• Side-effects (Box 9.1) are common, particularly in the elderly. Indigestion and gastric erosions occur and occasionally gastrointestinal haemorrhage. The risk increases from ibuprofen (low) to, for example, diclofenac, indometacin and piroxicam (intermediate/high). Piroxicam should therefore not be used as a first-line drug and the dose should not exceed 20 mg. Bronchospasm and urticaria occur due to type 1 hypersensitivity from release of leucotrienes. Fluid retention and an increase in blood pressure can occur. Although there is a reduction in renal blood flow, acute kidney injury is rare. Avoid in pregnancy and with breast feeding, even though the amounts in the milk are small. NSAIDs should not be used if a patient is on anticoagulants, unless a proton pump inhibitor (PPI) is also given.

• Cyclo-oxygenase-2 specific agents (COX-2 inhibitors) are equal in efficacy to naproxen or diclofenac. These agents include celecoxib 200–400 mg daily in divided doses and etoricoxib 30–120 mg daily. They reduce the risk of gastrointestinal side-effects by 50% but there have been reports of an increased rate of cardiovascular events; two agents (rofecoxib and valdecoxib) have already been withdrawn but this may be a class effect. As a consequence, COX-2 inhibitors should not be given in the presence of cardiovascular or cerebrovascular disease. COX-2 inhibitors are also relatively contraindicated in those with vascular risk factors (e.g. smoking, diabetes, hypertension, hypercholesterolaemia).

Fig. 9.1 Arachidonic acid metabolism and the effect of drugs. The sites of action of NSAIDs (e.g. aspirin, ibuprofen) are shown. The enzyme cyclo-oxygenase occurs in three isoforms: COX-1 (constitutive), COX-2 (inducible) and COX-3 (in brain). BLT, B leukotriene receptor; cysLT, cysteinyl leukotriene receptor; PG, prostaglandin.

If the use of NSAIDs cannot be avoided in patients at high risk of gastrointestinal side-effects (those over 65 years of age, past history of peptic ulcer/bleed, concomitant steroid or warfarin use, or presence of serious comorbidity), use a non-selective NSAID combined with a PPI, e.g. omeprazole 20 mg daily. This is preferred to COX-2 inhibitors (see above). Misoprostol 200 mcg 2–3 times daily can also be used as a cytoprotective agent but causes diarrhoea.

NSAID should be used for the shortest possible time at the lowest effective dose.

Glucocorticoids

Systemic corticosteroids

These are potent anti-inflammatory agents.

• Prednisolone in doses up to 60 mg daily is used in many systemic rheumatic conditions, preferably taken in the morning after breakfast.

• Methylprednisolone 0.5–1 g IV for 3 days is used in severe organ-threatening disease in vasculitis, and 80–120 mg IM for acute flares of inflammatory arthritis, particularly rheumatoid.

• Hydrocortisone 50–250 mg IV is given short-term when oral prednisolone cannot be taken.

• Side-effects of steroids are many (Box 9.2) and include:

• Insomnia, weight gain, thinning of the skin, bruising, hypertension, sodium retention, hyperglycaemia, cataracts and glaucoma.

• Osteoporosis. This is a long-term problem, developing within 6 months on doses above 7.5 mg daily. It should be monitored with dual energy X-ray absorptiometry (DEXA scanning), which guides treatment with calcium 1–1.5 g/day and vitamin D 400 U daily, and a weekly bisphosphonate (p. 324). A proximal myopathy and avascular necrosis (often of the femoral head) can also occur.

• Steroid reduction. Patients who have taken low doses of prednisolone for less than 3 weeks may stop the drug immediately, as adrenal suppression will not have occurred in this time frame. Other patients, however, require a gradual reduction in the dosage, which can be fairly rapidly decreased to 20 mg and then more slowly down to 7.5 mg, equivalent to a physiological steroid dose.

Local corticosteroids

Steroids are often given intra-articularly in non-septic inflammatory monoarthritis and in osteoarthritis, particularly when associated with an effusion. Additionally, local soft-tissue injections are often indicated for patients with tenosynovitis, bursitis, enthesitis and carpal tunnel syndrome. In patients with an effusion, joint aspiration is required first.

Joint aspiration and injection for diagnosis and therapy (Box 9.3)

Aspiration

Aspiration should always be performed in patients with unexplained large joint effusions to obtain a diagnosis; for symptomatic relief in a patient with known arthritis; and to monitor response to treatment in an infected joint.

• ‘Normal’ fluid is clear and non-inflammatory fluid is straw colour (high viscosity).

• Inflammatory and septic fluids are yellow and can be translucent or opaque. Opaque fluid suggests a high protein content and high white cell count, is of low viscosity and may clot.

• The fluid should be sent to the laboratory for a cell count, Gram strain and microscopic examination for crystals and culture.

Box 9.3 Joint aspiration

This is a sterile procedure, which should be carried out in a clean environment.

Explain the procedure to the patient; obtain consent.

1 Decide on the site to insert the needle and mark it

2 Clean the skin and your hands scrupulously; remove rings and wristwatch. Put on gloves

3 Draw up local anaesthetic (and corticosteroid if it is being used) and then use a new needle

4 Warn the patient. Insert the needle, injecting local anaesthetic as it advances; if a joint effusion is suspected, attempt to aspirate as you advance the needle

5 If fluid is obtained, change syringes and aspirate fully

6 Examine the fluid in the syringe and decide whether or not to proceed with a corticosteroid injection (if fluid clear)

7 Cover the injection site and advise the patient to rest the affected area for a few days. Warn patients that the pain may increase initially but to report urgently if the pain persists beyond a few days, if the swelling worsens, or if they become febrile, since this might indicate an infected joint

N.B. Aspiration and injection of joints can be painful!

