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Autoimmune Rheumatic Diseases 303
changes including a heliotrope (purple) discoloration of the eyelids and scaly
erythematous plaques over the knuckles (Gottron’s papules). Other features
include arthralgia, dysphagia resulting from oesophageal muscle involvement, and Raynaud’s phenomenon. DM is associated with an increased
incidence of underlying malignancy.
Investigations
• The definitive test to establish the diagnosis is a muscle biopsy, which
also excludes other causes of myopathy. There is inflammatory cell
infiltration and necrosis of muscle cells.
• Serum muscle enzymes (creatine kinase, aminotransferases, aldolase)
are elevated.
• Anti-Jo antibodies (anti-tRNA synthetase) are positive.
• ESR is usually not raised.
• Electromyography (EMG) shows characteristic changes.
• MRI can demonstrate areas of muscle inflammation.
Management
Oral prednisolone is the treatment of choice: 0.5–1.0 mg/kg body weight
continued for at least 1 month after myositis has become clinically and
enzymatically inactive and then tapered gradually down. Immunosuppressive
therapy (azathioprine, methotrexate, ciclosporin) is required if there is disease relapse on steroid tapering.
Sjögren’s syndrome
Sjögren’s syndrome is characterized by immunologically mediated destruction of epithelial exocrine glands, especially the lacrimal and salivary glands.
It predominantly affects middle-aged women.
Clinical features
The main features are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Clinical clues are difficulty eating a dry biscuit and an absence of pooling
of the saliva when the tongue is lifted. It occurs as an isolated disorder (primary
Sjögren’s syndrome) or in association with another autoimmune disease (secondary Sjögren’s syndrome), commonly rheumatoid arthritis or SLE. Other features of
Sjögren’s syndrome are arthritis, Raynaud’s phenomenon, renal tubular defects
causing diabetes insipidus and renal tubular acidosis, pulmonary fibrosis, vasculitis and an increased incidence of non-Hodgkin’s B-cell lymphoma.
Investigations
• Serum autoantibodies: antinuclear (in 80% of patients), anti-Ro (60%–90%)
and rheumatoid factor in primary Sjögren’s syndrome.
• Labial gland biopsy shows characteristic changes of lymphocyte
infiltration and destruction of acinar tissue.
304 Rheumatology
• A positive Schirmer test (a standard strip of filter paper is placed on the
inside of the lower eyelid; wetting of less than 10 mm in 5 minutes is
positive) confirms defective tear production.
Management
Treatment is symptomatic with artificial tears and saliva replacement solutions.
‘Overlap’ syndrome and undifferentiated autoimmune rheumatic disease
An overlap syndrome combines features of more than one ARD.
Undifferentiated ARD is the term used when patients have evidence of
autoimmunity and some clinical features of ARDs but not enough to make a
diagnosis of any individual ARD.
SYSTEMIC INFLAMMATORY VASCULITIS
Vasculitis is inflammation of the blood vessel walls and can be seen in many
diseases, including SLE, RA, polymyositis and some allergic drug reactions.
The term ‘systemic vasculitides’ describes a group of multisystem disorders in
which vasculitis is the principal feature and classification is based on the size
of the vessels affected (Table 7.11) and the presence or absence of antineutrophil cytoplasmic antibodies (ANCAs). They are all associated with anaemia
and a raised ESR and all are rare, except for giant cell (temporal) arteritis.
Table 7.11 Classification of systemic vasculitis
Large (aorta and its major branches)
Giant cell arteritis/polymyalgia rheumatica
Takayasu’s arteritis
Medium (main visceral vessels, e.g. renal, coronary)
Polyarteritis nodosa
Kawasaki disease (affects children <5 years)
Small (small arteries, arterioles, venules and capillaries)
ANCA positive
Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
ANCA negative
Henoch–Schönlein purpura
Cutaneous leucocytoclastic vasculitis
Essential cryoglobulinaemia
ANCA, antineutrophil cytoplasmic antibody.
Systemic Inflammatory Vasculitis 305
Polymyalgia rheumatica and giant cell arteritis
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are systemic
illnesses affecting patients older than 50 years. Both are associated with the
finding of GCA on temporal artery biopsy. Some patients may have symptoms
and signs limited to PMR or to GCA throughout the course of their illness,
whereas other patients may have manifestations of both.
