Differential diagnosis

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Inflammatory Arthritis 283

Table 7.6 Non-articular manifestations of rheumatoid arthritis

Systemic Fever

Fatigue

Weight loss

Eyes Sjögren’s syndrome

Scleritis

Scleromalacia perforans (perforation of the eye)

Neurological Carpal tunnel syndrome

Atlanto-axial subluxation

Cord compression

Polyneuropathy, predominantly sensory

Mononeuritis multiplex

Haematological Lymphadenopathy

Felty’s syndrome (rheumatoid arthritis, splenomegaly, neutropenia)

Anaemia (chronic disease, NSAID-induced gastrointestinal blood loss, haemolysis, hypersplenism)

Thrombocytosis

Pulmonary Pleural effusion

Lung ﬁbrosis

Rheumatoid nodules

Rheumatoid pneumoconiosis (Caplan’s syndrome)

Obliterative bronchiolitis

Heart and peripheral vessels

Kidneys Amyloidosis (rare)

Vasculitis Leg ulcers

NSAID, non-steroidal anti-inﬂammatory drug.

Pericarditis (rarely clinically apparent)

Pericardial effusion

Raynaud’s syndrome

Analgesic nephropathy

Nail fold infarcts

Gangrene of ﬁngers and toes

284 Rheumatology

useful to distinguish early RA from acute transient synovitis. Cyclic citrullinated peptides (CCP) are used to detect these antibodies in patients’ serum and so these antibodies are often referred to as anti-CCP antibodies.

• X-ray of the affected joints shows soft tissue swelling in early disease

and later joint narrowing, erosions at the joint margins and porosis of periarticular bone and cysts.

• Synovial fluid is sterile with a high neutrophil count in uncomplicated

disease. In a suddenly painful joint, septic arthritis should be suspected and appropriate tests completed (p. 296).

Differential diagnosis

In the patient with symmetrical peripheral polyarthritis, prolonged morning stiffness, rheumatoid nodules and positive ACPA or rheumatoid factor, the diagnosis is straightforward. RA must be distinguished from symmetrical seronegative spondyloarthropathies; severe RA can mimic a form of psoriatic arthritis known as ‘arthritis mutilans’ (p. 290). In a young woman presenting with joint pains, SLE must be considered, but in this condition the joints characteristically look normal on examination. Acute viral polyarthritis (rubella, hepatitis B or parvovirus) must be considered in the differential diagnosis of early RA but these rarely last longer than 6 weeks. ACPA will be negative.

Management

RA is incurable. Therefore the therapeutic goals are remission of symptoms, a return of full function and the maintenance of remission with diseasemodifying agents. Effective management of RA requires a multidisciplinary approach with input from rheumatologists, orthopaedic surgeons (joint replacement, arthroplasty), occupational therapists (aids to reduce disability) and physiotherapists (improvement of muscle power and maintenance of mobility to prevent flexion deformities). Patients should be advised to stop smoking to reduce the risk of cardiovascular disease.

NSAIDs and coxibs (p. 315) are effective in relieving the joint pain and

stiffness of RA, but they do not slow disease progression. Individual response to NSAIDs varies considerably and it is possible that several drugs may have to be tried in a particular patient to find the most suitable agent. Slow-release preparations (e.g. slow-release diclofenac) taken at night may produce dramatic relief of symptoms on the following day. Paracetamol with or without codeine or dihydrocodeine can be added for additional pain relief.

Corticosteroids suppress disease activity but the dose required is often

large, with the considerable risk of long-term toxicity (p. 641). Oral corticosteroids are used in early disease (short-term intensive regimens) and in some patients with severe non-articular manifestations, e.g. vasculitis. Local injection of a troublesome joint (see below) with a long-acting corticosteroid

improves pain, synovitis and effusion but repeated injections are avoided because they may accelerate joint damage. Intramuscular depot methylprednisolone helps to control severe disease flares.

Inflammatory Arthritis 285

Disease-modifying antirheumatic drugs (DMARDs) act mainly

through inhibition of inflammatory cytokines and are used early (6 weeks to 6 months of disease onset) to reduce inflammation and slow the development of joint erosion and irreversible damage, and reduce cardiovascular risk. Combinations of up to four drugs may be used, with the number of agents being reduced once remission is achieved. Prior to commencing therapy, a screening history, chest X-ray and an interferon gamma release assay (IGRA) in high-risk patients are performed to exclude tuberculosis. Initial pneumococcal and annual influenza vaccinations are given.

Methotrexate is the anchor drug in RA therapy. However, it is contraindicated in pregnancy due to its teratogenicity and should not be prescribed (women or men) in the 3 months prior to conception in those planning a pregnancy. Folic acid is always co-prescribed with methotrexate to prevent folate deficiency.

Sulfasalazine is used in patients with mild to moderate disease and for many is the drug of choice, especially in younger patients and women who are planning a family.

Leflunomide blocks T-cell proliferation. It has a similar initial response rate to sulfasalazine but improvement is better sustained at 2 years. It is used alone or in combination with methotrexate. All drugs can have serious side effects (Table 7.7), so monitoring with blood tests is necessary.

Hydroxychloroquine is used alone in mild disease or commonly as an adjunct to other DMARDs. Because of the risk of irreversible retinopathy with increasing dose and duration of use, baseline formal ophthalmic examination is now recommended within 1 year of commencing therapy. Azathioprine, gold (intramuscular or oral), and penicillamine are used less frequently.

Biological DMARDs which are currently available, work by the following

mechanisms:

• TNF-α inhibitors (etanercept, infliximab, adalimumab, certolizumab).

