Inflammatory arthritis includes a large number of arthritic conditions in which the predominant feature is synovial inflammation. There is joint pain and stiffness after rest and in the morning. Morning stiffness may last several hours (cf. osteoarthritis). Blood tests often show a normochromic normocytic anaemia and raised inflammatory markers (ESR and CRP).
RA is a chronic systemic autoimmune disorder causing a symmetrical polyarthritis.
RA affects 0.5-1% of the population world-wide with a peak prevalence between the ages of 30 and 50 years.
Aetiology and pathogenesis
Genetic and environmental factors play an aetiological role.
■ Gender. Women before the menopause are affected three times more often than men with an equal sex incidence thereafter suggesting an aetiological role for sex hormones.
■ Familial. There is an increased incidence in those with a family history of RA.
■ Genetic factors. Human leucocyte antigen (HLA)-DR4 and HLa-DRB1* 0404/0401 confer susceptibility to RA and are associated with develop-ment of more severe erosive disease. Protein tyrosine phosphatase N22 (PTPN22), STAT4 and PADI-4 have also been identified as susceptibility genes.
The triggering antigen in RA is not known but factors produced by activated T cells (interferon, IL-2 and IL-4), macrophages (IL-1, IL-8, TNF-α), macro-phage inflammatory protein), mast cells (histamine and TNF-α) and fibro-blasts (IL-6, vascular cell adhesion molecule, delay accelerating factor) contribute to the ongoing synovial inflammation. Local production of rheu-matoid factor (autoantibodies directed against the Fc portion of immuno-globulin) by B cells and formation of immune complexes with complement activation also maintain the chronic inflammation.
RA is characterized by synovitis (inflammation of the synovial lining of joints, tendon sheaths or bursae) with thickening of the synovial lining and infiltra-tion by inflammatory cells. Generation of new synovial blood vessels is induced by angiogenic cytokines, and activated endothelial cells produce adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) which expedite extravasation of leucocytes into the synovium. The synovium proliferates and grows out over the surface of cartilage, producing a tumour-like mass called ‘pannus'. Pannus destroys the articular cartilage and subchondral bone, producing bony erosions.
The typical presentation is with an insidious onset of pain, early-morning stiffness (lasting more than 30 minutes) and swelling in the small joints of the hands and feet. There is spindling of the fingers caused by swelling of the PIPJs but not DIPJs. The metacarpophalangeal and wrist joints are also swollen. As the disease progresses there is weakening of joint capsules, causing joint instability, subluxation (partial dislocation) and deformity. The characteristic deformities of the rheumatoid hand are shown in Fig. 7.3. Most patients eventually have many joints involved, including the wrists, elbows, shoulders, cervical spine, knees, ankles and feet. The dorsal and lumbar spine are not involved. Joint effusions and wasting of muscles around the affected joints are early features. Less common presentations are ‘explosive' (sudden onset of widespread arthritis), palindromic (relapsing and remitting monoarthritis of different large joints), or with a systemic illness with few joint symptoms initially.
In patients presenting with disproportionate involvement of a single joint, septic arthritis (p. 296) must be excluded before the symptoms are attributed to a disease flare-up.
Periarticular features of RA include bursitis, tenosynovitis, muscle wasting and subcutaneous nodules (rheumatoid nodules) usually over pressure points
Fig. 7.3 Characteristic hand deformities in rheumatoid arthritis. MCP, metacarpophalanges; PIPJs, proximal interphalangeal joints.
at the elbow, the finger joints and Achilles tendon. Nodules may also occur in the pleura, pericardium and lung.
Other non-articular manifestations are summarized in Table 7.5. Patients with RA also have a greater risk of infection and osteoporosis. The chronic inflammation and endothelial damage associated with RA contributes to accelerated atherosclerosis, which is partly responsible for the increased mortality rate in severe RA.
The diagnosis of RA cannot be established by a single laboratory test and depends on the aggregation of characteristic clinical features (symmetrical peripheral polyarthritis with morning stiffness and nodules in some patients), blood tests and radiological appearances.
■ Blood count. There is usually a normochromic, normocytic anaemia and thrombocytosis. The ESR and CRP are raised in proportion to the activity of the inflammatory process.
■ Serum autoantibodies. Anti-CCP p. 273 has high specificity (90%) and sensitivity (80%) for RA and is particularly useful to distinguish early RA from acute transient synovitis. Rheumatoid factor (see above) is positive in 70% of cases and antinuclear factor at low titre in 30% (p. 299). Rheumatoid factor is not specific for RA and may occur in connective tissue diseases and some infections.
■ X-ray of the affected joints shows soft tissue swelling in early disease and later joint narrowing, erosions at the joint margins and porosis of periarticular bone and cysts.
■ Synovial fluid is sterile with a high neutrophil count in uncomplicated disease. In a suddenly painful joint septic arthritis should be suspected and appropriate tests completed (p. 296).