Clinical features
PMR causes an abrupt onset of stiffness and intense pain in the muscles
of the neck and shoulder, and hips and lumbar spine. Symptoms are worst
in the morning. Significant objective weakness is uncommon. There may
be constitutional symptoms with malaise, fever, weight loss and anorexia.
Arteritic involvement by inflammation is most frequently noticed in the
superficial temporal arteries and causes headache, tenderness over the
scalp or temple (combing the hair may be painful), and claudication of
the jaw when eating. GCA affecting the vertebrobasilar, and sometimes the
carotid, circulation may result in stroke. The most devastating complication
of GCA is sudden loss of vision (which may be permanent) due to involvement of the ophthalmic artery. Early recognition and treatment is therefore
essential.
Investigations
Investigations typically show a very high ESR (around 50–120 mm/h) and
CRP with a normochromic, normocytic anaemia. Temporal artery biopsy is
performed if GCA is suspected and should be performed before or within
a week of starting corticosteroids. Lesions are patchy, so a negative biopsy
does not exclude the condition.
Management
Treatment is with corticosteroids, which produce a dramatic reduction in
symptoms of PMR within 24–48 hours of starting treatment. Corticosteroid
treatment should reduce the risk of patients who have PMR developing GCA.
In GCA, corticosteroids are obligatory because they significantly reduce the
risk of irreversible visual loss and other focal ischaemic lesions, but much
higher doses are needed than in PMR. If GCA is suspected, it may not be
possible to arrange an ultrasound scan or temporal artery biopsy rapidly. In
these circumstances, treatment should not be delayed, especially if there
have already been episodes of visual loss or stroke.
Prednisolone 10–15 mg/day is given for PMR and 60 mg/day for GCA.
The dose is reduced by weekly decrements of 5 mg. Once 10 mg is reached,
a reduction of 1 mg every 2–4 weeks is usually sufficient. The dose is
titrated against symptoms and the ESR. Prophylaxis against steroid-induced
osteoporosis should be given (p. 313). The disease may relapse when steroid
treatment is stopped.
306 Rheumatology
Takayasu’s arteritis
This condition is rare, except in Japan. Vasculitis involving the aortic arch and
other major arteries causes hypertension, absent peripheral pulses, strokes
and cardiac failure. Treatment is with corticosteroids.
Polyarteritis nodosa
Polyarteritis nodosa (PAN) predominantly affects middle-aged men. Its
occasional association with hepatitis B antigenaemia suggests a vasculitis
secondary to immune complex deposition. There is a necrotizing arteritis
associated with microaneurysm formation, thrombosis and infarction. Clinical
features include fever, malaise, weight loss, myalgia, mononeuritis multiplex,
abdominal pain (resulting from visceral infarcts), myocardial infarction and
heart failure (resulting from coronary arteritis), renal impairment and hypertension. The lungs are rarely involved (cf. ANCA-positive vasculitides). The
diagnosis is made on angiography (microaneurysms in hepatic, intestinal or
renal vessels) or biopsy of an affected organ, often the kidney. Treatment is
with corticosteroids, usually in combination with immunosuppressive drugs
(e.g. azathioprine).
Kawasaki disease
Kawasaki disease is an acute systemic vasculitis involving mediumsized vessels, affecting mainly children under 5 years of age. It is very
frequent in Japan and an infective trigger is suspected. Fewer than 10%
of cases occur in adults. The characteristic clinical features are fever
lasting longer than 4 days, bilateral conjunctival congestion, dry red lips
and oral cavity, cervical lymphadenopathy, rash and redness of the palms
and soles. Cardiovascular effects including pancarditis and coronary
arteritis, leading to aneurysms or dilatation visible on echocardiography,
MRI or angiography may occur. Treatment is with high-dose intravenous
immunoglobulin. There is no evidence that steroid treatment improves
the outcome.
Microscopic polyarteritis (polyangiitis)
This condition involves the lungs and the kidney, where it results in haemoptysis, haematuria, proteinuria and progressive renal failure. Other features
include arthralgia and purpuric rashes. Diagnosis is by renal biopsy and
measurement of serum perinuclear (p)-ANCA, present in 60% (see Table 7.2).
