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Crystal Arthritis 293
Acute gout presents typically in a middle-aged male with sudden onset
of severe pain, swelling and redness of the metatarsophalangeal joint of the
big toe. The signs of inflammation may extend beyond the joint, giving the
impression of cellulitis. The attack may be precipitated by dietary or alcoholic
excess, by dehydration or by starting a diuretic. Acute attacks must be differentiated from other causes of monoarthritis, particularly septic arthritis.
Presentation can also be with a polyarticular inflammatory arthritis, particularly in elderly women on long-term diuretics.
Chronic tophaceous gout presents with large, smooth, white deposits
(tophi) in the skin and around the joints, particularly on the ear, the fingers
and on the Achilles tendon.
Investigations
The clinical picture is often diagnostic, as is the rapid response to NSAIDs
or colchicine.
• Joint fluid microscopy is the most specific and diagnostic test, revealing
long, needle-shaped crystals which are negatively birefringent under
polarized light. This is not usually necessary in clinical practice.
• Serum uric acid is usually raised, but may be normal during an acute
attack – the levels subsequently increase and should be rechecked
several weeks after. However, the diagnosis is excluded if the serum uric
acid is in the lower half of the normal range.
• Serum urea and electrolytes for signs of renal impairment.
Management
Acute attacks are treated with anti-inflammatory drugs:
• NSAIDs (p. 315), e.g. diclofenac (75–100 mg immediately, then 50 mg
every 6–8 hours). After 24–48 hours reduced doses are given for a
further week.
• Colchicine (1000 μg immediately, then 500 μg every 6–12 hours) but
only if NSAIDs are not tolerated or ineffective. It has a narrow therapeutic
window and is extremely toxic in overdose as it causes multiorgan failure
and death.
• Corticosteroids: oral prednisolone or intramuscular or intra-articular
depot methylprednisolone is used.
Further attacks are prevented by reducing serum uric acid levels. Obese
patients should lose weight, alcohol consumption should be reduced and
drugs such as thiazides and salicylates should be withdrawn. A diet which
reduces total calorie and cholesterol intake and avoids purine-rich foods
(offal, some fish and shellfish and spinach) is advised. Patients with frequent
attacks (more than two per year) despite dietary changes or with gouty
tophi or renal impairment are treated with allopurinol. Treatment is not
started within 1 month after an acute attack and NSAIDs or colchicine are
given for 4weeks before and after starting allopurinol, as it may induce an
acute attack. Allopurinol inhibits xanthine oxidase (an enzyme in the purine
294 Rheumatology
breakdown pathway) and reduces serum urate levels rapidly. Febuxostat is
a non-purine analogue inhibitor of xanthine oxidase that is well tolerated
and as effective as allopurinol. Pegloticase, a pegylated recombinant uricase
given intravenously, lowers urate levels dramatically but is typically reserved
for patients with severe, refractory gout in whom target serum urate concentrations are not achieved or who cannot tolerate oral urate-lowering therapy.
Asymptomatic hyperuricaemia is not usually treated unless plasma levels
are very high or in patients with cancer to prevent the tumour lysis syndrome
(p. 251).
Pseudogout (pyrophosphate arthropathy)
Deposition of calcium pyrophosphate dihydrate in articular cartilage and
periarticular tissue produces the radiological appearance of chondrocalcinosis (linear calcification parallel to the articular surfaces). Shedding of
crystals into a joint produces acute synovitis that resembles acute gout,
except that it is more common in elderly women and usually affects the
knee or wrist. In young people it may be associated with haemochromatosis,
hyperparathyroidism, Wilson’s disease or alkaptonuria (excess homogentisic
acid polymerizes to produce a black/brown product deposited in cartilage
and other tissues).
Investigations
• The diagnosis is made on joint fluid microscopy demonstrating
small brick-shaped pyrophosphate crystals which are positively
birefringent under polarized light (compare uric acid). The presence of
chondrocalcinosis on X-ray is also suggestive of pseudogout.
• Full blood count may show a raised white cell count.
Management
Joint aspiration together with NSAIDs or colchicine forms the mainstay of
treatment. Injection of local corticosteroids may also be useful once septic
arthritis is excluded on joint fluid examination.
INFECTION OF BONES AND JOINTS
Infection of the joints is usually caused by bacteria and rarely by fungi. Some
viruses (rubella, mumps and hepatitis B virus infections) are associated with
a mild self-limiting arthritis but this is not due to direct joint involvement.