Joint injection

• Glucocorticoids. There are several preparations available; the dosages are variable and should be checked with the product literature. The ‘volume’ injected varies with the size of the joint, e.g. small joints (hands and feet) 0.25–0.5 mL, larger joints (knees, shoulder) 1–2 mL. Lidocaine 1% solution can be mixed with the steroid in the syringe to make up to 1–10 mL depending on joint size.

• Hydrocortisone acetate (25 mg/mL) 0.5–1 mL, can be used for soft tissue injections and is the least likely to cause skin atrophy or depigmentation, as it is a short-acting preparation.

• Methylprednisolone acetate (40 mg/mL or 10 mg/mL) 0.5–2 mL, is often used for intra-articular injections.

• Triamcinolone acetate (40 mg/mL) 0.25–1 mL is an alternative to methylprednisolone acetate.

• Contraindications. These include infection over the site of needle insertion (absolute), and coagulopathy or bacteraemia (relative).

• Complications. Infection following procedure is rare but a serious complication (< 0.1%).

N.B. No more than three injections per joint should be performed in 1 year.

Disease-modifying anti-rheumatic drugs (DMARDs)

See p. 309 and Table 9.2.

Table 9.2 Disease-modifying anti-rheumatic drugs (DMARDs)

Osteoarthritis (OA)

Inflammatory arthritis

Rheumatoid arthritis (RA)

Clinical features

RA is a chronic, systemic, inflammatory disorder of unknown aetiology. Any age can be affected but onset is generally between 30 and 60 years of age, with women affected three times more commonly than men.

• The characteristic feature is persistent (> 6 weeks) symmetrical polyarthritis affecting the hands (metacarpal phalangeal joints (MCPs), proximal interphalangeal joints (PIPs) and wrists) and feet (metatarsal phalangeal joint (MTPs)), although any synovial joint can be involved.

• Common extra-articular features include soft-tissue lesions, subcutaneous nodules, pleural effusions, carpal tunnel syndrome (CTS), systemic symptoms and Sjögren’s syndrome.

• RA causes progressive damage, with > 90% having joint erosions within 3 years (Fig. 9.3). Early aggressive treatment is therefore warranted. Poor prognostic factors include extra-articular manifestations, poor scores on functional assessment, high inflammatory markers, a positive rheumatoid factor and early erosions on imaging.

Fig. 9.3 X-ray of early rheumatoid arthritis. Typical erosions are seen at the thumb and middle MCP joints (arrowed) and at the ulnar styloid (white arrow on right).

Investigations

• Cyclic citrullinated peptide (CCP) antibodies have a high specificity for RA (90% with a sensitivity of 60%) and their presence indicates the development of more erosive disease compared to CCP-negative patients.

• Rheumatoid factor is present in ~70% of cases.

• ESR and CRP are raised in proportion to the activity of the inflammatory process and are useful in monitoring treatment. X-rays in early disease only show soft-tissue swelling but MRI will show early erosions.

Management

This requires a multi-disciplinary approach based on early aggressive treatment with non-drug measures and drug therapy. The main aims are to reduce inflammation, maintain joint function, and prevent or slow the advancement of arthritis and deformity.

• General measures. Give education with reassurance; physiotherapy, i.e. exercises to maintain joint range and power; occupational therapy to help maintain normal function through the use of joint splints, gadgets and mobility aids; and podiatry for foot care.

• Drug therapy. In the first 6–12 weeks after disease onset, around 50% of patients will have negative auto-antibodies and normal X-rays. It may be difficult to differentiate RA from self-limiting post-viral arthritis during this time. One approach to treatment is to give an IM injection of methylprednisolone 120 mg (or 80 mg if < 60 kg), along with an NSAID, and review at week 12; a self-limiting polyarthropathy will have settled by this time. Persisting disease requires use of a DMARD (see below), the most common being sulfasalazine or methotrexate.

• Glucocorticoids are potent anti-inflammatory drugs, which are used:

a) to settle a disease flare; options are a short course of oral prednisolone < 20 mg daily, IM methylprednisolone 80–120 mg, intra-articular injections or IV methylprednisolone pulses of 500 mg

b) as an adjunct to DMARDs (see combination therapy below)

c) as the sole treatment when the risks of DMARD therapy outweigh potential benefit (e.g. in the very elderly) at a dose of prednisolone 5–10 mg daily. Doses > 7.5 mg may slow radiographic progression.

• DMARDs (Table 9.2) reduce inflammation (as reflected by a reduction of joint swelling and fall in plasma acute-phase reactants), slow the development of joint erosions and prevent irreversible damage. They act slowly and achieve disease remissions in up to 70% of patients. Combinations of 2–3 drugs may be necessary. These drugs are potentially dangerous in pregnancy and contraception should be used; manufacturer’s advice should be followed.

• Sulfasalazine (SSZ) is a commonly prescribed agent. Radiological progression is reduced. Mild side-effects are common (30%), most occurring in the first 6 months. SSZ should not be used in glucose-6-phosphate dehydrogenase (G6PD) deficiency. There is a theoretical risk of neonatal haemolysis if it is used in pregnancy and folate supplements should be given.

• Methotrexate (MTX) is a folic acid antagonist. It is the most commonly prescribed initial DMARD. MTX can reduce radiological progression and clinical benefit is seen within 12 weeks. It is often preferred to SSZ due to a better benefit-to-toxicity ratio. It is given once weekly and this should be emphasized to all carers and the patient. Avoid in pregnancy and use contraceptives for at least 6 months after stopping treatment in men or women.

