The most common rheumatological emergency seen in the emergency department (ED) is acute monoarthritis (see Ch. 14.2). This chapter discusses the important emergencies associated with general rheumatological conditions. Many of these are multisystem diseases and emergencies may be related either to a primary joint problem or to an extra-articular manifestation of the disease. As many of these conditions are autoimmune, suppression of the immune system is usually central to their management. This can be complicated by infection, which can relate to usual pathogens but also opportunistic infection.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) affects 1–2% of the population across most ethnic subgroups and is two to three times more common in females than males. RA is a systemic inflammatory condition of unknown aetiology characterized by widespread synovitis resulting in joint erosions and destruction. It may also produce extra-articular manifestations, including vasculitis and visceral involvement.

Management typically involves symptom relief with non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, and prevention of disease progression with disease modifying antirheumatic drugs (DMARDs). These include methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. Newer, so-called biologic agents act by inhibiting tumour necrosis factor-α (TNF-α) (infliximab, etanercept, adalimumab) or interleukin-1 (anakinra) and are currently used for patients who fail traditional DMARD therapy. Rituximab is also recently available for those who fail the aforementioned medications – its mechanism of action is B-cell depletion. See Chapter 14.3 for further details on the clinical features of RA, its diagnosis, useful investigations and principles of management.

EMERGENCIES IN RA – ARTICULAR MANIFESTATIONS

Acute monoarthritis

The patient with established RA may present with an acutely painful, hot, swollen joint that may be a manifestation of the underlying condition. Alternatively, it may signal septic arthritis, a condition to which patients with RA are 2–3 times more susceptible than matched controls.¹ The possibility of septic arthritis should be considered in a patient with RA who has acute monoarthritis out of keeping with their disease activity. See Chapter 14.2 for the approach to acute monoarthritis.

Cervical spine involvement

Cervical spine involvement in RA is a common finding with a prevalence of up to 61%.² It is more common in those with long-standing, erosive disease and disease of greater severity and activity.³ Cervical spine involvement is associated with increased mortality.⁴ Involvement of the cervical spine may manifest as atlanto-axial subluxation (most commonly anterior movement on the axis) or subluxation of lower cervical vertebrae. Either of these can result in cervical myelopathy.

Cervical spine subluxation is frequently asymptomatic, up to 44% in one study.³ The most common symptom of cervical spine involvement is neck pain that may radiate towards the occiput. Other suggestive symptoms include slowly progressive spastic quadriparesis, sensory loss in hands or feet and paraesthesiae or weakness in the distribution of cervical nerve roots.

Important ‘red flag’ features suggestive of cervical myelopathy are shown in Table 14.1.1.

Table 14.1.1 Symptoms and signs of cervical myelopathy

Symptoms

Pain

Weakness

Peripheral paraesthesiae

Gait disturbance

Sphincter dysfunction

Changes in consciousness

Respiratory dysfunction

Signs

Spasticity

Weakness

Hyperreflexia of deep tendon reflexes

Extensor plantar response

Gait ataxia

Respiratory irregularity

Investigations

Plain X-rays of the cervical spine (lateral view) may demonstrate an increase in separation between the odontoid and arch of C1. Prior to taking flexion-extension films, perform plain ‘peg’ X-rays through the open mouth to exclude odontoid fracture or severe atlanto-axial subluxation. Computerized tomography (CT) can occasionally provide additional useful information; however, if there is concern regarding myelopathy, magnetic resonance imaging (MRI) is the most sensitive imaging technique.

Management

The primary implication of RA of the cervical spine in the ED is when endotracheal intubation is required. Inappropriate manipulation of the rheumatoid cervical spine in preparation for intubation can result in significant morbidity and even mortality from atlanto-axial and subaxial subluxation. Where possible, patients with RA who are scheduled to undergo surgery should have imaging of their cervical spine performed prior to intubation. Anaesthetic consultation may be required.

Patients with subluxation and signs of spinal cord compression are a neurosurgical emergency and prompt referral is essential.

EMERGENCIES IN RA – EXTRA-ARTICULAR MANIFESTATIONS

Rheumatoid vasculitis

Vasculitis in RA can occur in both small- and medium-sized vessels. Patients typically have long-standing, aggressive joint disease.

Clinical features

Presentations with rheumatoid vasculitis are varied and non-specific. Patients frequently present with constitutional symptoms and fatigue. The most common manifestation is of cutaneous vasculitis with deep skin ulcers on the lower limbs,⁵ digital ischaemia and gangrene (medium vessels) or palpable purpura (small vessels). Mononeuritis multiplex is another common presentation and results from infarction of the vasa nervorum due to vasculitis. It typically has an acute onset.

Medium vessel rheumatoid vasculitis can also produce organ infarction and necrosis. Rheumatoid vasculitis may mimic polyarteritis nodosa (PAN) with involvement of the renal arteries, and less commonly the mesenteric circulation. Pericarditis may accompany rheumatoid vasculitis but coronary vasculitis is rare. Ocular manifestations include episcleritis and peripheral ulcerative keratitis. Central nervous system (CNS) involvement is rare.