They vary in their mechanism of action and frequency and mode of administration. For instance, infliximab is a chimeric (human/mouse) antibody to TNF-α and is given intravenously every 8 weeks after an induction schedule. Etanercept is a soluble TNF-α receptor fusion protein that binds TNF-α and is given by self-administered subcutaneous injection

• IL-1 receptor blocker (anakinra)

• Lysis of B cells (rituximab)

• IL-6 receptor antibody (tocilizumab)

• Blocks T-cell activation (abatacept).

TNF-α inhibitors are first-line treatment and slow or halt erosion formation in up to 70% of patients. They are usually given in combination with methotrexate to reduce loss of efficacy due to anti-drug antibody formation.

Biological DMARDs are expensive. Costs, however, are being reduced by the introduction of biosimilar medicines which are medicines that are highly similar to another (originator) drug and have been shown to have no clinically meaningful differences in quality, safety or efficacy from the originator compound. In future the ‘biologicals’ will be used earlier and in more patients as the cost falls.

286 Rheumatology

Table 7.7 Side effects of disease-modifying antirheumatic drugs (DMARDs)

Drug Side effects

Sulfasalazine Mouth ulcers

Hepatitis Male infertility (reversible)

Methotrexate Mouth ulcers and diarrhoea

Liver ﬁbrosis Pulmonary ﬁbrosis Renal impairment

Leﬂunomide Diarrhoea

Hypertension Hepatitis Alopecia

TNF-α blockers Infusion reactions (inﬂiximab)

Infections (e.g. tuberculosis and septicaemia) Demyelinating disease Heart failure Lupus-like syndrome Autoimmune syndromes

All may cause myelosuppression (with neutropenia, thrombocytopenia and anaemia)

and regular check of the full blood count is indicated together with other speciﬁc

monitoring (e.g. liver function tests (LFTs) with methotrexate and leﬂunomide). Rash and

nausea are additional side effects of most of the drugs listed.

LFTs, liver function tests; TNF-α, tumour necrosis factor alpha.

Prognosis

The prognosis of RA is variable. Some patients will have minimal disability after many years and others will be severely disabled, with most patients between these extremes. Prognosis can be dramatically altered with early DMARDs given under expert supervision. A poor prognosis is indicated by the following: insidious onset, female sex, increasing number of joints involved, level of disability at onset, higher inflammatory and autoimmune markers and signs of early erosive damage on imaging.

THE SERONEGATIVE SPONDYLOARTHRITIS

This title describes a group of conditions (Table 7.8) that share certain clinical features:

• A predilection for axial (spinal and sacroiliac) inflammation

• Asymmetrical peripheral arthritis

The Seronegative Spondyloarthritis 287

Table 7.8 Seronegative spondyloarthritis

Axial spondylarthritis (ankylosing spondylitis)

Psoriatic arthritis

Reactive arthritis (sexually acquired, Reiter’s disease, post-dysenteric reactive arthritis)

Enteropathic arthritis (ulcerative colitis/Crohn’s disease)

• Absence of rheumatoid factor or ACPA antibodies, hence ‘seronegative’

• Inflammation of the enthesis (see Fig. 7.1)

• A strong association with HLA-B27, but its aetiological relevance is unclear.

Axial spondylarthritis

This is an inflammatory disorder of the spine, affecting mainly young adults. When radiographic changes at the sacroiliac joints are present, the term ‘ankylosing spondylitis’ is used. It is both more common (ratio of 5:1) and more severe in men than in women.

Clinical features

The typical patient is a young man (late teens, early 20s) who presents with increasing pain and prolonged morning stiffness in the lower back and buttocks. Pain and stiffness improve with exercise but not with rest. There is a progressive loss of spinal movement. Inspection of the spine reveals two characteristic abnormalities:

• Loss of lumbar lordosis and increased kyphosis (Fig. 7.4).

• Limitation of lumbar spine mobility in both sagittal and frontal planes.

Reduced spinal flexion is demonstrated by the Schober test. A mark is made at the fifth lumbar spinous process and 10 cm above, with the patient in the erect position. On bending forward, the distance should increase to >15 cm in normal individuals.

Other features include Achilles tendinitis and plantar fasciitis (enthesitis) and tenderness around the pelvis and chest wall. Reduction in chest expansion (<2.5 cm on deep inspiration measured at the fourth intercostal space) is due to costovertebral joint involvement. Non-articular features include anterior uveitis (p. 685) and, rarely, aortic regurgitation, cardiac conduction defects and apical lung fibrosis.

Investigations

• ESR and CRP are often raised.

• X-rays may be normal or show erosion and sclerosis of the margins

of the sacroiliac joints, proceeding to ankylosis (immobility and consolidation of the joint). In the spinal column, blurring of the

288 Rheumatology

Vertebrae fused

Exaggerated

thoracic

hyperextension of neck

kyphosis

Loss of lumbar

lordosis

together

Fixed flexion of hips

Compensatory flexion of knees

Compensatory

Normal posture

Posture in patient with advanced spondylitis

Fig. 7.4 Ankylosing spondylitis. The typical posture in advanced cases

compared to normal posture.

upperor lower vertebral rims at the thoracolumbar junction is caused by an enthesitis at the insertion of the intervertebral ligaments. This heals with new bone formation, resulting in bony spurs (syndesmophytes). Progressive calcification of the interspinousligaments and syndesmophytes eventually produces the‘bamboo spine’ (Fig. 7.5).

• MRI shows sacroiliitis before it is seen on plain X-ray.

• HLA-B27 testing is not usually performed as it would not change management.

The Seronegative Spondyloarthritis 289

Fig. 7.5 X-ray of bamboo spine in ankylosing spondylitis. In advanced disease

there is calcification of the interspinous ligaments and fusion of the facet joints as well as syndesmophytes at all levels. The sacroiliac joints fuse.