• Leflunomide is a pyrimidine inhibitor that is as effective as MTX and SSZ clinically and in inhibiting radiological progression. It is most commonly used if methotrexate is not tolerated or ineffective. Do not use in women or men planning pregnancy or in pregnancy. Use contraception for at least 2 years after stopping therapy in women and for 3 months in men, or alternatively washout with cholestyramine 8 g × 3 daily for 11 days before conception.

• Anticytokine therapies include the tumour necrosis factor (TNF) inhibitors (infliximab, etanercept, adalimumab and certolizumab) and other biological agents, including an interleukin-1 (IL-1) receptor antagonist (anakinra) and an anti-B-cell antibody, rituximab, which has been shown to be of significant benefit in MTX-resistant patients. These drugs should be avoided in pregnancy. Contraceptives should be used for 12 months after stopping therapy. These drugs all have a more rapid onset than MTX and are more effective at reducing the progression of radiological erosions. Although these drugs work well in early RA, they are costly and have a high complication rate, and hence are only used for active RA when two standard DMARDs (one of which is usually methotrexate) have failed. If one anticytokine fails, patients may respond to another. Reactivation of latent TB, often extrapulmonary, is a well-recognized complication of anti-TNF therapy, usually in the first 6 months. All patients must be screened for latent TB prior to treatment (p. 512). Cytokine inhibitors are contraindicated in pregnancy. However, if the potential benefit to the mother outweighs the risk of B-cell depletion in the fetus, it may be given. Contraception should be used during treatment and for 12 months after cessation of treatment in other circumstances.

• Combination DMARD therapy is used in patients who have had an incomplete response to monotherapy and also early in the disease in patients with poor prognostic factors. Early combination treatment should include methotraxate, short-term steroids and at least one other DMARD. Combination of methotrexate with anticytokine therapy in early RA leads to greater functional improvement and significantly less radiological damage compared to methotrexate monotherapy but because of cost it is not currently standard treatment.

• Drugs used less commonly

• Azathioprine (AZA) antagonizes purine metabolism. It is not as effective as MTX or SSZ and thus not commonly used. A thiopurine methyl transferase estimation should be performed prior to starting the drug (p. 160). There is no evidence that AZA is teratogenic in pregnancy.

• Ciclosporin, although clinically effective, is rarely used due to potential toxicity and unproven benefit radiologically. It is probably safe in pregnancy but needs careful monitoring.

Special situations

• Pregnancy. See Table 9.3.

• Surgery. Rheumatoid joint disease can be treated by surgical synovectomy to reduce the bulk of inflamed tissue and prevent damage. Excision arthroplasty of the ulnar styloid reduces pain and the risk of extensor tendon damage. Excision arthroplasties of the metatarsal heads reduce metatarsal pain and relieve pressure points. A major surgical advance has been the development of total replacement arthroplasty of the hip, knee, finger joints, elbows and shoulders.

Table 9.3 Rheumatic drugs in pregnancy and breast feeding

Drug	Pregnancy	Breast feeding
Steroids	P	P
Hydroxychloroquine	P	A
Sulfalazine	P (stop in men 3 months before attempting conception due to oligospermia)	P
Methotrexate	A (stop 6 months prior to attempting conception)	A
Leflunomide*	A	A
Gold	A	A
Azathioprine	P	A
Ciclosporin	P	A
Anticytokine therapy	A (insufficient data)	A (insufficient data)
Cyclophosphamide	A	A
Mycophenolate	A (insufficient data)	A (insufficient data)
Rituximab	A	A

P, use permissible; A, avoid use. *Because of long half-life drug elimination, treat with colestyramine 8 g 3 times daily for 11 days prior to conception or starting another DMARD.

N.B. These drugs are all potentially dangerous. Follow manufacturer’s advice.

Seronegative spondyloarthropathies

This group of conditions is characterized by:

• inflammation, mainly in spine and sacro-iliac joints

• an association with HLA-B27

• sero-negativity for rheumatoid factor

• asymmetrical large joint oligoarthritis (< 5) or monoarthritis

• enthesitis — inflammation at site of insertion of tendon or ligament into bone

• extra-articular features, e.g. uveitis, aortitis.

Ankylosing spondylitis (AS)

This condition tends to affect young adults, giving inflammatory low back pain associated with morning stiffness of > 1 hour, which improves with exercise. There can also be an asymmetrical lower limb arthritis and a uveitis. There is often a positive family history. Sacro-iliitis is demonstrable on X-ray or MRI and over 90% of Caucasians are HLA-B27-positive.

Psoriatic arthritis (PsA)

Between 5 and 8% of patients with psoriasis develop a type of arthritis: distal interphalangeal, arthritis mutilans (a destructive arthritis), symmetrical polyarthritis (resembling RA), asymmetric oligoarthritis (< 5 joints) of a spondyloarthropathy (similar to AS).

Reactive arthritis (REA)

An acute asymmetric lower limb arthritis occurs, usually in men, after a gastrointestinal or genitourinary infection. Enthesitis is common, causing plantar fasciitis or Achilles tendonitis. Other features include circinate balanitis, keratoderma blenorrhagica and conjunctivitis.

Enteropathic arthritis

Between 10 and 20% of patients with inflammatory bowel disease develop arthritis, which can be a spondylitis or sacro-iliitis similar to AS, or a large-joint (knee or ankle) arthritis.

Management

• General measures. All patients with spinal involvement should be referred to physiotherapy for instruction in a home exercise programme; this can decrease pain and improve function. Patients with AS should follow a regimen of exercise to slow progression. Smoking should be stopped, especially in AS, since respiratory problems are increased if obstructive lung disease compounds the restrictive lung disease that can occur in AS.

