Autoimmune connective tissue diseases • 1037

MMF has been used successfully with high-dose glucocorticoids Pathophysiology

for renal involvement with results similar to those of pulsed The cause of SScl is not completely understood. There is evidence
cyclophosphamide but fewer adverse effects. Belimumab in for a genetic component and associations with alleles at the HLA
combination with standard therapy significantly decreases disease locus have been found. The disease occurs in all ethnic groups
activity in SLE patients and is safe and well tolerated. Its role and race may influence severity. Isolated cases have been reported
in patients with renal and neurological disease is still under in which an SScl-like disease has been triggered by exposure to
investigation. silica dust, vinyl chloride, epoxy resins and trichloroethylene. There
Rituximab has been reported as being effective in selected is clear evidence of immunological dysfunction: T lymphocytes,
cases, though randomised controlled trials have not shown especially those of the Th17 subtype, infiltrate the skin and there
significant overall efficacy. is abnormal fibroblast activation, leading to increased production
Maintenance therapy of extracellular matrix in the dermis, primarily type I collagen. This
results in symmetrical thickening, tightening and induration of the
Following control of acute disease, a typical maintenance regimen
skin (scleroderma). Arterial and arteriolar narrowing occurs due
is oral prednisolone in a dose of 40–60 mg daily, gradually
to intimal proliferation and vessel wall inflammation. Endothelial
reducing to 10–15 mg/day or less by 3 months. Azathioprine
injury causes release of vasoconstrictors and platelet activation,
(2–2.5 mg/kg/day), methotrexate (10–25 mg/week) or MMF
resulting in further ischaemia, which is thought to exacerbate the
(2–3 g/day) should also be prescribed. The long-term
fibrotic process.
aim is to continue the lowest dose of glucocorticoid and
immunosuppressant to maintain remission. Cardiovascular risk Clinical features
factors, such as hypertension and hyperlipidaemia, should be Skin
controlled and patients should be advised to stop smoking.
Initially, there is non-pitting oedema of fingers and flexor tendon
Patients with SLE and the antiphospholipid antibody
sheaths. Subsequently, the skin becomes shiny and taut, and
syndrome, who have had previous thrombosis, require life-long
distal skin creases disappear. There can be capillary loss. The
warfarin therapy. SLE patients are at risk of osteoporosis and
face and neck are often involved, with thinning of the lips and
hypovitaminosis D, and should be screened with biochemistry
radial furrowing. In some patients, skin thickening stops at this
and DXA scanning accordingly.
stage. Skin involvement restricted to sites distal to the elbow
Systemic sclerosis or knee (apart from the face) is thus classified as lcSScl (Fig.
24.48). Involvement proximal to the knee and elbow and on the
Systemic sclerosis (SScl) is an autoimmune disorder of connective trunk is classified as ‘diffuse disease’ (dcSScl).
tissue, which results in fibrosis affecting the skin, internal organs
and vasculature. It is characterised typically by Raynaud’s Raynaud’s phenomenon
phenomenon, digital ischaemia (Fig. 24.47), sclerodactyly, and This is a universal feature and can precede other features by
cardiac, lung, gut and renal disease. The peak age of onset is many years. Involvement of small blood vessels in the extremities
in the fourth and fifth decades and overall prevalence is 10–20 may cause critical tissue ischaemia, leading to localised distal
per 100 000, with a 4 : 1 female-to-male. It is subdivided into skin infarction and necrosis.
diffuse cutaneous systemic sclerosis (dcSScl: 30% of cases)
and limited cutaneous systemic sclerosis (lcSScl: 70% of cases).
Musculoskeletal features
Some patients with lcSScl have calcinosis and telangiectasia. Arthralgia and flexor tenosynovitis are common. Restricted hand
The prognosis in dcSScl is poor (5-year survival about 70%). function is due to skin rather than joint disease and erosive
Features that associate with a poor prognosis include older arthropathy is uncommon. Muscle weakness and wasting can
age, diffuse skin disease, proteinuria, high ESR, a low gas result from myositis.
transfer factor for carbon monoxide (TLCO) and pulmonary
Gastrointestinal involvement
hypertension.
Smooth muscle atrophy and fibrosis in the lower two-thirds
of the oesophagus lead to reflux with erosive oesophagitis.
24

Fig. 24.47 Systemic sclerosis. Hands showing tight, shiny skin,

sclerodactyly, flexion contractures of the fingers and thickening of the left Fig. 24.48 Typical facial appearance showing telangiectasias in
middle finger extensor tendon sheath. localised cutaneous systemic sclerosis.
1038 • RHEUMATOLOGY AND BONE DISEASE

