Investigations

Inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are usually but not always elevated in active disease and are useful for monitoring response to treatment. Rheumatoid factor (RF) is an autoantibody directed against the host immunoglobulin and is most commonly found in rheumatoid arthritis. Routinely performed tests only detect immunoglobulin M rheumatoid factor (IgM RF) which is present in 75–80% of patients with rheumatoid arthritis (termed seropositive disease) and 5% of normal subjects. Those patients who do not have a detectable RF are said to be ‘seronegative’. RF is not specific to rheumatoid arthritis and is also present in patients with chronic lung and liver disease, other connective tissue diseases, neoplasia, infections (particularly bacterial endocarditis) and cryoglobulinaemia.

Anti-cyclic citrullinated peptide antibodies (anti-CCP antibody) are a more specific test for rheumatoid arthritis with a specificity of 90–96% compared with the specificity of IgM RF of 85%. They are more useful for the early detection of rheumatoid arthritis in a patient with inflammatory arthritis. The sensitivity of both anti-CCP antibody and IgM RF is approximately 70%.

Antinuclear antibodies (ANA) and extractable nuclear antigens (ENA) are useful for establishing the differential diagnosis, such as other connective tissue diseases presenting or associated with an arthritis. ANA is almost universally positive in systemic lupus erythematosus and only positive in 20% of patients with rheumatoid arthritis.

Other abnormal laboratory tests include an elevated alkaline phosphatase, an elevated platelet count, a decreased serum albumin and a normochromic, normocytic anaemia. White cell count, particularly neutrophils, is elevated in patients with infected joints and is also elevated whilst the patient is on steroids.

Treatment

There are four primary goals in the treatment of rheumatoid arthritis:

• Symptom relief including pain control

• Slowing or prevention of joint damage

• Preserving and improving functional ability

• Achieving and maintaining disease remission

Once the diagnosis has been established, an individualised care plan with treatment goals should be agreed, including monitoring of disease severity using objective measures such as the ACR or DAS28 scores. The ultimate aim is to achieve disease remission, which can be defined by a number of methods including a target DAS28 of less than 2.6, CRP, or a reduction in signs and symptoms of disease activity. If remission cannot be achieved, the aim of therapy is to minimise joint destruction and to preserve function. The longer the period of remission or the best possible reduction in disease activity that can be achieved, the better the long-term outcome.

Patients should have access to a multidisciplinary team to address the pharmacological and non-pharmacological aspects of disease management. Education is extremely important as patients cope better if they understand their condition and have realistic expectations of the benefits and disadvantages of their treatment strategies. Patients may need psychological support and employment counselling to help them adjust to living with their condition. Occupational therapy aims to provide support and aid to allow patients to improve function and limit disability in their activities of daily living. This includes devices to alleviate tasks which may be troublesome for those with restricted manual dexterity, such as twisting lids to open bottles. Physiotherapy involves assessment of function and designing a programme to aid pain relief and rehabilitation. The programme should aim to improve general fitness through regular exercise, and tailor exercises to the individual patient to enhance joint flexibility and muscle strength. Alternative short-term pain relief options may also be explored such as transcutaneous electrical nerve stimulators (TENS) and hydrotherapy. Surgical interventions, such as synovectomy and arthroplasty, may be useful to relieve pain and restore function.

Drug treatment

The pharmacological management of rheumatoid arthritis is evolving rapidly as more advanced therapies become available. The advent of biological therapies has brought new technologies which target different cytokine pathways involved in the pathogenesis of rheumatoid arthritis and have revolutionised disease management.

There are four main categories of drugs employed in the management of rheumatoid arthritis: non-steroidal anti-inflammatory drugs (NSAIDs) including cyclo-oxygenase (COX)-2 inhibitors, glucocorticoids, DMARDs and biological therapies. Simple analgesia also has a small role to play in basic symptom relief and includes paracetamol, codeine, and paracetamol and opiate combination products. These analgesics do not have any anti-inflammatory effect and will not aid disease modification. The aim of analgesia is to achieve symptom relief and reduce the need for long-term use of NSAIDs, COX-2 inhibitors and glucocorticoids.

Guidance for the treatment of rheumatoid arthritis has been issued and this is summarised in Fig. 53.2.

Fig. 53.2 Treatment algorithm for rheumatoid arthritis (NCCCC, 2009).

Non-steroidal anti-inflammatory drugs

The analgesic and anti-inflammatory properties of NSAIDs are used to reduce joint pain and swelling. However, as with simple analgesics, these drugs provide only symptomatic relief to improve joint function, and so should always be used in combination with other agents which modify the disease process.

The COX enzyme converts arachidonic acid into prostaglandins and thromboxanes. These prostanoids have a variety of physiological functions, and are also believed to be responsible for causing pain and swelling in inflammatory conditions. There are two main isoforms of the COX enzyme: COX-1 produces prostaglandins required for homeostatic functions, such as maintaining the gastric mucosa, support of renal function and platelet function. COX-2 is responsible for the production of inflammatory prostanoids.