In the patient with symmetrical peripheral polyarthritis, prolonged morning stiffness, rheumatoid nodules and positive anti-CCP or rheumatoid factor, the diagnosis is straightforward. RA must be distinguished from symmetrical seronegative spondyloarthropathies; severe RA can mimic a form of psoriatic arthritis known as ‘arthritis mutilans' (p. 292). In a young woman presenting with joint pains, systemic lupus erythematosus (SLE) must be considered, but characteristically the joints look normal on examination in this condition. Acute viral polyarthritis (rubella, hepatitis B or parvovirus) must be considered in the differential diagnosis of early RA but these rarely last longer than 6 weeks. Anti-CCP will be negative.
No treatment cures RA; therefore the therapeutic goals are remission of symptoms, a return of full function and the maintenance of remission with
Table 7.5 Non-articular manifestations of rheumatoid arthritis
Scleromalacia perforans (perforation of the eye)
Carpal tunnel syndrome
Polyneuropathy, predominantly sensory
Felty’s syndrome (rheumatoid arthritis, splenomegaly, neutropenia)
Anaemia (chronic disease, NSAID-induced gastrointestinal blood loss, haemolysis, hypersplenism)
Rheumatoid pneumoconiosis (Caplan’s syndrome)
Heart and peripheral vessels
Pericarditis (rarely clinically apparent)
Nail fold infarcts
Gangrene of fingers and toes
NSAID, non-steroidal anti-inflammatory drug.
disease-modifying agents. Effective management of RA requires a multidis-ciplinary approach, with input from rheumatologists, orthopaedic surgeons (joint replacement, arthroplasty), occupational therapists (aids to reduce dis-ability) and physiotherapists (improvement of muscle power and maintenance of mobility to prevent flexion deformities). Patients should be advised to stop smoking to reduce the risk of cardiovascular disease.
NSAIDs and coxibs (p. 317) are effective in relieving the joint pain and stiffness of RA, but they do not slow disease progression. Individual response to NSAIDs varies considerably and it is reasonable to try several drugs in a particular patient to find the most suitable. Slow-release preparations (e.g. slow-release diclofenac) taken at night may produce dramatic relief of symp-toms on the following day. Paracetamol with or without codeine or dihydro-codeine can be added for additional pain relief.
Corticosteroids suppress disease activity but the dose required is often large, with the considerable risk of long-term toxicity (p. 655). Oral corticos-teroids are used in early disease (short-term intensive regimens) and in some patients with severe non-articular manifestations, e.g. vasculitis. Local injec-tion of a troublesome joint (see below) with a long-acting corticosteroid improves pain, synovitis and effusion but repeated injections are avoided because they may accelerate joint damage. Intramuscular depot methylpred-nisolone helps to control severe disease flares.
Disease-modifying anti-rheumatic drugs (DMARDs) act mainly through inhibition of inflammatory cytokines and are used early (6 weeks to 6 months of disease onset) to reduce inflammation and thus slow the development of joint erosion and irreversible damage, and reduce cardiovascular risk. Sul-fasalazine is used in patients with mild to moderate disease and for many is the drug of choice especially in younger patients and women who are plan-ning a family. Methotrexate is the drug of choice for patients with more active disease. It is contraindicated in pregnancy (teratogenic) and should not be prescribed (men and women) in the 3 months prior to conception in those planning a pregnancy. Leflunomide blocks T cell proliferation. It has a similar initial response rate to sulfasalazine but improvement continues and it is better sustained at 2 years. It is used alone or in combination with methotrex-ate. All drugs can have serious side-effects (Table 7.6) so monitoring with blood tests is necessary. Azathioprine, gold (intramuscular or oral), hydroxy-chloroquine and penicillamine are used less frequently.
Biological DMARDs currently available work by the following mechan-isms:
■ TNF-α inhibitors (etanercept, infliximab, adalimumab, certolizumab). They vary in their mechanism of action and frequency and mode of administra-tion. For instance, infliximab is a chimeric (human/mouse) antibody to TNF-α and is given intravenously every 8 weeks after an induction sched-ule. Etanercept is a soluble TNF-α receptor fusion protein that binds TNF-α and is given by self-administered subcutaneous injection
|Table 7.6 Side-effects of disease-modifying anti-rheumatic drugs (DMARDs)|
|Male infertility (reversible)|
|Methotrexate||Mouth ulcers and diarrhoea
|TNF-α blockers||Infusion reactions (infliximab)
|Infections (e.g. tuberculosis and septicaemia)|
|All may cause myelosuppression (with neutropenia, thrombocytopenia and anaemia) and regular check of the full blood count is indicated together with other specific monitoring. Rash and nausea are additional side-effects of most of the drugs listed.|
■ IL-1 receptor blocker (anakinra)
■ Lysis of B cells (rituximab)
■ Interleukin-6 receptor antibody (tocilizumab)
■ Blocks T-cell activation (abatacept).
TNF-α inhibitors are first-line treatment and slow or halt erosion formation in up to 70% of patients. They currently are used in patients who have active disease despite adequate treatment with at least two DMARDs, including methotrexate. In future the ‘biologicals' will be used earlier and in more patients as the cost falls.
Prognosis is variable; some patients will have minimal disability after many years and others will be severely disabled with most patients between these extremes. Prognosis can be dramatically altered with early DMARDs given under expert supervision.
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