Dysphagia and odynophagia may also occur. Involvement of the may help patients with symptoms of dysmotility/
stomach causes early satiety and occasionally outlet obstruction. pseudo-obstruction.
Recurrent occult upper gastrointestinal bleeding may indicate • Hypertension. Aggressive treatment with ACE inhibitors is
a ‘watermelon’ stomach (antral vascular ectasia; up to 20% of needed, even if renal impairment is present.
patients). Small intestine involvement may lead to malabsorption • Joint involvement. This may be treated with analgesics
due to bacterial overgrowth and intermittent bloating, pain or and/or NSAIDs. If synovitis is present and both RA (i.e. an
constipation. Dilatation of bowel due to autonomic neuropathy ‘overlap’ condition, which needs treatment on its own
may cause pseudo-obstruction with nausea, vomiting, abdominal merit) and OA have been ruled out, low-dose methotrexate
discomfort and distension, often worse after food (symptoms can can be of value.
mimic those of an acute abdomen and can lead to erroneous • Progressive pulmonary hypertension. Early treatment with
laparotomy). bosentan is required. In severe or progressive disease,
heart–lung transplant may be considered.
Pulmonary involvement • Interstitial lung disease. Glucocorticoids and (pulse
Pulmonary hypertension complicates long-standing disease intravenous) cyclophosphamide are the mainstays of
and is six times more prevalent in lcSScl than in dcSScl. It treatment in patients who have progressive interstitial lung
usually presents with insidiously evolving exertional dyspnoea disease.
and signs of right heart failure. Interstitial lung disease is common
in patients with dcSScl who have topoisomerase 1 antibodies Mixed connective tissue disease
(Scl70). Dyspnoea can evolve slowly over time or rapidly in
occasional cases. Mixed connective tissue disease (MCTD) is a condition in which
some clinical features of SScl, myositis and SLE all occur in the
Renal involvement same patient. It commonly presents with indolent puffiness of the
One of the main causes of death is hypertensive renal crisis, fingers (the appearance is between that of SpA-type dactylitis
characterised by rapidly developing accelerated phase and sclerodactyly) with Raynaud’s phenomenon and myalgias.
hypertension (p. 514) and renal failure. Hypertensive renal crisis Most patients have anti-RNP antibodies. Management focuses
is much more likely to occur in dcSScl than in lcSScl, and in on treating the components of the disease (see other sections).
patients with topoisomerase 1 and RNP antibodies.
Primary Sjögren’s syndrome
Investigations
Primary Sjögren’s syndrome (PSS) is characterised by lymphocytic
As SScl can affect multiple organs, routine haematology, renal,
infiltration of salivary and lacrimal glands, leading to glandular
liver and bone function tests and urinalysis are essential. ANA is
fibrosis and exocrine failure. The typical age of onset is between
positive in about 70%. About 30% of patients with dcSScl have
40 and 50, with a 9 : 1 female-to-male ratio. The disease may
antibodies to topoisomerase 1 (Scl70). About 60% of patients
occur with other autoimmune diseases (secondary Sjögren’s
with lcSScl syndrome have anticentromere antibodies (p. 991).
syndrome).
Chest X-ray, transthoracic echocardiography and lung function
tests are recommended to assess for interstitial lung disease Clinical features
and pulmonary hypertension (low corrected transfer factor may The eye symptoms, termed keratoconjunctivitis sicca, are due to
indicate early pulmonary hypertension). High-resolution lung CT is a lack of lubricating tears, which reflects inflammatory infiltration
recommended if interstitial lung disease suspected. If pulmonary of the lacrimal glands. Conjunctivitis and blepharitis are frequent,
hypertension is suspected, right heart catheter measurements and may lead to filamentary keratitis due to binding of tenacious
should be arranged at a specialist cardiac centre. A barium mucous filaments to the cornea and conjunctiva. Oral involvement
swallow can assess oesophageal involvement. A hydrogen breath manifests as a dry mouth (xerostomia). There is a high incidence
test can indicate bacterial overgrowth (p. 808). of dental caries and high risk of dental failure. Other sites of
extraglandular involvement are listed in Box 24.64. Often the
Management
most disabling symptom is fatigue. There may be an association
No treatments are available that halt or reverse the fibrotic with inflammatory small-joint OA (clinical suspicion, though formal
changes that underlie the disease. The focus of management, studies have not been done). Sialadenitis, osteoarthritis and
therefore, is to slow the effects of the disease on target organs. xerostomia (SOX) syndrome has been described; this may occur
• Raynaud’s phenomenon and digital ulcers. Avoidance of independently of PSS or, more likely, constitute a mild form.
cold exposure, use of thermal insulating gloves/socks Both interstitial lung disease and interstitial nephritis (sometimes
and maintenance of a high core temperature all help. If complicated by renal tubular acidosis) require proactive screening.
symptoms are persistent, calcium channel blockers, PSS is associated with a 40-fold increased lifetime risk of
losartan, fluoxetine and sildenafil have efficacy. Courses of lymphoma, though the complication is still very rare.
intravenous prostacyclin are used for severe disease and
critical ischemia (e.g. 6–8 hours daily for 5 days). The Investigations
endothelin-1 antagonist bosentan is licensed for treating The diagnosis can be established by the Schirmer tear test,
ischaemic digital ulcers, and digital tip tissue health can be which measures tear flow over 5 minutes using absorbent
maintained with regular use of fucidin–hydrocortisone cream. paper strips placed on the lower eyelid; a normal result is more
• Gastrointestinal complications. Oesophageal reflux should than 6 mm of wetting. Staining with rose bengal may show
be treated with proton pump inhibitors and anti-reflux punctate epithelial abnormalities over the area not covered by
agents. Rotating courses of antibiotics may be required for the open eyelid. If the diagnosis remains in doubt, it can be
bacterial overgrowth (e.g. rifaximin, a tetracycline and confirmed by demonstrating focal lymphocytic infiltrate in a minor
metronidazole), while metoclopramide or domperidone salivary gland biopsy. Most patients have an elevated ESR and