Septic arthritis
Septic arthritis is a medical emergency. Delay in treatment can result in irreversible joint destruction, long-term disability or death. It results from infection
of the joint with pyogenic organisms, most commonly Staphylococcus aureus.
Infection of Bones and Joints 295
Gram-negative organisms are more common in the elderly or immunosuppressed. Joints become infected by direct injury or by blood-borne infection
from an infected skin lesion or other site. Risk factors for septic arthritis are
prosthetic joints, pre-existing joint disease, recent intra-articular steroid injection and diabetes mellitus.
Clinical features
Classically there is a hot, painful, swollen, red joint, which has developed
acutely. There may be fever and evidence of infection elsewhere. In the elderly
and immunosuppressed and in RA the articular signs may be muted and a
high index of suspicion is needed to make the diagnosis. In 20% of cases the
septic arthritis involves more than one joint. Prosthetic joint infection may be
early (within 3 months of joint infection) or delayed/late. Early infection presents with wound inflammation or discharge, joint effusion, loss of function and
pain. Late disease presents with pain or mechanical dysfunction.
Management
This is summarized in Emergency Box 7.1.
Specific types of bacterial arthritis
Gonococcal arthritis involves one or several joints and occurs secondary
to genital, rectal or oral infection (often asymptomatic). It is the most common cause of septic arthritis in previously fit young adults. Concomitant skin
involvement is common (maculopapular pustules). The organism can usually
be cultured from the bloodstream and from the joints. Culture is usually positive from the genital tract, even if the joint fluid is sterile. Treatment is with
penicillin, ciprofloxacin or doxycycline for 2 weeks, and joint rest.
Meningococcal arthritis may complicate meningococcal septicaemia
and presents as a migratory polyarthritis. It results from the deposition of circulating immune complexes containing meningococcal antigens. Treatment
is with penicillin.
Tuberculous arthritis Approximately 1% of patients with tuberculosis
have joint and also bone involvement. The hip, knee and spine (intervertebral disc) are most commonly affected. There is an insidious onset of pain,
swelling and dysfunction. The patient is febrile, has night sweats and loses
weight. Culture of synovial fluid, synovial biopsy or intervertebral disc biopsy
(under CT guidance) is necessary to make the diagnosis. Treatment is as
for tuberculosis elsewhere (p. 530) but extended to 9 months, together with
initial joint rest and immobilization.
Osteomyelitis
Osteomyelitis can be due to either metastatic haematogenous spread
(e.g. from a boil) or to local infection. Staphylococcus is the most common
296 Rheumatology
Emergency Box 7.1 Acute monoarthritis
Investigations
1. Joint aspiration (by ultrasound guidance if necessary) and synovial fluid
analysis:
• Appearance and white cell count (WCC)
• Normal fluid – straw coloured, contains <3000 WCC/mm
• Inflammatory fluid – cloudy, contains >3000 WCC/mm
• Septic fluid – opaque, contains up to 75 000 WCC/mm3, mostly
neutrophils
• Urgent Gram stain (but may be negative in bacterial infection) and
culture
• Polarized light microscopy for crystals (in gout and pseudogout)
2. Bloods: Full blood count, erythrocyte sedimentation rate, C-reactive
protein, blood cultures
3. X-rays of the affected joint are of no value in the diagnosis because
usually normal initially. Loosening or bone loss around a previously
well-fixed prosthetic implant suggests infection
4. Swab of urethra, cervix and anorectum if gonococcal infection a
possibility
Treatment of acute non-gonococcal bacterial arthritis
• Initial treatment pending sensitivities: flucloxacillin 1–2 g 6 hourly
i.v. (erythromycin or clindamycin if penicillin allergic) and oral fusidic
acid 500 mg 8 hourly. Add gentamicin in immunosuppressed
patients to cover Gram-negative organisms. Modify treatment depending on culture and sensitivity and continue with two antibiotics
for 6 weeks (initial 2 weeks i.v.) and a single antibiotic for a further
6weeks
• Adequate joint drainage: by needle aspiration, arthroscopy or open
drainage. Always refer infection of a prosthetic joint to orthopaedic
surgeons
• Immobilize joint in acute stages, mobilize early to avoid contractures
• NSAIDs for pain relief
3
3
causative organism. Other organisms are Haemophilus influenzae and
Salmonella (in sickle cell anaemia). Symptoms are fever, local pain and
erythema, and sinus formation in chronic osteomyelitis. Diagnosis is usually
by CT, MRI or bone scan (p. 270). Blood cultures, as well as bone biopsy
and culture, can be used to identify the organism and sensitivities. Usual
treatment is with flucloxacillin and fusidic acid for at least 4–6 weeks with
intravenous medication initially.
