgan symptoms such as skin thicken− ing, pulmonary fibrosis, pulmonary arterial hypertension, renal crisis, and gastrointestinal complications. There are two major subtypes of systemic sclerosis: limited and diffuse. The pathogenic process includes inflammatory cell activation, vascular damage, and fibroblast activation. Recent research has focused on understanding its patholog− ical pathways. A new strategy in therapy is developing substances which interfere with the main pathogenic path− ways and which will be able to improve prognostics in systemic sclerosis. The efficacy of current therapies is restricted (Adv Clin Exp Ned 2008, 17, 4, 441–446).
Key words:systemic sclerosis, vascular damage, cyclophosphamide, fibrosis, pathogenesis.
Streszczenie
Twardzina układowa jest autoimmunologiczną, przewlekłą chorobą, która charakteryzuje się zajęciem narządów wewnętrznych. Poważne następstwa choroby to włóknienie skóry i płuc, nadciśnienie płucne, kryza nerkowa oraz zaburzenia układu pokarmowego. Istnieją dwie postacie kliniczne choroby: twardzina układowa ograniczona i uo− gólniona. Na patogenezę choroby składają sie trzy główne procesy: aktywacja immunologiczna, uszkodzenie na− czyń oraz aktywacja fibroblastów. Ostatnie badania koncentrują się na zrozumieniu szlaków patogenetycznych twardziny układowej. Nowymi kierunkami w leczeniu tej choroby wydają się substancje, które zablokują specy− ficzny szlak patologiczny choroby, co poprawi rokowanie. Skuteczność obecnie stosowanych leków jest niestety ograniczona (Adv Clin Exp Ned 2008, 17, 4, 441–446).
Słowa kluczowe:twardzina układowa, uszkodzenie naczyń, cyklofosfamid, zwłóknienie, patogeneza.
Systemic sclerosis (SSc) is a chronic, autoim− mune, life−threatening disease characterized by excessive accumulation of extracellular matrix within connective tissue. It leads to the failure of some organs, especially the skin, heart, lung, kid− ney, and digestive tract. The clinical features of systemic sclerosis differ among patients. Nearly all patients have skin lesions, i.e. skin hardening and thickening. The first symptom of SSc is usual− ly Raynaud’s phenomenon. After exposure to cold, the skin of the fingers changes color to white, blue, and red. This sometimes precedes the diag− nosis by even several years. The next symptoms
are musculoskeletal pain, fatigue, and swelling, usually of the hands, but sometimes also other parts of the body. Many patients develop digital ulcers. Scleroderma patients have a high risk of internal organ involvement; they may suffer from interstitial lung disease, heart complications (such as conduction abnormalities, pericardial effusion), pulmonary hypertension, kidney complications with scleroderma renal crisis (SCR), and gastroin− testinal disorders (such as esophageal disease, bloating, diarrhea, or constipation).
criterion is the extent of skin affection. Limited systemic sclerosis is characterized by the skin thickening distally from the elbows and knees. The lesions involve mostly the face and hands. It starts with Raynaud’s phenomenon and progres− sion of the disease is usually slow. It may even last for many years. Previously, this type of systemic sclerosis was called CREST syndrome after its cardinal features: calcinosis, Raynaud’s phenome− non, esophageal dysmotility, sclerodactyly and telangiectasia. In this type of systemic sclerosis, anticentromere autoantibodies are usually detected in the serum. Diffuse systemic sclerosis is charac− terized by skin thickening in areas distal as well as proximal to the elbows and knees, with or without changes in the face and trunk. The prognosis in this type is worse than in limited systemic sclero− sis (lSSc). Patients with anti−SCL70 or topoiso− merase antibodies have a high risk of pulmonary fibrosis [1, 2].
Etiology
The etiology of systemic sclerosis is still not clear. Genetic factors play a role in all autoimmune diseases. The strong female predilection for sys− temic sclerosis indicates an influence of hor− mones. Many epidemiological studies suggest an association with some inciting agents such as cytomegalovirus (CMV) infection or toxic expo− sure (silica, tryptophan) [3].
Pathogenesis
The pathophysiology of this disorder is also unclear, but there are three general hypotheses based on the roles of immunological cells, endothelium cells, and fibroblasts. All reactions are united in one process leading to fibrosis and organ damage and can be seen as a pathophysio− logical triangle. Immunological cell activation and inflammation, vascular damage, and excessive collagen production and deposition are the mile− stones in the pathogenesis of SSc. Different path− ways cause disorders in various organs, so the treatment strategy is targeted to the affected organs. Unfortunately, there is no therapy dealing with all the symptoms and complications of sys− temic sclerosis [1–3].
Immune activation
Evidence of immune system activation is the presentation of autoantibodies in systemic sclero− sis. It is also clear that the profile of the antibodies
is connected with the clinical pattern and progno− sis in systemic sclerosis. Another sign is the pres− ence of immune−cell infiltration in the skin and pulmonary tissue. These are usually macrophages and T cells. Good clinical examples for immune activation are early scleroderma with typical hand skin changes (puffy fingers) and alveolitis, the first stage of intestinal lung disease. The presence of alveolitis is confirmed by examination of the bron− choalveolar lavage (BAL) fluid, where an increase in cellularity, especially macrophages, is observed. A “ground glass” pattern of opacification on high− resolution computer tomography (HRCT) scan− ning was associated with inflammatory alveolitis. Many studies have demonstrated increased amounts of IL−2, IL−4, and IL−6 in patients with systemic sclerosis, and recent studies concentrate on the level of profibrotic chemokines in the blood and tissue, for example TGFβ (transforming growth factor beta) and CTGF (connective tissue growth factor) [3]. Activation of the immune cells leads to the release of proinflammatory and profi− brotic cytokines and growth factors. This may cause impairment of endothelial cell function, pro− liferation of fibroblast, and collagen production [4].
Treatment Targeting
Immune Activation
Experience with the immunosuppressive treat− ment of other inflammatory connective tissue dis− eases led to analogous therapy trials in systemic sclerosis. Several studies suggested the efficacy of immunosuppressive drugs in SSc. In two random− ized placebo−controlled trials, methotrexate (MTX) was given orally or parenterally. A dose of 15–25 mg has been reported in the treatment of diffuse systemic sclerosis. A single−center study in the Netherlands (17 patients treated with MTX and 12 placebo patients) and a multicenter Canadian study (35 MTX−treated patients and 36 placebo patients) showed improvement in skin score; in the Canadian study there was an additional tendency to improve lung capacity, but not significantly [5, 6].
ients). In the first trial, 158 systemic sclerosis patients with interstitial lung disease confirmed by bronchoalveolar lavage fluid and HRCT were treated with oral CYC (≤2 mg/kg/day) or placebo for 1 year. Patients in the oral CYC group had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health−related quality of life. The improvement in forced vital capacity (FVC) was 2.5% and in TLC (total lung capacity) 4%. It reached statistical sig− nificance, but it should be noted that this value was very small [9]. In another study the authors showed that abnormal BAL cellularity identified patients with more advanced interstitial lung dis− ease, but was not a predictor of disease progre− ssion or response to CYC [10]. In the second ran− domized trial with CYC, 45 patients received 6 monthly infusions of CYC and low−dose pred− nisolone followed by oral azathioprine (AZA) or placebo. This study showed only a trend towards statistical significance for improvement of pul− monary function test [11]. Azathioprine is usually used as a supplementary therapy after CYC in interstitial lung disease because of its lower toxi− city and better tolerance. In one retrospective analysis of AZA treatment, a positive effect on skin score and pulmonary function test was observed [12].
Cyclosporine A was tested in the treatment of systemic sclerosis. There were no randomized control trials with cyclosporine, but there were a few retrospective studies. Cyclosporine (dose: 2.5–5 mg/kg/day) treatment studies have shown beneficial effects on skin score. But there are also results indicating its toxicity (rise in serum creati− nine, onset of hypertension) [13, 14].
An immunosuppressive treatment is autolo− gous stem−cell transplantation (ASCT). At the moment there are two trials in progress: the US SCOT (Scleroderma Cyclophosphamide or Trans− plant) and the multicenter European ASTIS (Autologous Stem Cell Transplantation Interna− tional Scleroderma). Patients with diffuse severe systemic sclerosis (high skin score, internal organ involvement, disease duration < 5 years) have been considered for this type of therapy. ASCT improves survival and has positive effects on skin condition, lung, kidney and heart [15]. These first experiences seem to be successful, but stem−cell transplant−related toxicity and mortality remain worrisome.
Mycophenolate mofetil (MMF) is widely used in nephrology as a long−term therapy to prevent solid−organ transplant rejection. It seems to have good tolerance and low toxicity. It has recently been used in lupus nephritis. In a few recent stud− ies, treatment with MMF has shown improvement
in skin thickening and beneficial effect in alveoli− tis [16].
The use of corticosteroids in systemic sclero− sis is controversial. They have anti−inflammatory effects and are usually used in intestinal lung dis− ease as a co−medication with CYC with good results [17]. They can also be indicated in myosi− tis related to systemic sclerosis. The use of corti− costeroids is a risk factor in scleroderma renal cri− sis; it is recommended not to use corticosteroids in doses > 10 mg/day [18].
Eicosanoids play a key role in the regulation of inflammation. A few recent studies showed that there is an overproduction of proinflammatory and profibrotic leukotrienes in the lungs and skin of patients with systemic sclerosis and upregulation of anti−inflammatory and antifibrotic lipoxins. Using leukotriene inhibitors or lipoxin analogues can be a new approach to the treatment of systemic sclerosis [19, 20].