Investigations

Rheumatoid factor titre is typically elevated in rheumatoid vasculitis, although this is a non-specific finding. Rheumatoid vasculitis in the absence of rheumatoid factor is rare. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are also elevated. Check a mid-stream urine specimen for active urinary sediment and a full blood count, urea and electrolytes.

Further investigations are directed by the relevant organ system involved and usually require specialist consultation:

• skin biopsy

• nerve conduction studies/electromyography (EMG)

• sural nerve biopsy

• kidney biopsy.

Angiography findings are non-specific and not always diagnostic.

Diagnosis

Suspect rheumatoid vasculitis in patients with a long-standing history of seropositive RA who presents with constitutional symptoms and one of the above clinical features, such as a typical rash, digital gangrene, red eye, neurological symptoms or active urinary sediment.

Management

Systemic rheumatoid vasculitis has a poor prognosis without immune-suppressive therapy. Urgent rheumatology consultation is required as treatment usually consists of high-dose corticosteroids as well as cyclophosphamide.

Summary of other extra-articular manifestations of RA

Lung disease

Lung disease may manifest as a pleural-based disease such as pleurisy or pleural effusions, or parenchymal lung disease such as interstitial lung disease (the most common manifestation), organizing pneumonia and rheumatoid nodules. Caplan’s syndrome occurs when RA is associated with pneumoconiosis. Important differential diagnoses include infection due to immune-suppression, treatment-related toxicity (e.g. methotrexate-induced pneumonitis) and other medical comorbidities such as chronic obstructive pulmonary disease.

Pleural disease often resolves without treatment, alternatively a NSAID may be used. Parenchymal disease as documented on chest X-ray or high-resolution CT requires specialist treatment.

Cardiac disease

Pericarditis occurs in 30% of RA patients based on echocardiography, but less than 10% have any clinical features. It generally occurs when there is active joint and other extra-articular disease. Management consists of NSAIDs or prednisolone.

Myocarditis is a rare manifestation of RA. It can be granulomatous and depending on its location may produce valvular (especially mitral) incompetence or conduction defects.

Sjogren’s syndrome

Sjogren’s syndrome may present in its primary form as a systemic disease, but can also occur secondary to RA and other connective tissue disorders. The classic symptoms are dry gritty eyes, dry mouth or both. Treatment is usually symptomatic in patients with no other features.

Felty’s syndrome

Felty’s syndrome is characterized by seropositive RA, splenomegaly and neutropenia. There may be other cytopenias, as well as leg ulcers.

Kidney disease

Renal involvement in RA is rare and includes vasculitis and glomerulonephritis. Secondary amyloidosis can occur in patients with long-standing active disease. However, many medications used in RA are nephrotoxic, in particular NSAIDs and ciclosporin.

Neurological disease

Vasculitis may produce mononeuritis multiplex, as mentioned previously, otherwise central nervous system involvement is rare.

Cardiovascular disease in RA and other connective tissue diseases

Patients with RA and other connective tissue diseases such as systemic lupus erythematosus (SLE) have an increased risk of ischaemic heart disease (IHD).⁶ This occurs independently of traditional risk factors such as smoking or dyslipidaemia, and is more common in those with extra-articular disease.⁷ The higher incidence of IHD could be related to disease factors such as widespread inflammation, or to medications used such as NSAIDs (including selective COX-2 inhibitors) and corticosteroids.

The emergency physician needs a low threshold for ruling out ischaemic causes of chest pain in the RA patient. Routine investigations are no different to those undertaken for non-RA patients. A patient with suggestive history but negative cardiac biomarkers and normal electrocardiograms should proceed to stress testing as per the recommendations for the general population. Management of acute coronary syndrome in RA is no different.

SYSTEMIC LUPUS ERYTHEMATOSUS

SLE is a multisystem, autoimmune disease. It is the prototype disease of immune complex deposition resulting in tissue damage across a variety of organ systems. It is one of the most common autoimmune conditions among women of childbearing age.

Clinical features

Common presenting features of SLE include general constitutional symptoms such as fatigue, malaise and weight loss. There are a variety of skin manifestations that can occur in SLE which are lupus-specific (malar rash, discoid lupus, subacute cutaneous lupus erythematosus) or non-specific (panniculitis, alopecia, oral ulceration). Arthralgias or an acute non-erosive arthritis are the most common presenting symptoms of SLE. Myositis may also occur. Another common manifestation is serositis producing pleurisy, pericarditis or peritonitis. SLE also causes renal and CNS disease (see below) and rarely can involve the lung (pneumonitis, pulmonary hypertension) and the heart (myocarditis, endocarditis).

Investigations

A full blood examination often reveals cytopenias which are a common feature of SLE. Biochemistry investigations may indicate renal involvement. Clotting abnormalities may include a prolonged activated partial thromboplastin time due to the lupus anticoagulant. ESR and CRP may be raised.

