Progressive systemic sclerosis

01Definition and overview

Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease in which injury to small blood vessels, autoantibodies and overactive fibroblasts lead to thickening of the skin and fibrosis of internal organs. "Progressive systemic sclerosis" is the older name; it is not always progressive, and many patients stabilise. Of the autoimmune rheumatic diseases it is the most often fatal.

It is classified by how far the skin thickening spreads, which also predicts the organs at risk:

The older name for limited disease, the CREST syndrome, lists its features: calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia. It is still heard, but it says nothing about the lungs. A few patients have the internal organ disease and antibodies without skin thickening: SSc sine scleroderma. Others have SSc overlapping with myositis, lupus or rheumatoid arthritis.

02Etiology and pathophysiology

Causes and risk

The cause is unknown. Genes contribute a little: relatives have a higher risk and some HLA and immune gene variants are commoner, but most cases are sporadic. Exposures linked to the disease or to scleroderma-like illnesses include silica dust, organic solvents such as trichloroethylene, vinyl chloride and the drug bleomycin.

Three processes

1. 1

   Vessel injury

   The first lesion is damage to the endothelium of small arteries, arterioles and capillaries: endothelin-1 constricts them, the intima proliferates and capillaries are lost. This gives Raynaud's, digital ulcers, the abnormal nailfold capillaries, pulmonary arterial hypertension and renal crisis.
2. 2

   Autoimmunity

   T cells and B cells are activated, and almost every patient makes antinuclear antibodies, each directed at one nuclear protein. Cytokines such as TGF-β and IL-6, and a type I interferon signature, drive inflammation, most of all early in diffuse disease.
3. 3

   Fibrosis

   Fibroblasts turn into myofibroblasts that lay down excess collagen in the dermis, lungs, gut wall and heart. Tissue starved of blood scars further.

The order is a simplification: the three overlap and feed each other, and in a given patient one may dominate, the vessels in long-standing limited disease, inflammation and fibrosis in early diffuse disease.

The antibodies

Antinuclear antibodies are found in more than 90 per cent of patients, usually as one of a set of disease-specific antibodies that rarely occur together. Testing and interpretation are in humoral immunity in rheumatic diseases.

03Clinical features

Raynaud's phenomenon

Raynaud's phenomenon is an exaggerated spasm of the digital arteries in the cold or with emotion: the fingers go white, then blue, then red and painful as blood returns. It affects more than 95 per cent of patients with SSc. Most people with Raynaud's, though, have primary Raynaud's, a harmless disorder of vascular tone.

Nailfold capillaroscopy, a magnified look at the capillaries at the base of the nail, is the key test. The scleroderma pattern moves from early (a few giant capillaries and haemorrhages) to active and then late (loss of capillaries, avascular areas and branched new vessels). Raynaud's with abnormal capillaries and an SSc antibody is often the first stage of systemic sclerosis; most such patients develop the disease over the following years, so they are followed. Puffy fingers in a patient with Raynaud's and a positive ANA are a red flag for referral.

Skin

The skin passes from oedematous (puffy, itchy fingers) to indurative (tight, shiny skin that cannot be pinched up) and, after years, atrophic. Tight fingers, sclerodactyly, lead to flexion contractures. The face loses its lines and the mouth narrows (microstomia). Other signs are telangiectasia, calcinosis (chalky deposits that can ulcerate) and "salt and pepper" pigmentation.

The extent of thickening is measured by the modified Rodnan skin score: 17 body areas, each scored by pinching from 0 (normal) to 3 (severe), a maximum of 51. In diffuse disease the score usually rises for the first one to three years, then often plateaus and softens. Rapid early progression signals a poor prognosis and the risk of renal crisis.

Digital ulcers

About half of patients have digital ulcers at some time: painful ischaemic ulcers on the fingertips, or ulcers over the knuckles and calcinosis. They heal slowly, get infected (sometimes with osteomyelitis) and can end in gangrene and loss of a fingertip. A cold, white, painful finger that does not recover on warming is critical digital ischaemia and needs same-day hospital treatment.