Treatment is similar to PAN.
Diseases of Bone 307
Eosinophilic granulomatosis with polyangiitis
This is rare and characterized by a triad of asthma, eosinophilia and a
systemic vasculitis affecting the peripheral nerves and skin (nodules,
petechiae, purpura) but kidney involvement is uncommon. Treatment is
similar to PAN.
Henoch–Schönlein purpura
This condition is most commonly seen in children and presents as a purpuric
rash, mainly on the legs and buttocks. Abdominal pain, arthritis, haematuria
and nephritis also occur. It is characterized by vascular deposition of IgAdominant immune complexes, and the onset is often preceded by an acute
upper respiratory tract infection. Recovery is usually spontaneous.
Cryoglobulinaemic vasculitis
Cryoglobulins are immunoglobulin and complement components that precipitate reversibly in the cold. Types include essential cryoglobulinaemia
(no underlying disease) or associated with infection (e.g. hepatitis B and C,
human immunodeficiency virus (HIV)) or autoimmune disease. There is
involvement of the skin (purpura, arthralgia, leg ulcers), kidneys (glomerulonephritis) and nervous system (polyneuropathy). Treatment is similar to PAN.
Behçet’s disease
This rare multisystem chronic disease of unknown cause is most common
in Turkey, Iran and Japan. It is characterized by recurrent oral ulceration.
Diagnosis is clinical and requires the presence of oral ulceration and any two
of the following: genital ulcers, eye lesions (uveitis, retinal vascular lesions),
skin lesions (erythema nodosum, papulopustular lesions) or a positive skin
pathergy test (skin injury, e.g. needle prick, leads to pustule formation within
48 hours). Other features include arthritis, gastrointestinal ulceration with
pain and diarrhoea, pulmonary and renal lesions, meningoencephalitis and
organic confusional states. Treatment is with immunosuppressive therapy
(steroids, azathioprine, ciclosporin) or, occasionally, thalidomide. Anti-TNF
agents can be used to control severe uveitis and serious manifestations such
as neurological and gastrointestinal Behçet's disease.
DISEASES OF BONE
Bone normally consists of 70% mineral and 30% organic matrix (mostly
type 1 collagen fibres). The mineral component consists mostly of a complex
crystalline salt of calcium and phosphate called hydroxyapatite. Although
major skeletal growth occurs in childhood, adult bone is continuously being
308 Rheumatology
remodelled, with bone formation and resorption. Two major cell types are
involved in bone remodelling:
• Osteoblasts produce matrix and regulate its mineralization. Bone
resorption is regulated through the balance of the stimulatory RANKL
and its antagonist, OPG. Osteoblasts express receptors for parathyroid
hormone (PTH), oestrogen, glucocorticoids, vitamin D, inflammatory
cytokines and the transforming growth factor-β family, all of which may
influence bone remodelling.
• Osteoclasts remove and resorb the mineral phase and collagen matrix in
response to RANKL.
Control of calcium and bone metabolism
Vitamin D and PTH are the major factors that control plasma calcium concentration and bone turnover. Bone metabolism is also controlled by calcitonin,
glucocorticoids, sex hormones, growth hormone and thyroid hormone. The
effect of different bone disorders on calcium, phosphate, PTH and alkaline
phosphatase (ALP) are given in Table 7.12.
Vitamin D
The metabolism and actions of vitamin D are shown in Fig. 7.6.
Parathyroid hormone
PTH is secreted from chief cells of the parathyroid gland. Plasma levels rise in
response to a fall in serum ionized calcium. The effects are several, all serving to increase plasma calcium and decrease plasma phosphate:
Table 7.12 Biochemistry results in bone disorders
Calcium Phosphate ALP PTH
Osteoporosis
Osteomalacia
Paget’s disease
Primary
hyperparathyroidism
Secondary
hyperparathyroidism
Hypoparathyroidism
↑, increased; ↓, decreased;
ALP, alkaline phosphatase; N, normal; PTH, parathyroid hormone.