Vascular Damage
Many investigators consider that endothelial damage could be the earliest lesion in systemic sclerosis. The first clinical manifestations of vas− cular dysfunction are Raynaud’s phenomenon and abnormal nail−fold capillaries; the next symptoms are digital ulcers, renal crisis, and pulmonary hypertension. Recent studies suggest that when endothelium cells are damaged, circulating leuko− cytes become activated and migrate into the inti− mal layer. The activated leukocytes secrete inflam− matory mediators and cytokines (TGFβ, CTGF, PDGF, endothelin, etc.), which promote fibroblast proliferation, overproduction of extracellular matrix, and fibrosis. This leads to alteration in endothelial function, thickening of intima, narrow− ing of the vessel lumen, and reduced blood flow. Endothelial damage causes the overproduction of vasoconstrictors such as endothelin and impaired release of vasodilatators such as prostacyclin and nitric oxide. The impaired production of vasoac− tive substance leads to ischemia, then to endothe− lial damage, increased inflammation, and fibrosis [1–3].
Treatment Targeting
Vascular Pathology
20% without ACE−I [21]. Is it still not clear if ACE−I should be used in all scleroderma patients for prevention of renal crisis or perhaps only in patients treated with corticosteroids. AT1−inhi− bitors probably also have a positive effect.
The next important group of “vascular drugs” are analogues of prostacycline. Epoprostenol improves exercise capacity and hemodynamic measures in arterial hypertension, but a limitation of its use is drug administration by continuous intravenous route [22]. Iloprost and treprostinil represent more stable analogues of prostacyclin; they are used in intravenous infusion or inhalation with a good clinical efficacy.
Bosentan, an inhibitor of endothelin receptor, is recommended in the therapy of pulmonary hypertension. In randomized control trials it has shown functional and survival rate improvements. Bosentan treatment prevents the formation of new ulcers [23]. Sitaxentan is a selective oral endothe− lin A receptor antagonist with proven efficacy in the treatment of pulmonary hypertension [24]. Sildenafil is an inhibitor of NO degradation with a potential good influence on endothelial and vas− cular damage. Its effect in the treatment of pul− monary hypertension and digital ulcers was report− ed by Badesch et al. [25]. Other treatments used in the therapy of systemic sclerosis with potential effect on vascular injury include calcium channel blockers, nitroglycerin, statins, serotonin inhi− bitors, and anticoagulant drugs.
Fibroblast Activation
Fibrosis is the last process in the pathogenesis of systemic sclerosis, and it leads to organ damage. Activated fibroblasts excessively produce collagen and extracellular matrix, which results in fibrosis. The skin and lungs are the major organs that are severely affected by fibrosis. There are many cytokines and other factors with profibrotic effect. TGFβis a cytokine directly responsible for fibrob− last proliferation, induction of extracellular matrix production, and inhibition of its degradation. CTGF is induced in activated fibroblasts by TGFβ. CTGF enhances and supports the fibrotic process [1–3].
In the last few years, great progress has been made in explaining the pathophysiological path− ways of fibrosis, indicating an important role of
platelet−derived growth factor and its receptor on fibroblasts. Investigators have described the pres− ence of autoantibodies against PDGF receptor in all scleroderma patients. These antibodies stimu− late PDGF receptor, inducing signaling cascades which lead to increased type 1 collagen gene expression and its deposition [26].
Treatments Targeting Fibrosis
In in vitro experiments, D−penicillamine shows an effect in disturbing the synthesis and connection of collagen fractions. D−penicillamine was earlier often used in the therapy of systemic sclerosis. A multicenter randomized control trial compared high−dose (750–1000 mg/day) versus low−dose (250 mg/day) D−penicillamine. The two groups were not different in mortality, onset of new renal crises, and skin score. This study did not answer the question whether D−penicillamine is an effective therapy of systemic sclerosis [27]. The benefit of D−penicillamine treatment did not show improvement in any randomized trial and remains doubtful.Relaxin is a pregnancy−related hormone that has connective tissue remodeling and antifibritic effects. It could play a potential role in the therapy of systemic sclerosis. In randomized control trials the effectiveness of relaxin was not confirmed [28]. New experiments are focused on understand− ing the molecular pathology pathways in systemic sclerosis. The therapy of the future includes some substances that can selectively block mediators in signaling pathways. TGFβ antagonist, CTGF antagonist, and PDGF−receptor signaling inhibitor are being tested; the first reports have been pub− lished and further studies are underway. The ther− apy of systemic sclerosis is still a great challenge for researchers and clinicians [29].
The authors concluded that 1) currently, there is no clear standard or even recommendation for the therapy of systemic sclerosis, 2) randomized, placebo−controlled trials on systemic sclerosis are difficult to conduct because of the heterogeneity in clinical symptoms, multifactorial pathogenesis, and relative rarity of the disease, 3) improved understanding of the pathophysiology pathways and molecular biology of systemic sclerosis are the keys to develop effective therapy.
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Address for correspondence:
Ewa Morgiel
Department of Rheumatology and Internal Diseases Silesian Piasts University of Medicine
Wrocław Poland
Tel. (+48) 694122543
E−mail: [email protected]
Conflict of interest: None declared