Gut

The gut is involved in about 90 per cent of patients, from mouth to anus. Fibrosis and atrophy of smooth muscle cause:

• oesophageal dysmotility: reflux, dysphagia, strictures, Barrett's oesophagus, and aspiration that may worsen lung disease;
• gastric antral vascular ectasia ("watermelon stomach"), a cause of iron deficiency anaemia;
• bloating, bacterial overgrowth with diarrhoea and malabsorption, pseudo-obstruction, constipation and faecal incontinence.

Lungs

• Interstitial lung disease, usually a nonspecific interstitial pneumonia pattern, is seen on HRCT in about half of patients and is clinically important in about a quarter to a third. Risk is highest in diffuse disease, with anti-Scl-70 antibodies, in men and in the first five years. It causes exertional breathlessness, a dry cough and fine basal crackles.
• Pulmonary arterial hypertension affects about 8 to 12 per cent, more often in long-standing limited disease with anti-centromere antibodies. Breathlessness and fatigue come late, so it is found by screening. A falling DLCO with a preserved FVC is the early clue. Pulmonary hypertension can also come from lung fibrosis or from stiffness of the left ventricle, and these are treated differently.

Kidneys: scleroderma renal crisis

Scleroderma renal crisis affects about 4 to 5 per cent of all patients: about 7 to 9 per cent of those with diffuse disease and fewer than 1 in 100 with limited disease, mostly within the first four years. Narrowing of the small renal arteries cuts renal blood flow, the juxtaglomerular cells release renin, and the pressure rises in a vicious circle.

Heart and the rest

Patchy myocardial fibrosis causes arrhythmias, conduction block, diastolic dysfunction, heart failure and some sudden deaths; small pericardial effusions are common. Arthritis, tendon friction rubs (a leathery creak over moving tendons, a sign of active diffuse disease), myopathy, resorption of the fingertip bones, fatigue, sicca symptoms and erectile dysfunction are common.

04Diagnosis and management

Making the diagnosis

The diagnosis is clinical, backed by the antibodies and capillaroscopy. The 2013 ACR/EULAR classification criteria, written for research, add up points:

A total of 9 or more classifies a patient as having SSc; the criteria are not applied when the fingers are spared or another disease explains the picture.

Thick skin that spares the fingers, without Raynaud's, suggests a mimic: eosinophilic fasciitis, scleroedema (diabetes), scleromyxoedema (a paraprotein), nephrogenic systemic fibrosis (gadolinium in kidney failure) or graft-versus-host disease.

Baseline tests and screening

The DETECT algorithm, for patients with SSc for more than three years, a DLCO below 60 per cent and an FVC of at least 40 per cent, combines simple tests (FVC to DLCO ratio, telangiectasia, anti-centromere antibodies, NT-proBNP, serum urate and right axis deviation on the ECG) with echocardiography to decide who needs right heart catheterisation. Catheterisation makes the diagnosis: pulmonary arterial hypertension is a mean pulmonary arterial pressure above 20 mmHg with a wedge pressure of 15 mmHg or less and a pulmonary vascular resistance above 2 Wood units. Patients with anti-RNA polymerase III antibodies are checked for cancer, breast cancer in particular, around the time of diagnosis, because the cancer and the scleroderma often appear within a couple of years of each other.

Treatment by organ

No drug cures SSc or reverses established fibrosis, so each organ is treated, early, by a team. Everyone gets education, hand and mouth exercises, skin care, warm clothing and, for smokers, help to stop.

Steroids and immunosuppression

Glucocorticoids help arthritis, myositis and early inflammatory skin disease, but high doses can trigger renal crisis. They are kept to the lowest dose for the shortest time, ideally below about 10 to 15 mg of prednisolone a day, and the blood pressure and kidney function are checked often while they are taken.

Mycophenolate (up to 3 g a day for two years) is the usual first drug for lung fibrosis: it was as effective as oral cyclophosphamide and better tolerated. Nintedanib, an antifibrotic tyrosine kinase inhibitor, slowed the yearly fall in FVC by about 40 per cent against placebo, with or without mycophenolate; it is licensed for SSc lung disease in Europe, and causes diarrhoea. Tocilizumab, an IL-6 receptor blocker, preserved lung function, a secondary outcome, in a trial that missed its skin endpoint; it is approved for SSc lung disease in the United States but not in the EU, where it is used off label. Rituximab matched cyclophosphamide in lung disease of connective tissue diseases.

Autologous stem cell transplantation

For selected patients with early, rapidly progressive diffuse disease and a poor prognosis, without advanced heart or lung damage, autologous haematopoietic stem cell transplantation after high-intensity immunosuppression (usually cyclophosphamide) improves long-term survival and organ function compared with monthly cyclophosphamide. The cost is a treatment-related mortality that reached about 1 in 10 in the first year of an early trial, lower in later ones with stricter selection, so it is done only in experienced centres.

Scleroderma renal crisis

1. 1

   Recognise

   New hypertension, a rising creatinine and haemolysis in a patient with early diffuse disease, often on steroids. Admit, measure the pressure often, check the film, platelets, LDH and urine, and look for heart failure and encephalopathy.
2. 2

   ACE inhibitor

   Start an ACE inhibitor immediately, usually short-acting captopril, raising the dose every few hours to a day to bring the pressure down steadily, by about 10 to 20 mmHg a day, without sudden falls. Calcium channel blockers, alpha-blockers or intravenous vasodilators are added if needed. Steroids are reduced where possible.
3. 3

   Keep going

   The ACE inhibitor is continued even if the creatinine rises or dialysis is needed. More than half of patients need dialysis, and a good share of them can stop it as the kidney recovers over months to about two years; transplantation waits until then.

Before ACE inhibitors, renal crisis was the commonest cause of death in SSc. They are not started to prevent it, because there is no evidence that they do: in observational studies, patients already taking one when a crisis struck did worse, perhaps because the early rise in pressure was masked, though other factors may explain it.

Localised scleroderma (morphoea)

Morphoea is a separate disease, commoner in children and women, that hardens the skin and sometimes the tissue beneath: oval ivory plaques with a lilac edge, generalised morphoea, linear scleroderma (along a limb, or on the forehead, "en coup de sabre", which can stunt growth in a child) and deep morphoea. There is no Raynaud's, no sclerodactyly, no internal organ disease and no SSc antibody. Topical steroids or phototherapy treat plaques; linear, deep or generalised disease needs methotrexate, often with steroids at first.

05Epidemiology

A pooled analysis of studies worldwide found a prevalence of about 18 per 100,000 and an incidence of about 1.4 per 100,000 a year, higher in North America than elsewhere and higher in recent studies than in older ones, perhaps partly because milder disease is now recognised. Women are affected about five times as often as men, usually between 30 and 50; it is rare in children. Men and people of African descent more often have severe, diffuse disease.

06Prognosis

The course is set mainly by the subset and the antibodies. Limited disease is usually slow, and the risk is pulmonary arterial hypertension after many years. In diffuse disease the danger is in the first three to five years, when the skin spreads and the lungs, kidneys and heart are injured; after that the skin often softens and the disease becomes quieter, but established organ damage remains.

About half of deaths in SSc are caused by the disease itself. In a large European cohort, lung fibrosis caused about a third of these, pulmonary arterial hypertension a quarter and the heart a quarter, while renal crisis has fallen far down the list since ACE inhibitors. The other deaths come from infection, cancer and cardiovascular disease. In recent European cohorts about 85 per cent of patients are alive five years after diagnosis and about 70 to 80 per cent at ten years, more in limited disease than in diffuse disease; older pooled studies give lower figures. A worse outlook comes with diffuse disease, a high or rising skin score, a falling FVC or DLCO, pulmonary arterial hypertension (worse than the idiopathic form), heart involvement, proteinuria, older age at onset and male sex.