• Drug therapy

• NSAIDs (Table 9.1) are often effective for the control of pain and stiffness. Commonly used agents are indometacin (25–50 mg 3 times daily or slow-release 75 mg twice daily) and naproxen (e.g. 500 mg twice daily).

• DMARDs (Table 9.2). Patients who have peripheral arthritis are often treated with the same standard DMARDs used for RA if there is a failure to respond to NSAIDs or if there is radiological erosive disease. In AS, ReA and enteropathic arthritis, SSZ is often first-line, with MTX as an alternative therapy. In PsA MTX is first-line, as it is also effective for skin disease; other options are SSZ, leflunomide, ciclosporin and azathioprine. However, unlike for RA, there are few well-controlled trials and the effect of these drugs on radiological progression in these disorders is unclear. The DMARDs listed above do not have an effect on spinal disease.

• Anti-TNF therapy has been shown to be effective for both peripheral and spinal disease in AS and PsA, and additionally can reduce radiological progression. Due to its cost and potential toxicity, use is currently restricted. AS patients who have active spinal disease despite sequential treatment with at least two NSAIDs are suitable for infliximab or etanercept; PsA patients with active peripheral disease, despite treatment with at least two standard DMARDs, are now given infliximab, etanercept or adalimumab.

Crystal arthropathy

The three main types of crystal that can cause inflammatory disease are urate (gout), calcium pyrophosphate dihydrate (CPPD) (pseudogout) and hydroxyapatite. Joint aspiration allows identification of urate and CPPD crystals, but not hydroxyapatite, by polarized light microscopy.

Gout

Clinical features

• Acute gout is most common in middle-aged men and generally presents with an acute monoarthritis of the first MTP joint. Other frequently involved joints are foot, ankle, knee and wrist. There is extreme pain and erythema with acute synovitis. There may be an associated systemic upset. Precipitants include alcohol, dehydration, diuretics and intercurrent illness. The attack subsides within 1–2 weeks. Acute gout can also cause an acute bursitis (e.g. olecranon, pre-patellar). Most patients (90%) will have hyperuricaemia but not all individuals with a raised urate develop gout.

• Chronic gout can occasionally develop over time with polyarticular joint swelling (without erythema); hand involvement can mimic RA. There are often urate deposits (tophi) in or around joints, e.g. pinna of ears, olecranon and patellar bursa, and Achilles tendon. Patients may also develop a urate nephropathy.

Management

• General measures. These include weight loss, reducing alcohol (especially beer) and purine (red meat, shellfish) intake, and hypertension control, ideally avoiding diuretics. Ingestion of cherries and vitamin C can help reduce urate levels. Low-dose aspirin should be avoided. Asymptomatic hyperuricaemia does not require any treatment. Secondary causes of gout, e.g. myelo- and lympho-proliferative disorders, should be managed (p. 263).

• Drug therapy (Table 9.4). Acute gout can be treated in three ways:

• NSAIDs in high dose (e.g. indometacin 50 mg 3 times daily, reducing to 25 mg 3 times daily after 4 days) are usually first-line and given for 7–10 days.

• Colchicine 0.5 mg 4 times daily orally (higher doses often cause diarrhoea) is useful in patients with heart failure (no fluid retention, unlike with NSAIDs) and does not affect anticoagulation.

• Steroids (either intra-articular, oral (e.g. prednisolone 30–40 mg tapering over 10 days) or IM (e.g. methylprednisolone 80–120 mg) may be given.

Table 9.4 Urate-lowering drugs

Most patients will require long-term urate-lowering therapy as prophylaxis against further attacks, the goal being to reduce serum urate to normal.

• Allopurinol, a xanthine oxidase inhibitor and the most commonly used agent, is given at a dose of 300 mg daily, started 2–3 weeks after the acute attack has settled and gradually titrated up to a maximum of 900 mg to normalize uric acid levels. Hypersensitivity reactions, including a rash, can occur. Colchicine or an NSAID should be co-prescribed for 3 months to avoid an acute episode.

• Febuxostat 80 mg/day, a non-purine selective inhibitor of xanthine oxidase, is given where there is a contraindication or intolerance to allopurinol.

• Sulfinpyrazone (100–200 mg, increasing to 600 mg over 2–3 weeks and then reducing to a maintenance dose when uric acid level is normal), and probenecid (0.5–2 g daily) are both uricosuric drugs used in place of xanthine oxidase inhibitors if there is intolerance.

Calcium pyrophosphate (CPPD) disease

This causes an acute monoarthritis (pseudogout) in elderly patients, particularly in the knees and wrists. The precipitating factors are as for gout. X-rays may show chondrocalcinosis. Some patients, particularly those < 55 years of age or those with polyarticular involvement, may have an underlying metabolic disease (e.g. haemochromatosis, hyperparathyroidism or Wilson’s disease). Crystal deposition can also cause chronic disease, most commonly mimicking symptoms or signs of OA but in unusual sites, e.g. MCP joints, shoulders, ankles and wrists.

Treatment

Management of pseudogout is as for acute gout. There is no prophylactic therapy for CPPD; chronic disease is managed as OA.

Hydroxyapatite deposition disease

Hydroxyapatite crystals can deposit in soft tissues and large joints. Patients may present with a calcific tendonitis or bursitis, most commonly around the shoulder. There is acute pain with peri-articular swelling, which gradually improves over 2–3 weeks. The typical patient is an elderly female. X-rays demonstrate soft-tissue calcification. Hydroxyapatite deposits in the shoulder joint can cause a destructive arthropathy (Milwaukee shoulder) associated with a bloody effusion, chronic joint pain and limitation, and rotator cuff tears.

Treatment

Treatment is as for acute gout.

• Additionally, needle aspiration of the calcific deposit may be helpful.

• Repeated joint aspiration is used.

• Supraclavicular nerve blocks and surgery may be needed.

• Intra-articular steroids are usually ineffective.

Autoimmune rheumatic disorders

These constitute a heterogeneous group of autoimmune disorders of unknown aetiology, but associated with antibodies to ‘self’ antigens.

Systemic lupus erythematosus (SLE)

This is a multi-system inflammatory disorder, most common in women of childbearing years. The disease is more common and has a worse prognosis in black and Asian people. The 10-year survival is 90%.

Clinical features

Symptoms include fever, fatigue, myalgia, mouth ulcers and Raynaud’s phenomenon. Involvement of the skin includes a butterfly facial rash, a discoid rash being specific for SLE, and photosensitivity. An arthralgia is present in 90% of patients, with pulmonary involvement in 75%. Thrombocytopenia, haemolytic anaemia, pericarditis and coronary artery disease occur, as well as neuropsychiatric involvement giving headache, epilepsy, stroke, depression and psychosis. The course of the disease is variable and often episodic but with exacerbations and complete remissions that may last for long periods.

Diagnosis

• Autoantibodies to DNA and other nuclear antigens frequently occur.

• The presence of double-stranded DNA antibodies is specific for SLE.

Management

• General measures. Mild disease settles down with rest. Sunblock (at least factor 30) should be applied to reduce photosensitivity. Patients should be screened for cardiovascular risk factors (diabetes, hypertension, hypercholesterolaemia) and, if abnormal, managed appropriately. Patients should stop smoking. Influenza vaccination is given annually.

• Drug therapy (Table 9.4). Mild cases (i.e. those that are clinically stable without major organ involvement, e.g. fatigue, rash, arthralgia, serositis) can usually be managed with:

• NSAIDs

• Hydroxychloroquine 200–400 mg/day. Patients should have pre-treatment visual acuity tested for each eye, followed by annual checks.

• Steroids, topically for skin lesions, or low-dose oral prednisolone (< 10 mg daily). Patients with major organ involvement (e.g. glomerulonephritis, cerebral vasculitis, haemolytic anaemia, immune thrombocytopenia) require higher doses of oral prednisolone (1 mg/kg) or, if there is life-threatening involvement, IV methylprednisolone 0.5–1 g daily for 3 days followed by oral steroids. Oral steroids are tapered slowly according to response.

• Immunosuppressants, such as cyclophosphamide, azathioprine or mycophenolate mofetil, will be required by patients with major organ involvement and those with mild involvement needing more than prednisolone 10 mg.

• IV cyclophosphamide, given as boluses every 2–4 weeks, is generally used for severe disease, particularly diffuse proliferative glomerulonephritis and systemic vasculitis. Mesna (mercapto-ethane sulphonic acid) should be given (along with a high volume of fluids), as it reacts specifically with a metabolite of cyclophosphamide and ifosfamide, called acrolein, which is toxic to the urethra. It should be given concomitantly with IV therapy, or before if cyclophosphamide is given orally. Once disease remission is achieved, frequency of cyclophosphamide dosage is reduced (every 3 months) or patients are switched to less toxic therapies such as mycophenolate mofetil (metabolized to mycophenolic acid) or azathioprine. In less severe disease, patients can be started on azathioprine, mycophenolate or, less commonly, ciclosporin instead of cyclophosphamide. Azathioprine is also commonly used as a steroid-sparing agent in patients who are steroid-dependent.

The anti-B-cell antibody, rituximab, has shown promise in early trials and has been used effectively in lupus nephritis unresponsive to standard agents.

Antiphospholipid syndrome (APS)

Clinical features

This syndrome causes arterial thromboses (most commonly strokes), venous thromboses (most commonly DVT of the legs ± pulmonary embolism), recurrent miscarriages and thrombocytopenia in the presence of antiphospholipid antibodies. Patients may have livedo reticularis. The syndrome can be primary or secondary, when the most common underlying disease is SLE.

Management

• General measures. Risk factors for hypercoagulopathy should be reduced, e.g. stopping the oral contraceptive pill and smoking. BP should be controlled and hypercholesterolaemia treated (p. 617).

• Drug therapy. Patients with thromboses generally require lifelong anticoagulation (p. 243). Those with an initial venous thrombosis can be warfarinized with an INR of 2.0–3.0; those who have recurrent venous thromboses or an arterial thrombosis should keep their INR between 3.0 and 4.0. Women who have had previous miscarriages but no thromboses should be started on aspirin 75 mg when they are planning pregnancy, and heparin (low molecular weight heparin (LMWH), e.g. enoxaparin 20–40 mg/day) should be added once pregnancy is confirmed. Those who are on warfarin due to thromboses before pregnancy should be switched to heparin (again LMWH) before week 6 of gestation, as warfarin is teratogenic. Heparin is withheld for the delivery and then continued to week 6 post-partum. Patients on heparin through pregnancy should have calcium and vitamin D prophylaxis to prevent osteoporosis. Therapy for patients with antiphospholipid antibodies but no thromboses or miscarriages is controversial, but a reasonable approach is aspirin 75 mg for those with lupus anticoagulant or moderate-/high-titre anticardiolipin antibodies.

Sjögren’s syndrome

This is an autoimmune disorder that primarily causes lymphocytic inflammation in the exocrine glands, especially the salivary (dry mouth) and lacrimal glands (dry eyes). A third of patients have extraglandular manifestations, which include constitutional symptoms, arthralgia/arthritis, lymphadenopathy, Raynaud’s phenomenon, vasculitis, peripheral neuropathy and occasionally pulmonary, gastrointestinal and renal disease. Lymphoma is a complication. Sjögren’s syndrome can be primary (typically affecting middle-aged women) or secondary to RA or one of the other autoimmune rheumatic disorders.

Management

• Most patients will require only symptomatic treatment for dry eyes and dry mouth.

• Drugs with antimuscarinic properties, such as tricyclic antidepressants and neuroleptics, should be avoided.

• Dry and windy environments should be avoided and smoking stopped.

• Artificial tears can be prescribed, with liberal daytime use of low-viscosity drops such as hypromellose 0.3% and a higher viscosity agent such as liquid paraffin at night. In severe cases punctal occlusion can reduce tear drainage and a lateral tarsorrhaphy (suturing a portion of the eyelids together) can reduce the ocular surface area.

• Salivary flow can be promoted with sugar-free lozenges or chewing gum. Frequent sips of water and artificial saliva can give additional relief.

• Sugars, alcohol, caffeinated drinks and spicy foods should be avoided.

• Pilocarpine, a cholinergic agonist, 5 mg 4 times daily, can be helpful for both dry eyes and mouth but can cause flushing and sweating.

Management of associated features

Hydroxychloroquine 200–400 mg/day can improve arthralgia, myalgia and possibly fatigue. NSAIDs can help arthralgia. Severe manifestations, such as vasculitis, glomerulonephritis, neurological problems and interstitial lung disease, are treated in a similar way to SLE with major organ involvement (see above) using steroids (e.g. prednisolone 1 mg/kg) and immunosuppression with azathioprine, cyclophosphamide or mycophenolate (Table 9.2).

Systemic sclerosis (SS)

Clinical features

This is of unknown aetiology and is more common in women, with an onset usually between 30 and 40 years. There are two main subtypes: limited and diffuse SS. The latter is less common but is the more severe form, with more rapid onset and greater likelihood of internal organ involvement.

Management

There is no cure for SS and no drug has been proven to alter the natural course of disease. Therapy is symptomatic and directed towards the organ system involved. Regular exercises and skin lubricants may limit contractures.

• Skin-tightening. No treatment is of proven benefit but penicillamine is occasionally used and mycophenolate has shown promise in uncontrolled studies. Physiotherapy prevents joint contractures. Emollients can be helpful.

• Raynaud’s phenomenon. Hand-warmers and peripheral vasodilators (most commonly nifedipine) are used.

• Pulmonary hypertension. Start warfarin, vasodilator therapy including calcium channel blockers (e.g. nifedipine), prostacyclin analogues (e.g. iloprost by inhalation 5 mcg 6–9 times daily), endothelin-receptor antagonist (bosentan 62.5–125 mg twice daily, sitaxsentan 100 mg daily) and oxygen; arrange a lung transplant if disease is severe.

• Pulmonary fibrosis. In the early stages, inflammatory alveolitis may respond to steroids plus cyclophosphamide or mycophenolate. Arrange a lung transplant if disease is severe.

• Dysphagia/reflux. Incline the bed, advise small meals, and give PPIs, give metoclopramide for dysmotility and bloating, and dilatation for strictures.

• Malabsorption. Antibiotics (e.g. metronidazole) may be useful for bacterial overgrowth.

• Malignant hypertension. Measures include bed rest, ACE inhibitor, calcium antagonists, prostacyclin analogue and dialysis. Use a prophylactic ACE inhibitor, e.g. ramipril, in all hypertensive patients. Avoid prednisolone (> 20 mg) as it may increase the risk of sclerodermal renal crisis.

• Arthralgia/myalgia. Arrange an exercise programme, and occasionally give NSAIDs; inflammatory myositis is treated as polymyositis (see below).

Raynaud’s phenomenon/disease

Raynaud’s phenomenon consists of spasm of the digital arteries, usually precipitated by cold and relieved by heat. If there is no underlying cause, it is known as Raynaud’s disease. The vasoconstriction causes skin pallor, and cyanosis due to sluggish blood flow, followed by secondary hyperaemia, which is painful.

• Treatment. Avoid the cold, wear warm clothes and stop smoking. Nifedipine 5-mg × 3 daily reduces the frequency and severity of attacks. Vasodilators cause headaches.

Polymyositis/dermatomyositis

Clinical features

These disorders are characterized by an insidious onset of symmetrical proximal muscle weakness, often painless, with an increase in serum muscle enzymes, electromyographic changes and an abnormal muscle biopsy. Dermatomyositis is characterized by additional skin involvement (a red–purple rash, particularly over eyelids and knuckles). The disorders may be associated with other autoimmune rheumatic disorders (e.g. SLE, SS or Sjögren’s syndrome) and with solid organ malignancies. Patients should be screened clinically for underlying malignancy, with more detailed investigations reserved for those at high risk (e.g. those with dermatomyositis, age > 45 years or vasculitis) and those not responding to treatment.

Management

• General measures. Rehabilitation should be started early, initially with passive exercises and stretching. Once inflammation is settling, active strengthening/stretching exercises are begun. Patients with dysphagia should be evaluated by a speech therapist. Sunblock is used for those with photosensitivity.

• Drug therapy. Most patients are started on prednisolone 1–2 mg/kg daily in divided doses (usually at least 60 mg/day). There is usually a clinical response and normalization of serum creatine kinase within 1–2 months. Prednisolone is then slowly tapered. During this period patients are monitored for disease flare-ups (recurrent weakness and rise in muscle enzymes) requiring intensification of treatment. All patients require osteoporosis prophylaxis. Immunosuppressants, typically methotrexate or azathioprine, are frequently necessary and are often added at onset as this reduces the time to steroid discontinuation. Patients presenting with severe manifestations, such as dysphagia and alveolitis, are initially treated with 3 days of methylprednisolone 0.5–1 g/daily and occasionally IV gammaglobulin (IV IgG) 400 mg/kg/daily for 5 days (Table 9.2).

Vasculitis

The vasculitides are systemic disorders caused by vessel wall inflammation. Vasculitis should be considered in a systemically ill patient with unexplained involvement of two or more organ systems and in patients with unexplained ischaemia (e.g. claudication, myocardial infarction, stroke or cutaneous ischaemia). Vasculitis can be primary, or secondary to drugs (e.g. antibiotics), infections (e.g. hepatitis B or C, HIV, streptococci), connective tissue diseases (e.g. SLE, RA, Sjögren’s syndrome) and malignancy (e.g. lymphoma, adenocarcinoma). Classification is based on vessel size involved.

Large-vessel vasculitis

Giant cell arteritis (GCA)

This usually affects Caucasians over the age of 50 years. Typical features include constitutional symptoms, temporal headache, jaw claudication and visual disturbance, including blindness. Temporal arteries may be thickened and pulseless. Polymyalgia rheumatica (discussed below) accompanies GCA in 40–50% of cases. The ESR is typically > 50 mm/hour; a temporal artery biopsy is usually diagnostic.

• Treatment

• Prednisolone is started immediately at 40–60 mg daily. (Biopsy can be performed up to 7 days after steroids are started.) The higher dose is used if there is visual disturbance; if this is severe (particularly with unilateral visual loss), it can be preceded with 3 days of IV methylprednisolone (500 mg/day). Symptoms usually settle within 24–48 hours. Provided the disease remains in clinical remission and the ESR normalizes, steroids are slowly weaned over at least 2 years.

• Low dose aspirin is recommended as there is evidence this may offer additional protection against ischaemic events.

• Calcium and vitamin D supplements should be co-prescribed with steroids. Bisphosphonates should also be given.

Polymyalgia rheumatica (PMR)

PMR affects Caucasians over 50 years and is characterized by muscle pain around the neck, shoulder and pelvic girdle, accompanied by early morning stiffness lasting at least 30 mins. Patients may have constitutional symptoms and synovitis (e.g. shoulders, knees, wrists and hands). Approximately 10–20% have or can develop GCA, in which case management is as for GCA. The ESR is over 40 mm/hour in most patients. Temporal artery biopsies are positive in 10–30% and are useful in doubtful cases.

• Treatment. Prednisolone is started at 15 mg daily. There is usually a prompt response within a few days, which can be helpful diagnostically. This dose is maintained for 1 month and subsequently tapered slowly according to clinical response, initially by 2.5 mg weekly. Calcium, vitamin D and bisphosphonates are also co-prescribed for bone protection.

Takayasu’s arteritis

This vasculitis, which affects the aorta and major vessels, is most common in Asian people and occurs mainly in women under 40 years of age. Clinical features include early systemic symptoms followed by vascular features (claudication, headaches, dizziness, syncope, hypertension), associated with asymmetrical pulses and high BP. Arterial imaging with CT, MRI, PET or angiography is diagnostic.

• Treatment. Treatment is with a steroid-reducing regimen, starting at 1–2 mg/kg (usually 60 mg/day) and weaning according to clinical response. Methotrexate weekly or azathioprine is used in refractory disease.

Medium-vessel vasculitis

Polyarteritis nodosa (PAN)

This rare disorder is most common in middle-aged men. Clinical features include systemic symptoms, myalgia, arthralgia/arthritis, skin lesions (livedo reticularis, ulcers, necrosis), peripheral neuropathy (particularly mononeuritis multiplex), abdominal pain, renal disease and hypertension. Up to one-third of patients have hepatitis B infection. Renal or mesenteric angiography may be diagnostic, avoiding the necessity for a tissue biopsy.

• Treatment. Prednisolone 1 mg/kg/day is first-line therapy, given as a gradually reducing regimen with the aim of withdrawal over 1 year. Some patients require long-term, low-dose prednisolone. Patients with major organ involvement (renal, neurological, gastrointestinal or cardiac) should additionally be given cyclophosphamide either orally 2 mg/kg/day or IV 2–4-weekly (Table 9.2). Once remission is achieved (usually 3–6 months), cyclophosphamide can be substituted with methotrexate or azathioprine for a total duration of treatment of 1–2 years. Relapses are rare. Concomitant modification of vascular risk factors is necessary (stop smoking; control BP, diabetes and hyperlipidaemia). Patients with hepatitis-associated PAN benefit from antiviral therapy. Entecavir plus plasma exchange is used with severe vasculitis over 2–3 months; if hepatitis is active, cyclophosphamide must not be used and prednisolone should be tapered quickly (2–3 weeks).

Small-vessel vasculitis

These disorders — Wegener’s granulomatosis, Churg–Strauss syndrome and microscopic polyangiitis — are all associated with antineutrophilic cytoplasmic antibodies (ANCA) (90%, 60% and 80% respectively).

• Wegener’s granulomatosis (WG) involves the upper respiratory tract, causing a bloody nasal discharge, oral ulcers and hoarseness. Lower respiratory tract symptoms also develop. A rapidly progressive glomerulonephritis and neurological involvement occur.

• Churg–Strauss syndrome (CSS) is asthma associated with an eosinophilia of > 10% of total white cells. Skin features (purpura), cardiovascular features (myocardial infarction), GI bleeding, polyneuropathy and strokes occur.

• Microscopic polyangiitis (MPA) is similar to Wegener’s but without upper respiratory tract involvement.

Management

Management of these disorders is similar to that of PAN (see above). Most patients with WG or MPA will require cyclophosphamide in combination with steroids for induction of disease remission in view of renal involvement; in contrast, many (80%) with CSS can be managed only with steroids. For stable patients with WG or MPA without renal disease and mild involvement of other organs, methotrexate can be used with prednisolone from the initial stages. Although medication can often be discontinued within 2 years, relapses are common, particularly with WG, necessitating long-term follow-up and, if necessary, reintroduction of treatment. In WG, other measures include nasal saline irrigation and treatment of nasal superinfection (particularly Staphylococcus aureus) with antibiotics and sometimes with surgical drainage. Severe forms of CSS require cyclophosphamide followed by azathioprine.

Septic arthritis

Non-gonococcal septic arthritis

Clinical features

This typically causes a monoarthritis of large joints, most commonly due to Staph. aureus, streptococcal species or, less commonly, Gram-negative organisms. The knee is the most common joint affected. Predisposing factors include immunosuppression and pre-existing structurally abnormal joints. Patients most often present with an acute monoarthritis, usually with erythema, marked limitation of movement and fever. Elderly patients may be apyrexial and have a normal white cell count. Blood cultures are positive in 50%. Joint fluid must be aspirated for Gram stain (60% positive) and culture (95% positive).

Management – See Chapter 20 (Emergencies in medicine p. 710)

• Mobilization. Initially the joint should be splinted for pain control but mobilization should begin within the first week with passive range-of-movement exercises, followed by strengthening exercises.

• Drainage. All septic joints should be drained, either by serial needle aspiration (may require daily aspiration) or surgically (e.g. arthroscopic).

• NSAIDs. These are given for pain control.

• Empirical antibiotic treatment in septic arthritis. IV antibiotics are started after joint aspiration and after the Gram stain result is known, but before culture results are obtained (Table 9.5). Discuss with a microbiologist.

• Infected prostheses. These should be removed.

Table 9.5 Antibiotics used in septic arthritis and osteomyelitis

Organism	Antibiotic
Gram-positive organism (staphylococcus, streptococcus)	IV flucloxacillin 1–2 g 4 times daily and oral fusidic acid 500 mg 3 times daily If penicillin allergy — replace flucloxacillin by erythromycin 1 g IV 4 times daily or clindamycin 600 mg IV 3 times daily If MRSA suspected — use vancomycin to replace flucloxacillin
Gram-negative organism	Cefotaxime IV 1 g twice daily
No organism seen	IV flucloxacillin 1–2 g 4 times daily and oral fusidic acid 500 g 3 times daily, or cefotaxime IV 1 g twice daily in sexually active, ?gonococcus in immunosuppressed, elderly and IV drug users Penicillin allergy as above

MRSA, meticillin-resistant Staphylococcus aureus.

Gonococcal septic arthritis

Neisseria gonorrhoeae typically causes a septic arthritis in young sexually active adults with normal joints. Presentation may be identical to that of non-gonococcal arthritis, but often there are associated migratory polyarthralgia, tenosynovitis and vesiculo-pustular lesions. Synovial fluid Gram stain is positive in only 25% and culture in 50%, but the organism may be isolated by culturing from other potential portals of entry, e.g. cervix, urethra or skin lesions. Nucleic acid amplification tests on urine are non-invasive and highly sensitive.

Management

Non-drug therapy is as for non-gonococcal septic arthritis but surgical drainage is rarely required.

• Ceftriaxone IV 1 g/daily for 24–48 hours is followed by oral ciprofloxacin 500 mg twice daily or, if the organism is penicillin-sensitive, amoxicillin 500 mg 4 times daily; in penicillin-allergic patients ciprofloxacin can be the initial IV agent. Treatment is for a total of 2 weeks.

• Patients should also be treated for silent Chlamydia (e.g. doxycycline 100 mg twice daily for 1 week). Sexual partners should be screened.

Other types of infective arthritis

Bacteria, viruses and fungi can cause arthritis.

• Brucellosis (p. 38). This usually causes a mono- or oligo-arthritis, which may be septic or reactive. Arthritis is more common in chronic infections.

• Lyme disease (p. 40). Around 25% develop an acute pauci-articular arthritis, which usually resolves. Another 20%, however, go on to develop a chronic arthritis. Treatment, which may take months, is with antibiotics and analgesics.

• Viral infections. A transient polyarthritis or arthralgia can occur before, during or after many viral illnesses. Treatment of the arthritis is symptomatic.

Osteomyelitis

Clinical features

This is most common at the extremes of age and is usually due to staphylococcal infection; less common causes are Gram-negative rods, anaerobic organisms and TB. Patients generally have predisposing factors, such as open wounds, diabetes, IV drug use, immunosuppression or sickle cell disease. In adults the vertebral bodies are the most common site of infection. Patients usually have local bone pain/tenderness but fever is not invariable. Vertebral osteomyelitis can cause neurological signs.

Investigations

• ESR is generally raised but the white cell count may not be.

• X-ray changes of bone destruction and periosteal reaction take at least 2 weeks to develop but the bone scan, CT and MRI show early abnormalities.

• Microbiological diagnosis requires blood cultures (50% positive), wound cultures or bone biopsy (gold standard).

Management

In the acute stages the bone should be rested/immobilized. Many adults will require surgery to debride necrotic bone, to gain bone stability or to manage a discharging sinus or local abscess.

• Drug therapy (Table 9.2). Antibiotics are often given empirically to cover staphylococcal infection (e.g. flucloxacillin + fusidic acid or vancomycin if MRSA is suspected) until culture results are known. Gram-negative organisms should additionally be covered in the elderly. Subsequent antibiotic treatment should be guided by a microbiologist. Analgesia is required. For acute infection, antibiotics are given for 4–6 weeks with at least 2 weeks of IV therapy; for chronic osteomyelitis up to 6 months of antibiotics are required. TB requires anti-TB drugs for 12–18 months (p. 513).