Serological abnormalities

Serological abnormalities may reveal decreased levels of complement components C3 and C4, as well as the presence of auto-antibodies. The antinuclear antibody (ANA) is present in 95% of patients with SLE, but may also occur in a variety of other connective tissue and inflammatory diseases. The anti-Smith (Sm) and anti-dsDNA (double-stranded DNA) antibodies are more specific for SLE but less sensitive. The anti-Sm is obtained as part of a panel of tests for extractable nuclear antigens (ENA).

Other tests are directed towards the organ system involved, for example mid-stream urine specimen looking for proteinuria or glomerular haematuria (>70% dysmorphic red blood cells or red-cell casts) or chest X-ray for the patient with serositis.

Assessing SLE disease activity

It is important in the ED to determine SLE disease activity. Useful symptoms of disease activity include mouth ulcers, alopecia and constitutional symptoms, as well as organ-specific symptoms such as arthralgia or pleuritic chest pain.

Investigations used to assess disease activity include complement levels (low in active SLE), CRP and ESR (elevated), as well as anti-dsDNA titre. These are not diagnostic and many people with quiescent SLE may remain hypocomplementaemic or display elevated anti-dsDNA titres.

A mid-stream urine for urinary sediment is an essential part of the assessment of the SLE patient, as a marker of renal involvement.

Management

Management of SLE is directed by the organ system involved, and includes topical therapies for cutaneous lupus and NSAIDs for arthralgias and mild serositis. Most patients with SLE will be on an antimalarial such as hydroxychloroquine, which is helpful for skin and musculo-skeletal manifestations, as well as organ involvement. Many patients will also be on corticosteroids. Those with major organ involvement will also be taking other immunosuppressants such as methotrexate, cyclophosphamide or azathioprine. Mycophenolate mofetil is emerging as an alternative to cyclophosphamide for lupus nephritis.

Lupus nephritis

Early diagnosis of lupus nephritis is essential in instituting prompt management and preventing the progression of renal damage. Patients may be asymptomatic, or present with nocturia or ‘frothy’ urine. Other presentations include hypertension, the nephritic syndrome and the nephrotic syndrome.

Urinalysis is the most useful investigation in detecting lupus nephritis, and proteinuria is the most common abnormality detected. The fresh urine specimen should be sent for phase contrast microscopy in order to detect the presence of dysmorphic erythrocytes (>70 % indicates glomerular disease) or cellular casts.

Urinalysis can expedite the investigation and further management of this potentially organ-threatening condition. Prompt referral to a rheumatologist or renal physician for consideration of renal biopsy and further management is indicated.

Neuropsychiatric SLE

There are a myriad of neuropsychiatric manifestations of neuropsychiatric SLE. Neurological presentations include:

• stroke (due to vasculitis, emboli, atherosclerosis or antiphospholipid antibodies)

• seizure

• migraine

• aseptic meningitis.

Psychiatric presentations include:

These presentations are non-specific and have a broad differential diagnosis which includes medication side effects, infection and tumour. Unfortunately, there is no specific diagnostic test which helps differentiate SLE from other potential aetiologies. Thus, the diagnosis is made from a range of diagnostic tests and clinical features. The role of the emergency physician in this setting is to exclude common non-SLE presentations such as meningitis or intracranial haemorrhage.

Imaging studies are necessary in addition to tests for SLE activity (see above). CT brain scan may detect changes of acute infarction but is also useful in excluding other unrelated causes such as haemorrhage or tumour. MRI is more sensitive in detecting white matter abnormalities although these are frequently non-specific.

Cerebrospinal fluid (CSF) analysis is essential to exclude infection, but may be normal in SLE. Changes such as elevated protein, low glucose or even a positive ANA are non-specific and do not always reflect active SLE. The electro-encephalogram is occasionally useful in cases of suspected non-convulsive status epilepticus with unexplained altered conscious level.

GIANT CELL (TEMPORAL) ARTERITIS AND OTHER VASCULITIDES

Giant cell (temporal) arteritis

Giant cell arteritis (GCA) is the most common vasculitis and almost exclusively affects Caucasians. It is a large and medium vessel vasculitis of unknown aetiology, which predominantly affects the cranial branches of arteries originating from the aortic arch.

Polymyalgia rheumatica (PMR) is a syndrome of inflammatory pain and stiffness in the shoulder and pelvic girdles that occurs alone or frequently in association with GCA.

Epidemiology

GCA and PMR rarely occur before the age of 50 years of age.⁸ The mean age at diagnosis is approximately 72 years, with an incidence of GCA of roughly 1 in 500 of people over the age of 50 years. The incidence and prevalence of PMR are less well studied.

Clinical features

The most common symptom of GCA is headache, usually localizing to the temporal region, although it can be more diffuse. The area is often tender and worsened by brushing the hair. Most patients complain of constitutional symptoms such as malaise, fatigue, anorexia and weight loss. Jaw claudication (pain after a period of chewing) is the most specific symptom for GCA, although not sensitive, as it is only present in 34%.⁸ On examination the temporal arteries may be thickened, ‘ropey’ and tender with an absent or reduced pulse.

The most significant complication of GCA is anterior ischaemic optic neuropathy resulting in sudden painless loss of vision. Less commonly, other branches of the aorta may be involved resulting in hemiparesis, arm claudication, aortic dissection or myocardial infarction.

Polymyalgia rheumatica

PMR usually affects the neck, shoulder and pelvic girdles resulting in stiffness and inflammatory pain, worse in the morning and after rest. The pain is often poorly localized and there may be muscle atrophy late in the disease. There can also be evidence of synovitis affecting the shoulders, knees, wrists and hands.

The relationship between onset of symptoms of GCA and PMR is highly variable. PMR symptoms may occur before, after or with GCA symptoms.

Differential diagnosis of PMR and GCA

The differential diagnosis of PMR includes late-onset RA, inflammatory myositis and other myopathies, fibromyalgia and hypothyroidism. GCA can mimic any of the other vasculitides. Non-arteritic anterior ischaemic optic neuropathy can also mimic GCA.

Investigations

The classic non-specific laboratory finding in GCA and/or PMR is a markedly elevated ESR (often >100 mm/h). CRP is also usually elevated, and full blood count often shows a mild normochromic normocytic anaemia.

A temporal artery biopsy confirms the diagnosis of GCA and is particularly useful when the diagnosis is doubtful or the presentation atypical. Unfortunately, there is a false negative rate of 10–30%, so a negative biopsy does not exclude GCA.

Criteria for diagnosis

The ACR classification criteria for GCA are helpful in differentiating GCA from other forms of vasculitis.⁹ They include age at onset >50 years, a new headache, temporal artery tenderness or decreased pulsation and an ESR >50. An abnormal artery biopsy showing vasculitis with mononuclear infiltrate or granulomatous inflammation with multi-nucleated giant cells is also required to confirm the diagnosis.

Management

Corticosteroids are the treatment of choice and should not be withheld to perform a biopsy, if there is a strong clinical suspicion. The initial dose for GCA is unclear, but prednisone 1mg/kg/day is usually indicated ¹⁰ especially for ischaemic complications; however, lower doses such as prednisone 40–50mg have been used.¹¹ The dose of prednisone for PMR alone is lower at 10–20mg/day.¹¹ Most patients do not require hospital admission, provided a temporal artery biopsy can be organized within a few days. However, patients with visual loss at diagnosis require urgent treatment, often with pulsed parenteral corticosteroids, and inpatient admission. Patients with GCA should also be commenced on aspirin.

An approach to the systemic vasculitides

The systemic vasculitides are a group of disorders characterized by an inflammatory infiltrate in the walls of blood vessels resulting in damage to the vessel wall. The clinical manifestations depend upon the size of vessel and location in the vascular tree and may result in systemic or organ-specific manifestations. Table 14.1.2 classifies vasculitic syndromes according to vessel size (there is much overlap).

Table 14.1.2 Classification of systemic vasculitis according to vessel size

Vessel size	Vasculitis
Large	Takayasu’s arteritis
Large	Giant cell arteritis
Medium	Polyarteritis nodosa
Medium	Kawasaki disease
Small	Wegener’s granulomatosis (ANCA+)
	Microscopic polyangiitis (ANCA+)
	Churg–Strauss syndrome
	Henoch–Schonlein purpura
	Cryoglobulinaemic vasculitis
	Leukocytoclastic cutaneous vasculitis

Investigations and diagnosis

Baseline investigations should include FBE, U&E, LFTs and clotting studies as well as CRP and ESR. Blood cultures should be taken if the patient is systemically unwell.

A panel of auto-immune serological tests is carried out in suspected cases. This includes ANA, ENA, rheumatoid factor, dsDNA, anti-cyclic citrullinated peptides (anti-CCP), complement levels (C3, C4), antineutrophil cytoplasmic antibodies (ANCA) and cryoglobulins. PAN is associated with hepatitis B and cryoglobulinaemic vasculitis with hepatitis C infection.

Collection of a mid-stream urine specimen to look for glomerular haematuria is mandatory when vasculitis is suspected. Imaging is required such as chest X-ray, CT scan of the chest or sinuses or other areas depending on the suspected organ involved. The definitive diagnosis of vasculitis requires biopsy of affected tissue or angiography.

Differential diagnosis of systemic vasculitis

Other conditions which may mimic vasculitis include:

• infections such as infective endocarditis, meningococcaemia, gonococcaemia

• disorders of haemostasis and thrombosis such as thrombotic thrombocytopenic purpura, antiphospholipid syndrome

• malignancy such as lymphoma, myxoma

• sarcoidosis.

Management of systemic vasculitis

Treatment is usually with high-dose corticosteroids and, depending on the condition, additional immunosuppression such as cyclophosphamide. Urgent specialist referral is essential.

Emergencies associated with rheumatology therapy

The medications used most commonly in rheumatology include NSAIDs, corticosteroids and DMARDs. Over the past 5 to 10 years, the ‘biologic’ DMARDs have become available for the treatment of RA, psoriatic arthritis and ankylosing spondylitis. These medications are all associated with adverse effects which occasionally result in serious morbidity.

Non-steroidal anti-inflammatory drugs

NSAIDs are used for symptom relief in a variety of conditions, especially inflammatory joint pain. They are of equal efficacy, although those with shorter half lives appear to have less gastrointestinal toxicity.¹² NSAIDs should be used in the lowest possible dose for the shortest duration and combination of NSAIDs (not aspirin) should be avoided.¹²

The most common adverse effects of NSAIDs seen as an emergency include peptic ulcer disease and acute renal failure, both related to inhibition of prostaglandin synthesis. GI toxicity is more common in the elderly, those on anticoagulants and with high doses or prolonged duration of NSAIDs. Prescribe a proton pump inhibitor when there is concern about GI toxicity. The COX-2 selective inhibitors such as celecoxib have a reduced incidence of peptic ulcer disease, but a similar incidence of other adverse effects including hypertension, peripheral oedema and cardiac failure and in particular an increased risk of cardiovascular deaths with prolonged courses.

Corticosteroids

Corticosteroids are the mainstay of treatment for most inflammatory rheumatological conditions. At high doses they provide rapid control of inflammatory disease and are often required for long-term management at low doses. Long-term use is associated with numerous adverse effects such as diabetes, hypertension and osteoporosis. In addition, psychosis and mood disorders related to corticosteroid use as well as peptic ulcer disease may present as an emergency.

Immunosuppressants/disease modifying antirheumatic drugs

This heterogeneous group of medications is used to prevent joint destruction in the inflammatory arthritides and as steroid-sparing therapy in many connective tissue diseases. They include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, ciclosporin, azathioprine and cyclophosphamide. Each drug has its own range of adverse effects, but common adverse effects presenting at an ED include cytopenias, rashes including the Stevens–Johnson syndrome, abnormal liver function tests, GI toxicity and heightened susceptibility to infections (see Table 14.1.3).

Table 14.1.3 Adverse effects of disease modifying antirheumatic drugs (DMARDs)

DMARD	Adverse effects
Methotrexate	Nausea and other GI upset, mouth ulcers, abnormal liver function (transaminases), bone marrow suppression, rash, alopecia, pneumonitis Teratogenic Increased bone marrow toxicity in renal impairment – withhold in acute renal failure
Leflunomide	Abnormal liver function (transaminases), diarrhoea, rash, alopecia, hypertension, peripheral neuropathy Teratogenic
Hydroxychloroquine	Nausea, rash, dizziness (‘cinchonism’), retinal toxicity at higher doses (all uncommon)
Sulfasalazine	GI upset, uncommonly abnormal liver function and bone marrow suppression, rashes (rarely, Stevens–Johnson syndrome)
Ciclosporin	Renal impairment, hypertension, electrolyte disturbance, hyperuricaemia and gout, gingival hyperplasia, hirsutism
Cyclophosphamide	Bone marrow suppression especially neutropenia, GI upset, bladder toxicity, including haemorrhagic cystitis (acute) and bladder cancer (chronic), opportunistic infections Teratogenic
Azathioprine	GI upset, rash, systemic symptoms, abnormal liver function, bone marrow suppression, skin cancers, infections

GI, gastrointestinal.

Biologic disease modifying antirheumatic drugs

The so-called ‘biologic’ DMARDs are a newer and expanding collection of therapies directed against molecules that mediate joint destruction and help drive the inflammatory process. Principally, agentsare directed against TNF-α such as adalimumab, etanercept and infliximab, and against interleukin-1 (IL-1) such as anakinra. More recently, rituximab has become available for those who fail the above therapies. Its main function is to deplete B lymphocytes from peripheral circulation. These therapies are being increasingly used for those who fail conventional DMARD therapy for RA.

Adverse effects of biologic DMARDs

Adverse effects associated with the use of TNF-α inhibitors include a heightened risk of all infections, particularly soft-tissue and joint infections, as well as re-activation of tuberculosis. Other opportunistic infections appear more common such as listeriosis. Patients may also develop local injection site reactions and infusion-related reactions, which may be delayed. Less common adverse effects include a form of drug-induced lupus and demyelination.

Presentations of treatment-related emergencies

Bone marrow suppression

Anaemia, leukopenia and thrombocytopenia all occur in patients taking DMARDs such as methotrexate, cyclophosphamide, sulfasalazine and azathioprine. The patient who presents with sepsis and leukopenia is a medical emergency and requires resuscitation, supportive care and broad-spectrum parenteral antibiotics.

Cytopenia in a patient taking methotrexate is uncommon but those at increased risk include the elderly and with renal impairment, related to the drug’s mechanism of action as an inhibitor of dihydrofolate reductase. Management involves temporary cessation of treatment and administration of folinic acid.

The most common adverse effect of cyclophosphamide is myelosuppression, particularly leukopenia. The white cell nadir occurs at 2 weeks post infusion following intravenous therapy. Patients on oral therapy may experience a gradual decrease in white cell count.

Bone marrow suppression may also occur as a side effect of azathioprine treatment especially if given in combination with allopurinol, which inhibits its metabolism, thus potentiating bone marrow toxicity. Cytopenias are also more common in patients with deficient thiopurine methyltransferase enzyme. Sulfasalazine therapy is uncommonly complicated by bone marrow suppression.

Infections

Treatment of rheumatological conditions is directed at immunosuppression, thus infections are a common and expected adverse effect of corticosteroids, certain DMARDs and, in particular, anti-TNF-α therapy. Although studies have shown RA patients to have a de novo increased risk of infection, biologic DMARDs may further increase this risk.

Some studies have reported an increased risk of infection and serious infection in patients receiving anti-TNF therapy, although the largest study of infection risk in patients on anti-TNF agents showed that while there is an increased risk of skin and soft tissue injections, there was no significant difference in risk of serious infections.¹³ Patients on anti-TNF therapy who develop infections are advised to temporarily cease their treatment and to commence antibiotics. If in doubt, they should be admitted to hospital to receive parenteral antibiotics. There is also an increased risk of re-activation of tuberculosis and possibly of infections with other organisms such as Listeria and Salmonella.¹³ Rigorous tuberculosis screening prior to commencement of anti-TNF therapy should now be universal.

DMARD-related pneumonitis

Methotrexate and leflunomide both result in lung toxicity. The incidence of methotrexate-induced lung toxicity is difficult to assess but uncommon. The most common type of toxicity is a hypersensitivity pneumonitis, but other forms of lung injury may also occur. Clinical features are non-specific and include constitutional symptoms, cough and progressive dyspnoea. Subacute presentations are more common, although acute and chronic presentations may also occur, with rapid progress to respiratory failure in more acute situations. Patients at higher risk for methotrexate-induced lung injury have prolonged duration of methotrexate treatment, pre-existing rheumatoid involvement of the lungs and pleura, increased extra-articular manifestations, diabetes mellitus, previous DMARD use and low serum albumin.¹⁴ Age and smoking also appear to be important.

Imaging reveals interstitial opacities and patchy consolidation. High-resolution CT scanning typically shows a ground-glass appearance. The main differential diagnosis is of a respiratory infection which may be due to typical pathogens or opportunistic infections such as Pneumocystis jirovecii.

Management is supportive with empiric antibiotic therapy in case of infection. Corticosteroids are also used. Patients may become seriously ill and require intensive care, but mortality is still low (1%).

Leflunomide may also cause lung injury, typically in the first few months of therapy and usually when given in combination with methotrexate.

Allopurinol hypersensitivity syndrome

Minor hypersensitivity reactions to allopurinol occur in around 2% of patients and usually consist of a mild rash. Rarely, a severe hypersensitivity syndrome may present as an unwell patient with fever, erythematous rash, abnormalities of liver function, peripheral blood eosinophilia and acute renal failure due to interstitial nephritis.¹⁵ It is more common in those with renal impairment who do not have appropriate dose reduction. This presentation has a mortality rate of 25%. Treatment is supportive.

References

1 Margaretten ME, Kohlwes J, Moore D, et al. Does this adult patient have septic arthritis? Journal of American Medical Association. 2007;297:1478-1488.

2 Collins DN, Barnes CL, Fitzrandolph RL. Cervical spine instability in rheumatoid patients having total hip or knee arthroplasty. Clinical Orthopaedics and Related Research. 1991;272:127-135.

3 Neva MH, Hakkinen A, Makinen H, et al. High prevalence of asymptomatic cervical spine subluxation in patients with rheumatoid arthritis waiting for orthopaedic surgery. Annals of Rheumatic Diseases. 2006;65:884-888.

4 Riise T, Jacobsen BK, Gran JT. High mortality in patients with rheumatoid arthritis and atlantoaxial subluxation. Journal of Rheumatoloy. 2001;28:2425-2429.

5 Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Seminars in Arthritis and Rheumatism. 2006;36:88-98.

6 Turesson C, Jarenros A, Jacobsson L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Annals of Rheumatic Diseases. 2004;63:952-955.

7 Turesson C, Jarenros A, Jacobsson L. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Annals of Rheumatic Diseases. 2007;66(1):70-75.

8 Smetana GW, Shmerling RH. Does this patient have temporal arteritis? Journal of American Medical Association. 2002;287:92-101.

9 Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatololgy 1990 criteria for the classification of giant cell arteritis. Arthrtitis Rheumatics. 1990;33:1122-1128.

10 Spiera RF, Spiera H. Therapy for giant cell arteritis: can we do better? Arthritis Rheumatics. 2006;54:3071-3074.

11 Kyle V, Hazleman BL. Treatment of polymyalgia and giant cell arteritis: 1. Steroid regimens in the first two months. Annals of Rheumatic Diseases. 1989;48:658-661.

12 Therapeutic Guidelines. Rheumatology, Version 1. Melbourne: Therapeutics Guidelines Ltd, 2006.

13 Dixon WG, Watson K, Lunt M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection in rheumatoid arthritis patients receiving anti-tumour necrosis factor therapy. results from the British Society of Rheumatology Biologics Register. 2006;54:2368-2376.

14 Alarcon GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicentre, case control study. Annals of Internal Medicine. 1997;127:356-364.

15 Guttierez-Macias A, Lizarralde-Palacios E, Martinez-Odriozola P, et al. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. British Medical Journal. 2005;331:623-624.

SEPTIC ARTHRITIS

The assessment of a patient with acute monoarthritis is focused on excluding a septic arthritis. Septic arthritis can cause rapid joint destruction, and mortality has been reported as high as up to 15%.¹

Pathogenesis and pathology

Non-gonococcal bacterial arthritis occurs when bacteria enter the synovial lining of a joint via the haematogenous route, local spread from nearby soft tissue infections or following penetrating trauma or injury to a joint.

When the bacteria reach the synovium they trigger an inflammatory response, and bacteria and inflammatory cells enter the synovial fluid in the joint space, causing swelling and destruction of articular cartilage. These destructive changes may extend to subchondral bone and produce irreversible damage within days. The commonest causative organisms are staphylococci and streptococci.

Epidemiology and risk factors

The prevalence of septic arthritis among patients presenting to an emergency department with acute monoarthritis is up to 27%.²

Risk factors for septic arthritis include inflammatory arthritis (especially rheumatoid arthritis), diabetes mellitus and systemic factors such as age greater than 80 years, as well as local factors such as recent joint surgery, joint prosthesis and overlying skin infection. These individual risk factors increase the risk of septic arthritis by two- to three-fold.³ Skin infection overlying a prosthetic joint increases the risk of infection by 15-fold.³

Clinical features

Septic arthritis presents with joint pain and swelling in over 80% of cases, which may or may not be associated with systemic symptoms such as sweats and rigors.³ The hip and knee joints are the most commonly involved joints.

The patient may be febrile and the affected joint is usually swollen, warm, erythematous and tender. Classically, there is reduced ability to actively move the joint and marked pain on passive movement. Unfortunately, the symptoms and signs are non-specific and a patient with septic arthritis may present with all or only certain of these features. Thus, septic arthritis cannot be excluded with confidence on the history and examination alone.

Differential diagnosis

The differential diagnosis of acute monoarthritis is shown in Table 14.2.1. Ask the patient about a history of previous rheumatological disease such as rheumatoid arthritis, gout or other inflammatory arthritis, as well as risk factors for infection such asimmunosuppression, including steroids and diabetes. Recent trauma or history of a bleeding diathesis or anticoagulant is also relevant. Finally, ask the patient about any recent sexually transmitted infection, including gonococcal infection or non-specific urethritis, and any systemic features, including uveitis and/or gastrointestinal infection, which may point towards a reactive arthritis.

Table 14.2.1 Most common presentations with acute monoarthritis to an emergency department ⁴

Gout

Reactive arthritis such as post-viral, Reiters

Acute exacerbation of pre-existing inflammatory arthritis

Rheumatoid arthritis

Septic arthritis

Note: Orthopaedic-related joint problems such as trauma and/or haemarthrosis, plus osteoarthritis(OA) were not included in this series.

Clinical investigations

Blood tests

Send blood for a full blood count, which may reveal an elevated peripheral white blood cell count, as well as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). ESR and CRP are non-specific and not sensitive for septic arthritis, but may help in the differential diagnosis. Blood cultures are taken in the presence of fever. Finally, a serum urate may be elevated, but can be normal in acute gout.

X-rays

Imaging may be normal in septic arthritis, as it takes at least 1 week for destructive changes to appear on plain X-ray. Magnetic resonance imaging, if available, is non-specific but may be helpful to determine if the pathology is in the joint or juxta-articular bone.

Joint aspiration

The most useful investigation is synovial fluid aspiration and analysis. Send the aspirate in a sterile container for Gram stain and culture, as well as for polarizing light microscopy to look for the presence of urate (strongly negative birefringent) crystals or calcium pyrophosphate crystals (weakly positive birefringent crystals).

Place some of the aspirate in an EDTA tube for a cell count to be performed. The likelihood of septic arthritis increases from 2.9% with a synovial white cell count greater than 25 000/μL up to 28% with a synovial white cell count of greater than 100 000/μL. Synovial glucose and protein levels are unhelpful.

Criteria for diagnosis septic arthritis

There is no ‘gold standard’ test for the diagnosis of septic arthritis. Gram stain of synovial fluid has a sensitivity of only 50% maximum, while culture has a sensitivity of up to 85%.³ However, combined with an appropriate clinical presentation, the presence of micro-organisms in synovial fluid on Gram stain and/or a positive synovial fluid culture with high synovial white cell count are diagnostic.

Treatment

Treatment of septic arthritis requires parenteral antibiotics, and urgent referral to orthopaedics for surgical drainage, with the patient admitted to hospital. Commence empirical antibiotic therapy with dicloxacillin or flucloxacillin 2 g i.v. 6-hourly, or cephalothin 2 g i.v. 6-hourly if patient is allergic to penicillin to cover against staphylococcus, until guided by microbiology results.

The patient with suspected hip sepsis or sepsis affecting a prosthetic joint must be referred to orthopaedics urgently without attempting joint aspiration.

GOUT

Gout is an intra-articular inflammatory response to monosodium urate crystal deposition usually related to hyperuricaemia. It is more common in males than females, but is extremely rare in the premenopausal female.

Aetiology and pathogenesis

Uric acid is derived from purine metabolism. Hyperuricaemia is the strongest predictor for gout and relates to either over-production or under-excretion of uric acid. Hyperuricaemia may also cause radiolucent renal calculi.

Over-production of uric acid is due to dietary factors such as beer, shellfish and other purine-rich foods, or endogenous factors associated with high cell turnover such as a haematological malignancy. Reduced excretion is related to chronic kidney disease, hypovolaemia, acidosis and medications such as diuretics, ciclosporin, pyrazinamide and ethambutol and low-dose aspirin. There is frequently a family history of gout.

Epidemiology

The peak incidence of acute gout occurs in men between the ages of 30 and 60 years and in women between 55 and 70 years. The presentation of gout in younger patients should prompt a search for a secondary cause (including lifestyle factors). Gout is more common in Maori and Polynesian populations.

Clinical features

The classic presentation is of acute onset of a hot, swollen and painful first metatarsophalangeal joint (75% of cases) known as podagra. Other commonly affected joints include other joints in the foot, the ankle, knee and small joints of the hand.

Common triggers of an acute attack include binges of alcohol or purine-rich foods, dehydration, severe illness such as sepsis, trauma and surgery. Sudden cessation or the introduction (especially in an acute attack) of hypo-uricaemic agents such as allopurinol or probenecid can also precipitate gouty arthritis, as can the introduction or a dose change of a diuretic.

Untreated, the symptoms will abate over the course of several days to 2 weeks. Occasionally, the patient may appear systemically unwell during an acute attack with malaise and septic symptoms. Examination reveals a tender, warm and erythematous joint with severely restricted range of movement. The patient may also be febrile. Presentations of acute gout may also be polyarticular.

Recurrent untreated acute gout and hyperuricaemia results in chronic tophaceous gout, where the patient is no longer pain-free between attacks. Examination will reveal joint deformity and tophus formation on the ears, fingers and around the elbows.

Investigations and diagnosis

Synovial fluid aspiration

Synovial fluid aspirate identifying monosodium urate crystals is diagnostic of acute gout. The crystals may be phagocytosed, and the synovial fluid will have a high white cell count. Send fluid for Gram stain and culture to rule out septic arthritis, which may rarely coexist with gout. Podagra in the typical clinical scenario has a sensitivity of 96% and specificity of 95% for acute gout.⁵

Blood tests

Hyperuricaemia on blood testing is not diagnostic of gout, and although up to 5% of adults may have a raised serum uric acid at some point, only one-fifth (1% overall) will ever have an attack of gout. Conversely, in about one-third of patients with gout the serum uric acid level is normal during an acute attack. Other blood tests such as FBE, ESR and CRP are sent, and may be abnormal including elevated inflammatory markers. Check the renal function with serum urea and creatinine, to both identify a potential aetiology and help guide treatment such as avoidance or reduced doses of non-steroidal anti-inflammatory drugs (NSAIDs).

Radiology

Plain X-ray is performed to exclude injury, but should be normal in the acute attack other than soft-tissue swelling. Peri-articular punched-out erosions are seen in chronic gouty arthritis, which when associated with calcium deposition, deforming arthritis and soft-tissue swelling are quite characteristic of chronic tophaceous gout.

Management

The aim is to treat the acute pain and then prevent chronic relapse with hypo-uricaemic drugs.

Acute attack

Non-steroidal anti-inflammatory drugs

After excluding infection, give either colchicine and/or an NSAID in the absence of any contraindications. Give diclofenac 50 mg tds orally followed by 25 mg tds orally, or naproxen 500 mg followed by 250 mg tds orally until symptoms subside. A selective COX-2 inhibitor such as celecoxib 100 mg bd orally is preferred in patients with a history of peptic ulcer disease, although there is a similar risk of renal dysfunction in the elderly or with pre-existing renal disease.

Colchicine

When NSAIDs are contraindicated, colchicine is used. Doses of colchicine of 0.5 mg 6- or 8-hourly orally have equivalent efficacy and a lower rate of gastrointestinal toxicity compared to higher doses.⁶ The higher doses such as colchicine 1.0 mg followed by 0.5 mg up to four times daily, with a maximum cumulative dose of 8 mg for an acute attack, are no longer recommended. All colchicine doses should be less with renal impairment, and may be restricted by the onset of nausea, vomiting and diarrhoea. Avoid prolonged colchicine use in patients with renal impairment as this may lead to a peripheral myoneuropathy.