Scleroderma and related disorders Epidemiology and diagnostic criteria

Scleroderma and related disorders Epidemiology and diagnostic criteria: Systemic sclerosis (SSC) is a multisystem disease of unknown cause. It can be localized to the skin or more commonly involve the skin and internal organs. Generalized scleroderma predominantly affects women (3: 1) with peak incidence at 30 -50 years of age, and is associated with hyperproduction of connective tissue, notably collagen, widespread microvascular damage and inflammation

The spectrum of scleroderma and sclerodermalike syndromes includes: • Raynaud’s phenomenon- 97% of cases • Scleroderma localized • Scleroderma systemic: limited cutaneous and diffuse cutaneous, • Chemical induced-environmental, drugs • Scleroderma-like disease-metabolic, immunological, localized sclerosis, and visceral disease

• The are 3 main abnormalities in scleroderma. A vasculopathy is found that manifests clinically as Raynaud’s phenomenon, and pathologically as endothelial cell injury. Vascular injury may be the primary event either by vasomotor instability or microvascular intimal proliferation and vessel obliteration. Intravascular pathology in the form of increase platelet activity, red cell rigidity, and thrombosis may also be a factor. Inflammation is also seen. Fibrosis in the skin and internal organs is the hallmark and nonorgan-specific

Chemical agents have been implicated in the development of scleroderma, including: • Silica • Organic chemicals: aliphatic hydrocarbons – vinyl chloride, naphtha; aromatic hydrocarbons-benzene, toluene, epoxy resin, toxic oil, paraffins • Drugs: hydroxytryptophan, carbidopa, fenfluramine, bleomycin, cocaine

General symptoms • The skin is initially oedematous and then becomes tight several months after the patient develops Raynaud’s phenomenon. Diffuse swelling and stiffness of the fingers occurs. Later the skin becomes atrophic. • Early involvement of other organs occurs with general symptoms of lethargy, anorexia and weight loss.

• Cutaneous features of scleroderma In early stage there may be non-pitting oedema associated with Raunaud’s. The skin becomes taut, the epidermis thins, hair growth ceases, and skin creases disapppear and classic changes of scleroderma become more pronounced. When limited to the fingers alone the term sclerodactyly is applied. The classic changes remain static for many years.

• Raynaud’s phenomenon • The classical features are episodic pallor of the digits due to ischaemia, followed by cyanosis, and then redness and suffusion with pain and tingling. • The last stage of redness is a reactive hyperemia following the return of blood. Pathological changes seen on capillaroscopy include nailfold capillary dilatation, haemorrhage, and dropout.

CREST syndrome • • CREST syndrome include: calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly and skin changes in the fingers, telangiectasia.

The gastrointestinal tract Mouth: Caries. Sicca syndrome. Oesophagus: Hypomotility. Reflux. Srtictures. Stomach: Gastroparesis. Gastric ulcer. Small bowel: Hypomotility. Malabsorption Large bowel: Hypomotility and atony of the rectum and sigmoid • Pancreatic insufficiency and biliary cirrhosis may require • Anaemia due to vascular lesions in the gastrointestinal mucosa • • •

Lung disease • • • Pulmonary fibrosis Pleurisy Bronchoectasis Pneumothorax Pulmonary hypertension Pulmonary disease is now the major cause of death. Parenchymal lung disease is found in 2/3 of cases and pulmonary hypertension in 50%.

Renal disease • Both epithelial and endothelial damage occur before becoming clinically detectable. • The most characteristic pattern of involvement is the renal hypertensive crisis, generally occurring within the first 5 years of disease onset. The incidence may by as high as 20 % and associated with microangiopathic haemolitic anaemia, encephalopathy, and convulsions. Mortality may reach 10%.

Other organ involment in systhemic sclerosis • Thyroid gland: spectrum of autoimmune disease. • Hypothyroidism common • Liver: primary billary cirrhosis. Obstructive jaundice, calcification, nodules. • Nervous system: Trigeminal neuralgia. Capral tunnel syndrome. Sensomotor neuropathy. Autonomic neuropathy • Genital: Cavernosal artery fibrosis causing impotence

Investigations • • Full blood count Urea and electrolytes Creatinine clearance and urinary protein Barium swallow/Gl endoscopy Chest radiograph. Lung function tests Electrocardiogram. Doppler echocardiography High-resolution CT lung scan function Autoantibodies: antitopoisomerase-1 (30%), RNA polymerase antibodies I, III(25%). Reumatoid factor (30%)

Antifibrotic and immunosuppressive therapies • A number of general systemic therapies are under investigation though none have demonstrated marked benefit. • Currently no treatment can induce complete remission of the disease. • D-penicillamine was been widely used in the past but a single randomized controlled trial has shown no benefit.

Antimetabolite and alkylating immunomodulatory agents being evaluated for use in treatment of scleroderma • Ciclosporin - Beneficial on skin sclerosis, watch for renal crisis, reduce dose if on calciumchannel blockers • Methotrexate – Control trial in progress for evaluation in Scleroderma • Cyclophosphamide – Efficacy on lung fibrosis • Mycophenolate – Improvement in skin disease • These drugs have been shown to be beneficial only in open studies.

Symptomatic treatment • In severe disease, education, counselling and family support are essential • Exercises and lubricants may limit contractures. • Raynaud’s may be improved by hand warmers, oral and parenternal vasodilators ( calciumchannel blockers, prostacyclin analogues and calcitonin gene related peptide). Lumbar and digital sympathectomy may help. • Oesophageal symptoms can improved by ptoton-pump inhibitors and prokinetic drugs

• Symptomatic malabsorption requires lowresidue diets, nutritional supplements and antibiotics. • Renal involvement requires intensive hypertensive control (with ACE inhibitors or calcium antagonists) • Pulmonary vascular disease may initially respond to vasodilatators. • Pulmonary fibrosis does not significantly respond to current therapies.

Prognosis • Scleroderma has highest mortality of any autoimmune disease. Estimates of 5 years mortality range from 34 -73%. • Patients with renal crisis have been estimated to have a 50% mortality, although the use of renal replacement therapies may have reduced this. • Advances in the understanding of mechanisms leading to pulmonary hypertension has led to new therapies that, with time, show significant impact in slowing disease progression.