Autoimmune disease is a pathological condition caused by an immune response directed against an antigen within the host, i.e. a self-antigen. The autoimmune response may, however, be triggered by an exogenous, i.e. foreign, antigen. Organ-specific autoimmune diseases include Graves' disease, Hashimoto's thyroiditis, pernicious anaemia and type 1 diabetes mellitus. In the autoimmune rheumatic diseases (ARDs) the autoantibodies
are not organ-specific (Table 7.9) and the clinical manifestations are systemic and diverse. These diseases are:
■ Antiphospholipid syndrome
■ Systemic sclerosis (scleroderma)
■ Polymyositis and dermatomyositis
■ ‘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.
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.
Table 7.9 Autoantibodies and disease associations
Non-specific - autoimmune disease, infections, normal individuals
Anti-topoisomerase I (Scl-70)
Diffuse cutaneous SSc
Primary SS, SLE
Primary SS, SLE
SLE, overlap syndrome
Microscopic polyarteritis, Churg–Strauss syndrome, inflammatory bowel disease
Antiphospholipid syndrome, SLE
Ds, double-stranded; SS, Sjögren’s syndrome; RNP, ribonucleoprotein; SSc, systemic
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 premenopausal women and males with Klinefelter's (XXY) 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isoniazid, procainamide and penicillamine can cause a mild lupus-like syndrome, which often resolves after the drug is withdrawn.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.
Apoptotic cells and cell fragments are cleared inefficiently by phagocytes resulting in transfer to lymphoid tissue where they are taken up by 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 manifesta-tions of SLE are mediated by antibody formation and the development and deposition of immune complexes, complement activation and influx of neu-trophils and abnormal cytokine production (increased blood levels of IL-10 and a-interferon).
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. Non-specific 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.
■ 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.
|Table 7.10 Clinical features of systemic lupus erythematosus|
Small joint arthralgia
Aseptic necrosis of hip or knee
‘Butterfly’ rash – erythematous rash on cheeks and bridge of nose
Anaemia (chronic disease and/or haemolytic)
Pleurisy/pleural effusions (exudates)
Restrictive defect (rare)
Heart and cardiovascular system
Pericarditis and pericardial effusions
Aortic valve lesions
Thrombosis – arterial and venous
Cranial nerve lesions
■ 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 (Table 7.9). Anti-dsDNA 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 abnormali-ties (deposition of IgG and complement) are seen in biopsies from the kidney or skin.
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.
■ Immunosuppressives (e.g. azathioprine, cyclophosphamide), usually in combination with corticosteroids, are used for patients with severe mani-festations, e.g. renal or cerebral disease. Newer agents such as rituximab (anti-CD20, p. 254) are used in refractory cases.
■ Topical steroids are used for discoid lupus.
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.
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-p2-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.
The major clinical features are the result of thrombosis:
■ In arteries: stroke, transient ischaemic attacks, myocardial infarction
■ In veins: DVT, Budd-Chiari syndrome (p. 177)
■ In the placenta: recurrent miscarriages.
Other features include valvular heart disease, migraine, epilepsy, thrombo-cytopenia, renal impairment and accelerated atheroma.
Long-term warfarin is given to patients who have had a thrombosis. Pregnant patients with antiphospholipid syndrome are given aspirin and heparin. Aspirin or clopidogrel are sometimes given as prophylaxis to patients with antiphospholipid syndrome who have no history of thrombosis.
Systemic sclerosis (scleroderma)
Systemic sclerosis (scleroderma) is a multisystem disease with involvement of the skin and Raynaud's phenomenon (p. 487) occurring early. It is three times more common in women than in men, and usually presents between the ages of 30 and 50 years.
Pathogenesis is complex and not completely understood. Genetic predisposi-tion, 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 adhe-sion molecules (E-selectin, vascular cell adhesion molecule [VCAM], intercel-lular adhesion molecule-1 [ICAM-1]), cell adhesion (T and B cells, monocytes, neutrophils) and migration through the leaky endothelium and into the extra-cellular 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.
Limited cutaneous scleroderma (LcSSc, 70% of cases) 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 deposi-tion in the fingers (calcinosis). CREST syndrome (Calcinosis, Raynaud's phe-nomenon, 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 mal-absorption) and colon (pseudo-obstruction).
■ Renal involvement - acute and chronic kidney disease. Acute hyper-tensive crisis is a complication of the renal involvement.
■ Lung disease - fibrosis and pulmonary vascular disease resulting in pulmonary hypertension.
■ Myocardial fibrosis leads to arrhythmias and conduction disturbances.
The diagnosis of scleroderma is primarily based upon the presence of characteristic skin changes.
■ Blood count shows a normochromic, normocytic anaemia and the ESR may be raised.
■ Urea and creatinine rise with renal disease.
■ Serum autoantibodies (Table 7.9). 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 sclero-derma. 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 involve-ment. Barium swallow shows impaired oesophageal motility.
■ Oesophageal manometry demonstrates failure of peristalsis in the distal oesophagus, with reduced oesophageal sphincter pressure.
This is symptomatic and based on organ involvement. There is no specific treatment. Angiotensin-converting enzyme inhibitors are the drug of first choice to treat hypertension and to prevent further kidney damage.
The 10-year survival is 70% and 55% in limited cutaneous and diffuse cutaneous disease, respectively. Pulmonary fibrosis and pulmonary hyper-tension 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). PM and DM affect adults and children and are more common in women.
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 changes: heliotrope (purple) discolouration of the eyelids and scaly erythema-tous 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.
■ Muscle biopsy is the definitive test in establishing the diagnosis and in excluding 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.
Oral prednisolone is the treatment of choice: 0.5-1.0 mg/kg bodyweight continued for at least one 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.
Sjogren's syndrome is characterized by immunologically mediated destruc-tion of epithelial exocrine glands, especially the lacrimal and salivary glands. It predominantly affects middle-aged women.
The main features are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Clinical clues are difficulty eating a dry biscuit and absence of pooling of the saliva when the tongue is lifted. It occurs as an isolated disorder (primary Sjogren's syndrome) or in association with another autoimmune disease (secondary Sjogren's syndrome), commonly rheumatoid arthritis or SLE. Other features of Sjogren'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.
■ Serum autoantibodies: antinuclear (in 80% of patients), Anti-Ro (60-90%) and rheumatoid factor in primary Sjogren's syndrome.
■ Labial gland biopsy shows characteristic changes of lymphocyte infiltra-tion and destruction of acinar tissue.
■ 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 min is positive) confirms defective tear production.
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. Undifferenti-ated 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.
1. Ethics and communication
2. Infectious diseases
3. Gastroenterology and nutrition
4. Liver, biliary tract and pancreatic disease
Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER DISEASE IN PREGNANCY
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS
5. Haematological disease
Assessment and treatment of suspected neutropenic sepsis
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
6. Malignant disease
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
8. Water, electrolytes and acid–base balance
WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
9. Renal disease
INVESTIGATION OF RENAL DISEASE
URINARY TRACT INFECTION
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
10. Cardiovascular disease
COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
ISCHAEMIC HEART DISEASE
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
ARTERIAL AND VENOUS DISEASE
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS
11. Respiratory disease
12. Intensive care medicine
13. Drug therapy, poisoning, and alcohol misuse
14. Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
15. Diabetes mellitus and other disorders of metabolism
16. The special senses
COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES