AUTOIMMUNE RHEUMATIC DISEASES - Clinical features, Investigations

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:

■ SLE

■ 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.

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.

Table 7.9 Autoantibodies and disease associations

Antibody

Disease

Antinuclear antibodies

Non-specific - autoimmune disease, infections, normal individuals

Anti-dsDNA

SLE

Anti-histone

Drug-induced lupus

Anti-topoisomerase I (Scl-70)

Diffuse cutaneous SSc

Anti-centromeric

Limited SS

Anti-Ro (SS-A)

Primary SS, SLE

Anti-La (SS-B)

Primary SS, SLE

Anti-Smith (Sm)

SLE

Anti-UI-RNP

SLE, overlap syndrome

Anti-JO

Polymyositis, dermatomyositis

Cytoplasmic ANCA

Wegener’s granulomatosis

Perinuclear ANCA

Microscopic polyarteritis, Churg–Strauss syndrome, inflammatory bowel disease

Antiphospholipid

Antiphospholipid syndrome, SLE

Ds, double-stranded; SS, Sjögren’s syndrome; RNP, ribonucleoprotein; SSc, systemic
scleroderma; ANCA, antineutrophil cytoplasmic antibody.

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 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.

Pathogenesis

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 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. 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.

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.

Table 7.10 Clinical features of systemic lupus erythematosus
Musculoskeletal
Small joint arthralgia
Myalgia
Aseptic necrosis of hip or knee
General
Tiredness
Fever
Depression
Weight loss
Skin
‘Butterfly’ rash – erythematous rash on cheeks and bridge of nose
Vasculitis
Urticaria
Photosensitivity
Alopecia
Blood
Anaemia (chronic disease and/or haemolytic)
Leucopenia/lymphopenia
Thrombocytopenia
Lungs
Pleurisy/pleural effusions (exudates)
Restrictive defect (rare)
Heart and cardiovascular system
Pericarditis and pericardial effusions
Myocarditis
Aortic valve lesions
Thrombosis – arterial and venous
Accelerated atherosclerosis
Raynaud’s phenomenon
Kidneys
Glomerulonephritis
Nervous system
Epilepsy
Migraine
Cerebellar ataxia
Aseptic meningitis
Cranial nerve lesions
Polyneuropathy

■ 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.

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.

■ 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.

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-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.

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. 177)

■ In the placenta: recurrent miscarriages.

Other features include valvular heart disease, migraine, epilepsy, thrombo-cytopenia, 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 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.

Aetiology

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.

Clinical features

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.

Investigations

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.

Management

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.

Prognosis

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.

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 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.

Investigations

■ 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.

Management

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.

Sjögren’s syndrome

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.

Clinical features

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.

Investigations

■ 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.

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. 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.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

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
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

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
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
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
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

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
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

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
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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