Scleroderma in 2005—Have we made progress?

Professor Dame Carol Black DBE, CBE, MD, FRCP.

Summary of the talk presented at the Scleroderma Society's AGM/Conference on 30 th July 2005

Scleroderma belongs to a group of connective tissue diseases including rheumatoid arthritis, polymyositis, dermatomyositis, Sjogrens syndrome, sarcoidosis and vasculitis. These diseases have common constitutional symptoms, and common pathological processes including vascular and inflammatory components which lead to a process of fibrosis.

Scarring after injury from whatever trauma involves a process of fibrosis or laying down of collagen. This normally leads to repair and scar resolution. In scleroderma a process of excessive repair follows an initial insult which sets up an ongoing inflammatory response and continuous deposition of collagen or fibrosis in the surrounding tissues. Examples of excess collagen production in a scar include Dupytren's contracture of the hand and keloid scar formation.

Collagen is the most abundant protein in man. Its long intercalated strands are important. They act as a scaffold to hold the various tissues of an organ together. Without this we would look like a jellyfish!

Excess fibrosis is a contributory factor to other more common diseases in the UK such as cancer (119 thousand deaths per year), cardiovascular disease (238 thousand deaths per year), musculoskeletal diseases such as rheumatoid arthritis and neurological diseases such as amyloid.

Life expectancy is increasing. Between 1911 and 1915 63% of people died before the age of 60 years now it is 12%. Age related diseases affect the heart, lung, kidney and brain. They owe their loss of function in part due to replacement fibrosis occurring as part of the natural ageing process. Life style diseases such as diabetes and heart disease secondary to obesity, cirrhosis secondary to alcohol, chronic lung disease secondary to smoking, and HIV-AIDS associated pulmonary hypertension are all conditions which have accompanying fibrosis.

The economic burden to the NHS is colossal. Stroke and heart disease cost £3 billion per year, lung disease £2.6 billion, chronic kidney disease and dialysis £0.13 billion, liver cirrhosis £0.3 billion and scleroderma £90 million.

With each disease affected by fibrosis there are a few common features. There are a number of cells that provide the stimulus to fibrosis by producing growth factors and enzymes. These cells include endothelial cells lining our blood vessels, leucocytes or white blood cells, epithelial cells, pericytes and stellate cells. These activate fibroblasts to form myofibroblasts the active cells which produce the extracellular matrix including collagen. There is also thought to be a down regulation of the degradation of extracellular matrix thus producing a net effect of increased fibrosis.

The main subsets of scleroderma are localised and systemic. The former confined to the skin and occasionally the underlying muscle and bone particularly in children. The systemic form implies internal organ involvement and is mainly defined by the degree of skin thickening. Limited confined to the lower arms, face and feet while the diffuse form also involves the skin of the trunk.

Although the natural resolution of the skin in the diffuse form of the disease, in the majority of cases, often leads to softening of the skin to all except the hands and face. For some this is not always the case. We also know that the specific organs involved in each subset of scleroderma is well defined with gut disease, prominent vascular disease and isolated pulmonary hypertension typical of limited cutaneous systemic sclerosis (lcScl). Whilst renal crisis, predominant pulmonary and cardiac disease occurs in diffuse cutaneous systemic sclerosis (dcScl).

Of our total of 1,742 patients on our database here at the Royal Free Hospital, one third have the limited form 85% of whom are female. There is a similar predominance of females with the diffuse form.

From analysis of these patients over time we have noted that skin score or the amount of skin involved peaks within one year. There is an association between severe skin involvement and the amount of organ based complications of dcScl. Major organ based morbidity occurs within 3 years of disease onset in some 40-50% of cases. Treatment of dcScl must be as early and as efficient as possible. Disease modifying treatments for scleroderma, particularly dcScl, are targeted towards either the vascular component of the disease or the immunological component. We have no proven effective antifibrotic agents though we are looking at agents such as anti- TGF beta antibody and Bosentan.

Vascular remodelling agents include ACE inhibitors, angiotensin receptor blockers and Bosentan.

Immunological suppressors include Methotrexate, Cyclophosphamide, Anti-thymocyte globulin, Azathioprine, Mycophenolate Mofetil, Stem cell transplant, low dose steroids i.e. prednisolone less than 10 mgms/ day and the anti-TNF agents such as Infliximab used in rheumatoid arthritis.

For the limited disease what treatment target is appropriate? Do we need major drugs or do we need mainly a vascular approach? Perhaps we should go back even further and speculate on the causes of scleroderma. We know from scientific evidence that there are some well known triggers to this disease including various environmental ones including chemical agents and drugs. But do other factors take part such as viruses and what is the place of stress?

Heberden in 1959 stressed the importance of biochemistry, immunology and biophysics in the advancement of our knowledge of connective tissue diseases such as scleroderma. Recent examples of this research include, on the vascular side, the importance of endothelin, a product of endothelial cells and the discovery of a new important cell called the pericyte.

Immunologically there is a T cell subset that expresses an important growth factor called TGFbeta1.

With regard to the development of fibrosis we have discovered that; TGFbeta signalling goes wrong, that CTGF (connective tissue growth factor) is a potential driver of fibrosis, that endothelin acts as a stimulant to fibrosis, TIMP (tissue inhibitor of metalloproteinase) over expression builds up connective tissue and circulating fibrocytes play a possible role in collagen overproduction.

Endothelin is a small protein produced by the cells lining the blood vessels, the endothelium. It is a potent vasoconstrictor (it causes blood vessels to contract) by its action on smooth muscle cells but it also acts on fibroblasts initiating and maintaining the process of fibrosis. Endothelin is known to promote inflammation as well as act on the cells of the sympathetic nervous system.

Bosentan reduces the activity of endothelin by blocking the two receptors to which endothelin attaches itself to the surface of these cells. Bosentan is licensed for the treatment of pulmonary hypertension and trials have conclusively shown increased survival in such patients with scleroderma induced pulmonary hypertension. By its antagonistic action to endothelin it has the potential to prevent and treat digital ulcers and also lung fibrosis. It could also have an effect on kidney disease associated with scleroderma, but this has yet to be assessed.

Recent research has uncovered a new important cell called the pericyte which normally surrounds the endothelial cells lining small arteriole vessels. In scleroderma they are stimulated to migrate into the surrounding tissues by the action of platelet derived growth factor to become fibroblasts and myofibroblasts.

Thus increasing the thickness of the arterial wall with loss of diameter of the lumen in the lung leading to the development of pulmonary hypertension.

The advancement of the treatment of pulmonary hypertension has been revolutionised by the use of Bosentan but we are also well aware of the necessity for early recognition. We have lowered our threshold for cardiac catheterization in order to more accurately assess the true value of the pulmonary artery pressure. The Royal Free Hospital is a designated centre for referral of patients with pulmonary hypertension.

The therapeutic options include prostacyclin intravenously, subcutaneously, inhaled or orally, anticoagulants, oxygen, Sildenafil, combination therapy, septostomy and heart-lung transplantation.

Treatment of pulmonary fibrosis likewise includes early recognition and treatment of active disease. The results of the FAST trial which compared low dose prednisolone and monthly cyclophosphamide for 6 months followed by azathioprine or placebo. The results showed improvement in lung volumes in the actively treated patients with minimal side effects. The results of assessing the lung scans and other endpoints are awaited.

The BUILD studies involve the assessment of the effect of Bosentan on patients with interstitial pulmonary fibrosis and on patients with scleroderma associated pulmonary fibrosis. There are 132 patients in each class, a multicentred randomised trial whose results are eagerly awaited.

Finally our approach to the management of systemic sclerosis can be summarised as one of accurate diagnosis and staging of the disease. Proactive management by screening asymptomatic cases. Early detection of organ based pathologies. Improved risk stratification using genetic and serological markers. Treatment based on evolving pathogenesis. Targeted therapies directed against mediators such as cytokines which are the small chemical messengers which go between cells and finally the recognition that advances can only be made through multicentre trials and careful records kept by a central register such as that kept at the Royal Free Hospital.

Scleroderma News October 2005