Autoimmune Rheumatic Diseases 297
AUTOIMMUNE RHEUMATIC DISEASES
Autoimmune diseases are pathological conditions caused by an immune
response directed against an antigen within the host, i.e. a self-antigen.
Organ-specific autoimmune diseases include Graves’ disease, Hashimoto’s
thyroiditis and type 1 diabetes mellitus. In the autoimmune rheumatic diseases (ARDs) the autoantibodies are not organ-specific. The term ‘ARD’ is
preferable to the older term ‘connective tissue disease’ because the clinical
effects of ARD are not limited to connective tissue (see Table 7.2) and the
clinical manifestations are systemic and diverse. These diseases are:
• SLE
• Antiphospholipid syndrome
• Systemic sclerosis (scleroderma)
• Polymyositis and dermatomyositis
• Sjögren’s syndrome
• ‘Overlap’ syndromes and undifferentiated autoimmune rheumatic disease.
Systemic lupus erythematosus
SLE is an inflammatory multisystem disease characterized by the presence
of serum antibodies against nuclear components.
Epidemiology
It is a disease mostly of young women, with a peak age of onset between 20
and 40 years. It affects about 0.1% of the population but is more common in
African–American women, with a prevalence of 1 in 250.
Aetiology
The cause of the disease is unknown and is probably multifactorial:
• Heredity. There is a higher concordance rate in monozygotic (identical)
twins (up to 25%) compared to dizygotic twins (3%).
• Genetics. Genes linked to the development of SLE include HLA-B8, -DR3
and -A1 and deficiencies of the complement genes C1q, C2 or C4.
• Sex hormone status. The higher incidence in pre-menopausal women
and males with Klinefelter’s (XXY) syndrome suggests an oestrogen
hormonal effect.
• Drugs. Hydralazine, isoniazid, procainamide and penicillamine can
cause a mild lupus-like syndrome, which often resolves after the drug is
withdrawn.
• Ultraviolet light can trigger flares of SLE, especially in the skin.
• Exposure to Epstein–Barr virus has been suggested as a trigger for SLE.
Pathogenesis
Apoptotic cells and cell fragments are cleared inefficiently by phagocytes, resulting in transfer to lymphoid tissue where they are taken up by
298 Rheumatology
antigen-presenting cells. These self-antigens, including nuclear constituents
(e.g. DNA and histones), are presented to T cells, which in turn stimulate B
cells to produce autoantibodies directed against the antigens. The clinical
manifestations of SLE are mediated by antibody formation and the development and deposition of immune complexes, complement activation and influx
of neutrophils and abnormal cytokine production (increased blood levels of
IL-10 and α-interferon).
Clinical features
Clinical manifestations are varied (Table 7.10). A symmetrical small-joint
arthralgia and skin manifestations are common presenting features. Synovitis
and joint effusions are uncommon and joint destruction is very rare. Nonspecific features such as fever, malaise and depression can dominate the
clinical picture.
Discoid lupus is a benign variant of the disease, in which only the skin
is involved. There is a characteristic facial rash with erythematous plaques
which progress to scarring and pigmentation.
Investigations
• Blood count usually shows a normochromic, normocytic anaemia,
often with neutropenia/lymphopenia and thrombocytopenia. The ESR is
raised but the CRP is usually normal unless the patient has a coexistent
infection.
• Urea and creatinine only rise when renal disease is advanced. Low
serum albumin or high urine protein/creatinine ratio are early indicators
of lupus nephritis.
• Serum autoantibodies: many different autoantibodies are present in SLE
(see Table 7.2). Anti-dsDNA (double-stranded DNA) is specific for SLE and
is positive in 70% of cases.
• Serum complement C3 and C4 levels are reduced in active disease.
• Histology. Characteristic histological and immunofluorescent
abnormalities (deposition of IgG and complement) are seen in biopsies
from the kidney or skin.
Management
Treatment depends on the symptoms and severity of disease. Patients should
be advised to avoid excessive sunlight and reduce cardiovascular risk factors,
e.g. cessation of smoking.
• NSAIDs are useful for patients with mild disease and with arthralgia.
• Chloroquine and hydroxychloroquine are used for mild disease when
symptoms cannot be controlled with NSAIDs, or for cutaneous disease.
• Corticosteroids form the mainstay of treatment, particularly in moderate
to severe disease. The aim is to control disease activity (e.g. prednisolone
30 mg/day for 4 weeks) before gradually reducing the dose.
Autoimmune Rheumatic Diseases 299
Table 7.10 Clinical features of systemic lupus erythematosus
Musculoskeletal (affected in >90%)
Small-joint arthralgia
Myalgia
Aseptic necrosis of hip or knee
General
Tiredness
Fever
Depression
Weight loss
Skin (affected in 85% cases)
‘Butterfly’ rash – erythematous rash on cheeks and bridge of nose
Vasculitic lesions (finger tips, nail folds)
Urticaria and purpura
Photosensitivity
Alopecia
Blood
Anaemia (chronic disease and/or haemolytic)
Leucopenia/lymphopenia
Thrombocytopenia
Nervous system (affected in 60% cases)
Epilepsy
Migraine
Cerebellar ataxia
Aseptic meningitis
Cranial nerve lesions
Polyneuropathy
Lungs (affected in 50% cases)
Pleurisy/pleural effusions (exudates)
Restrictive defect (rare)
Heart and cardiovascular system (affected in 25% cases)
Pericarditis and pericardial effusions
Myocarditis leading to arrhythmias
Aortic valve lesions (rare)
Thrombosis – arterial and venous
Accelerated atherosclerosis
Raynaud’s phenomenon
Kidneys (clinical involvement in 30% cases)
Glomerulonephritis
Gastrointestinal symptoms
Mouth ulcers (common, may be presenting feature)
Mesenteric vasculitis
300 Rheumatology
• Immunosuppressives (e.g. mycophenolate mofetil, azathioprine), usually
in combination with corticosteroids, are used for patients with severe
manifestations, e.g. renal or cerebral disease. Newer agents such as
rituximab (anti-CD20, p. 250) are used in refractory cases.
• Topical steroids are used for discoid lupus.
Prognosis
The disease is characterized by relapses and remissions even in severe
disease. The 10-year survival is about 90%, although much lower if there is
major organ involvement.
Antiphospholipid syndrome
This syndrome is characterized by thrombosis and/or recurrent miscarriages
and persistently positive blood tests for antiphospholipid antibodies (detected
by the anticardiolipin, lupus anticoagulant or anti-β2-glycoprotein I test). These
antibodies are thought to play a role in thrombosis by reacting with plasma proteins and phospholipids with an effect on platelet membranes, endothelial cells
and clotting compounds. Antiphospholipid syndrome occurs on its own or in
association with another autoimmune rheumatic disease, most commonly SLE.
Clinical features
The major clinical features are the result of thrombosis:
• In arteries: stroke, transient ischaemic attacks, myocardial infarction
• In veins: DVT, Budd–Chiari syndrome (p. 178)
• In the placenta: recurrent miscarriages.
Other features include valvular heart disease, migraine, epilepsy, thrombocytopenia, renal impairment and accelerated atheroma.
Management
Long-term warfarin is given to patients who have had a thrombosis. Pregnant
patients with antiphospholipid syndrome are given aspirin and subcutaneous
low molecular weight heparin from early in gestation. Aspirin or clopidogrel
are sometimes given as prophylaxis to patients with antiphospholipid syndrome who have no history of thrombosis. Direct-acting oral anticoagulants
(DOACs; e.g. apixaban, rivaroxaban) are not recommended in patients with
antiphospholipid syndrome because of recent evidence demonstrating an
increase in thromboembolic events in patients taking these drugs.
Systemic sclerosis (scleroderma)
Systemic sclerosis (scleroderma) is a multisystem disease with involvement
of the skin and Raynaud’s phenomenon (p. 479) occurring early. It is three
times more common in women than in men and usually presents between
the ages of 30 and 50 years.
Autoimmune Rheumatic Diseases 301
Aetiology
Pathogenesis is complex and not completely understood. Genetic predisposition, immune activation, infection and an environmental toxin initiate an
endothelial cell lesion and widespread vascular damage. Increased vascular
permeability and activation of endothelial cells result in upregulation of
adhesion molecules (E-selectin, vascular cell adhesion molecule (VCAM),
intercellular adhesion molecule-1 (ICAM-1)), cell adhesion (T and B cells,
monocytes, neutrophils) and migration through the leaky endothelium and into
the extracellular matrix. These cell–cell and cell–matrix interactions stimulate
the production of cytokines and growth factors which mediate the proliferation
and activation of vascular and connective tissue cells, particularly fibroblasts.