N N N N
↓ (may be N) N (may be ↓)
N N
↑ ↓
↓/N
↓ ↑
N
↑
N
N/↑
N
May be raised
(secondary
hyperparathyroidism)
N
↑
↑
↓
Skin
Diseases of Bone 309
Sunlight (UV)
Diet 7-DehydrocholesterolCholecalciferol
)
(D
3
Liver
+ve
PTH
PO
25-Hydroxy-D
3
Kidney
2+
Gut Ca
absorption
Bone calcification
1,25-Dihydroxy-D
3
Bone resorption
Fig. 7.6 The metabolism and actions of vitamin D. The primary source of
vitamin D in humans is photoactivation in the skin of 7-dehydrocholesterol
to cholecalciferol (D3), which is then converted first in the liver to
25-hydroxyvitamin D and subsequently in the kidney to the much more active
form, 1,25-dihydroxycholecalciferol (1,25(OH)2D3). Regulation of the latter step
is by parathyroid hormone, phosphate and feedback inhibition by 1,25(OH)2D3.
This step can also occur in lymphomatous and sarcoid tissue, resulting in
the hypercalcaemia that may complicate these diseases. Ca2+, calcium; PO4,
phosphate; PTH, parathyroid hormone; UV, ultraviolet.
• Increased osteoclastic resorption of bone
• Increased intestinal absorption of calcium
• Increased synthesis of 1,25-(OH)2D3 (see Fig. 7.6)
• Increased renal tubular reabsorption of calcium.
Hyper- and hypoparathyroidism are covered in Chapter 14 (pp. 631–636).
4
Osteoporosis
This reduction in bone mass and micro-architectural deterioration of bone
tissue leads to bone fragility and an increased risk of fracture. Osteoporotic
fractures (fragility fractures, low-trauma fractures) occur without major
310 Rheumatology
Table 7.13 Risk factors for osteoporosis and fragility fracture
BMD-dependent BMD-independent
Female sex Increasing age
Caucasian/Asian Previous fragility fracture
Hypogonadism Family history of hip fracture
Immobilization Low body mass index
Chronic liver disease Smoking
Chronic renal disease Alcohol abuse
Chronic obstructive pulmonary disease Glucocorticoid therapy
Gastrointestinal disease High bone turnover
Low dietary calcium intake Increased risk of falling
Vitamin D insufficiency Rheumatoid arthritis
Drugs (heparin, ciclosporin, anticonvulsants)
Endocrine disease (Cushing’s syndrome,
hyperthyroidism, hyperparathyroidism)
Other diseases (diabetes mellitus, mastocytosis, multiple myeloma)
BMD, bone mineral density.
trauma. Osteoporosis is defined as a BMD of more than 2.5 standard
deviations (SDs) below the young adult mean value (T-score ≤ − 2.5). Values
between 1 and 2.5 SDs below the young adult mean are termed ‘osteopenia’.
There are additional risk factors identifiable from the history and examination which increase the fracture risk independently of BMD (Table 7.13) and
thus assessment of fracture risk based solely on BMD will miss individuals
at risk for fracture.
Aetiology
Osteoporosis is related to either inadequate peak bone mass and/or ongoing
bone loss. Peak bone mass is achieved in early adult life and depends on
genetic factors, nutritional factors, sex hormone status and physical activity.
Then age-related bone loss occurs with an accelerated loss in women starting around the time of the menopause. The risk factors for osteoporosis are
those that cause a reduction in peak bone mass attained in adult life or those
that cause increased bone loss (see Table 7.13).
Clinical features
Symptoms of osteoporosis are the result of fractures, which typically occur
at four sites: the thoracic and lumbar vertebrae, proximal femur, and distal
radius (Colles’ fracture). Thoracic vertebral fractures may lead to kyphosis
and loss of height (‘widow’s stoop’).
Diseases of Bone 311
Table 7.14 Indications for dual-energy X-ray absorptiometry
scanning
Radiographic osteopenia
Previous fragility fracture (in those aged <75 years)
Glucocorticoid therapy (in those aged <65 years)
Body mass index below 19 kg/m
2
Maternal history of hip fracture
BMD-dependent risk factors in Table 7.13
In patients presenting with height loss and/or kyphosis, lateral thoracic spine X-ray is
the initial investigation and shows loss of anterior vertebral body height and wedging
due to fracture.
BMD, bone mineral density.
Investigations
• DXA is the gold standard in measurement of bone density, usually of the
lumbar spine and proximal femur. Osteoporosis is diagnosed when the
BMD T-score falls to − 2.5 or below.
• Radiology (X-rays) demonstrates fractures but is insensitive for detecting
osteopenia.
• Serum biochemistry is normal (see Table 7.12).
• Secondary causes of osteoporosis (Table 7.13) should be looked for by
appropriate blood tests in men and pre-menopausal women.
Assessment of fracture risk
This should take into account both BMD and clinical risk factors (see
Table 7.13). Indications for DXA scanning are listed in Table 7.14. A previous
fracture is the strongest risk factor for further fractures. Patients with a previous fragility fracture or a BMD T-score less than or equal to −2.5 should be
considered for treatment. It is vital to recognize, however, that the majority of
fragility fractures occur in women with a T-score better than −2.5. In these
patients an assessment for future fracture risk should be made; this can be
performed using clinical judgement by an experienced physician or using a
formal risk calculator, e.g. FRAX; http://www.shef.ac.uk/FRAX/). It integrates
clinical risk factors with femoral neck BMD (hip BMD may also be used in
women). It is a guide only, and will not be helpful in all patients, e.g. those
with low spinal BMD but normal femoral neck. In patients aged over 75
years with a fragility fracture, DXA scanning is often not necessary prior to
treatment for osteoporosis. FRAX does not identify the level of fracture risk at
which treatment should be started and this will vary depending partly on the
medical resources of the country. In the UK, osteoporosis treatment is costeffective for a 4% 10-year risk of hip fracture and 3% in the USA.
312 Rheumatology
Management
Prevention and treatment. New vertebral fractures require bed rest for
1–2 weeks and strong analgesia. Muscle relaxants (e.g. diazepam 2 mg three
times daily) are also given for pain relief. Non-spinal fractures are treated by
conventional orthopaedic means. Lifestyle advice includes stopping smoking,
reducing alcohol intake, adequate intake of calcium (700–1000 mg/day,
1500 mg post-menopausally) and vitamin D (400–800 IU/day) and regular
weight-bearing exercises. In the elderly, physiotherapy and assessment of
home safety are performed to reduce the risk of falls. Hip protectors may
reduce the risk of hip fracture in residential care.
Pharmacological intervention
• Bisphosphonates (e.g. alendronate, risedronate, zoledronate, p. 317)
are first-line treatment in most patients with osteoporosis. They inhibit
osteoclasts (and therefore bone resorption), increase bone mass at the
hip and spine, and most have been shown to reduce fracture incidence.
Bisphosphonates may be associated with upper gastrointestinal
side effects such as oesophagitis. Osteonecrosis of the jaw is a rare
complication of high-dose intravenous bisphosphonates in patients who
have malignant disease. As prolonged suppression of bone turnover is
linked with atypical femoral fractures, it is currently advised to reassess
bisphosphonate treatment after 5 years.
• Denosumab is a human monoclonal antibody to RANKL administered as
a single subcutaneous injection every 6 months. It is an anti-resorptive
agent which increases BMD and reduces fractures at the spine, hip and
other non-vertebral sites. Adverse effects are infrequent.
• Selective oestrogen-receptor modulators (SERMs), such as raloxifene
and bazedoxifene, activate oestrogen receptors on bone while having no
stimulatory effect on the endometrium (cf: hormone replacement therapy
(HRT), see below). They have been shown to reduce BMD loss at spine
and hip, though fracture rates are reduced only in the spine. Side effects
are leg cramps, flushing, increased risk of thromboembolism (similar to
HRT) and stroke.
• Recombinant human parathyroid peptide 1–34 (teriparatide) and
recombinant human parathyroid hormone 1–84 stimulate bone formation
and are given by daily subcutaneous injection. They are indicated for
severe osteoporosis or in women who are intolerant of, or fail to respond
to, other therapies. They have only been shown to reduce vertebral
fractures. A side effect is hypercalcaemia.
• Oestrogen therapy (HRT) is reserved for early post-menopausal women
with perimenopausal symptoms. This is because of adverse effects on
breast cancer and cardiovascular risk (see p. 611).
• Testosterone is given to men with biochemical evidence of hypogonadism.
• Strontium ranelate is reserved for specialist use because of concerns
about cardiovascular safety.