The end result is uncontrolled and irreversible proliferation of connective tissue, and thickening of vascular walls with narrowing of the lumen.
Clinical features
Limited cutaneous scleroderma (LcSSc, 70% of cases)
This condition usually starts with Raynaud’s phenomenon many years before
any skin changes (of hands, face, feet and forearms). The skin is thickened,
bound down to underlying structures, and the fingers taper (sclerodactyly).
There is a characteristic facial appearance, with ‘beaking’ of the nose, radial
furrowing of the lips and limitation of mouth opening (microstomia). There
may be painful digital ulcers, telangiectasia and palpable subcutaneous
nodules of calcium deposition in the fingers (calcinosis). CREST syndrome
(Calcinosis, Raynaud’s phenomenon, Esophageal involvement, Sclerodactyly,
Telangiectasia) was the term previously used to describe this syndrome.
Diffuse cutaneous scleroderma (DcSSc, 30% of cases)
The skin changes develop more rapidly and are more widespread than in
limited cutaneous scleroderma. There is early involvement of other organs:
• Gastrointestinal involvement with dilatation and atony in the oesophagus
(heartburn and dysphagia), small intestine (bacterial overgrowth and
malabsorption) and colon (pseudo-obstruction).
• Renal involvement with acute and chronic kidney disease. Acute
hypertensive crisis is a complication of the renal involvement.
• Lung involvement with pulmonary fibrosis and pulmonary vascular
disease resulting in pulmonary hypertension.
• Cardiac involvement with myocardial fibrosis leading to arrhythmias and
conduction disturbances.
Investigations
The diagnosis of scleroderma is primarily based upon the presence of characteristic skin changes.
302 Rheumatology
• Blood count shows a normochromic, normocytic anaemia and the ESR
may be raised.
• Urea and creatinine rise with renal disease.
• Serum autoantibodies (see Table 7.2). Antinuclear antibodies are often
positive. Anti-topoisomerase 1 (Scl 70) and anti-RNA polymerase I and
III antibodies are highly specific for patients with diffuse cutaneous
scleroderma. Anticentromere antibodies occur in limited cutaneous
scleroderma. Autoantibodies do not occur in all patients.
• Radiology. An X-ray of the hands may show deposits of calcium around
the fingers, and there may be erosion and resorption of the tufts of
the distal phalanges. High-resolution CT demonstrates fibrotic lung
involvement. Barium swallow shows impaired oesophageal motility.
• Barium swallow generally confirms impaired motility.
Management
This is symptomatic and based on organ involvement. There is no specific
treatment. Education, counselling and family support are essential aspects of
management. Raynaud’s phenomenon may be improved by hand warmers
and oral vasodilators (calcium channel antagonists). Oesophageal symptoms
can be improved by proton pump inhibitors. Symptomatic malabsorption
requires nutritional supplementation. Angiotensin-converting enzyme inhibitors are the drug of first choice to treat hypertension and to prevent further
kidney damage. Pulmonary hypertension is treated with oral vasodilators,
oxygen and warfarin. Pulmonary fibrosis is treated with cyclophosphamide or
azathioprine combined with low-dose oral prednisolone.
Prognosis
The 10-year survival is 70% and 55% in limited cutaneous and diffuse cutaneous disease, respectively. Pulmonary fibrosis and pulmonary hypertension
are the major causes of death.
Polymyositis and dermatomyositis
Polymyositis (PM) is a rare muscle disorder of unknown aetiology in which
there is inflammation and necrosis of skeletal muscle fibres. When the skin
is involved it is called dermatomyositis (DM). The incidence is about 2–10/
million population per annum and it occurs in all races and all ages.
Clinical features
There is symmetrical progressive muscle weakness and wasting affecting
the proximal muscles of the shoulder and pelvic girdle. Patients have difficulty squatting, going upstairs, rising from a chair and raising their hands
above the head. Pain and tenderness are uncommon. Involvement of pharyngeal, laryngeal and respiratory muscles can lead to dysphagia, dysphonia
and respiratory failure. In dermatomyositis there are also characteristic skin