NSAIDs vary in their selectivity for the COX-1 and COX-2 isoforms, and are categorised as either non-selective NSAIDs or selective COX-2 inhibitors, otherwise known as the coxibs (Table 53.1). Non-selective NSAIDs generally block both COX-1 and COX-2, whereas the coxibs have higher selectivity for the COX-2 isoform. However, COX-2 selectivity in NSAIDs varies according to the dose of drug given, which is demonstrated by the dose-related toxicity exhibited by some agents such as ibuprofen. The three most commonly used non-selective NSAIDs have differing levels of COX-1 or COX-2 selectivity: diclofenac is COX-2 ‘preferential’, whereas ibuprofen and particularly naproxen preferentially inhibit COX-1. Originally, inhibition of COX-2 was thought to be involved solely with the anti-inflammatory, anti-pyretic and analgesic properties of NSAIDs. However, it is possible that COX-2 inhibition may also impair endothelial health, cause a prothrombotic state and promote cardiovascular disease.

Table 53.1 NSAIDs currently licensed in the UK

Non-selective NSAIDs	COX-2 inhibitors
Aceclofenac	Celecoxib
Acemetacin	Etoricoxib
Azapropazone
Dexibuprofen
Dexketoprofen
Diclofenac
Etodolac
Fenbufen
Fluribprofen
Ibuprofen
Indometacin
Ketoprofen
Meloxicam
Nabumetone
Naproxen
Piroxicam
Tenoxicam
Tiaprofenic acid

Safety

In 2004, rofecoxib, a selective COX-2 inhibitors, was withdrawn from the worldwide market due to evidence of an increased risk of confirmed serious thrombotic events that included myocardial infarction and stroke, following long-term use. In the following years, similar evidence against the other COX-2 inhibitors and also against some of the non-selective NSAIDs accumulated.

At present, the exact cardiovascular risk for individual selective COX-2 inhibitors and NSAIDs is not known. Evidence from clinical trials of COX-2 inhibitors suggests that about 3 additional thrombotic events per 1000 patients/year may occur in the general population (MHRA, 2006).

A dose-dependent increase in cardiovascular risk is associated with use of celecoxib, high-dose diclofenac (150 mg/day) and high-dose ibuprofen (2400 mg/day). There does not appear to be an increased risk of myocardial infarction in association with low-dose ibuprofen (≤1200 mg/day). Naproxen is associated with a lower risk of arterial thrombotic events than COX-2 inhibitors. There may be some increased cardiovascular risk in all patients receiving any NSAID, irrespective of their baseline risk or duration of therapy. The key message is that patients should use the lowest effective dose and the shortest duration of treatment necessary to control symptoms to minimise the risk of adverse events.

The most common adverse events of NSAIDs are those that predominantly inhibit COX-1 and cause adverse gastro- intestinal effects. These range from minor symptoms, including dyspepsia, nausea and diarrhoea, to more serious events, such as gastric erosion, bleeding and duodenal and gastric ulceration. Patients are at a higher risk of serious gastro-intestinal complications if they are over 65 years of age, have a previous history of gastro-intestinal ulceration/bleeding or peptic ulcer disease, or are taking concomitant anti-platelet, anti-coagulation or steroid therapy. There are several gastroprotective agents available which may be used to reduce adverse events, including H₂ antagonists, misoprostol and proton pump inhibitors (PPIs). PPIs, such as omeprazole and lansoprazole, have been shown to be particularly effective at preventing gastric and duodenal ulcers with NSAIDs. All patients taking a non-selective NSAID or COX-2 inhibitor should receive concomitant treatment with a PPI to minimise gastro-intestinal adverse effects.

Aspirin inhibits the COX enzyme irreversibly through a different mechanism of action to the NSAIDs. Therefore, there is an increased risk of gastro-intestinal toxicity if aspirin and non-selective NSAIDs are used concomitantly, and the gastro-intestinal advantage of using a selective COX-2 inhibitor is severely reduced. Low-dose aspirin should only be co-prescribed with NSAIDs where absolutely necessary.

All NSAIDs may potentially cause adverse cardio-renal effects such as oedema, hypertension and heart failure. The distribution of COX-1 and COX-2 differs in the kidney, but there is no evidence to suggest differing degrees of isoform inhibition have an impact on the severity of cardio-renal adverse effects. Pharmacokinetic parameters, such as half-life and metabolism, may affect both thrombotic and cardio-renal properties of NSAIDs.

Choice of agent

Evidence suggests that all non-selective NSAIDs and COX-2 inhibitors are of similar efficacy, but vary in their toxicity profiles. However, there is individual patient variability in terms of response to a given NSAID, and so some patients may need to try several agents before reaching an effective and well-tolerated agent. Non-selective NSAIDs or COX-2 inhibitors should be used at the lowest effective dose for the shortest possible period of time. There are no recommendations on which agent to use first-line as all NSAIDs have analgesic effects of similar magnitude. However, as these drugs vary in terms of potential gastro-intestinal, liver and cardio-renal toxicity, it is advised that the choice of drug should take into account the patient’s individual risk factors, including age.

Disease-modifying anti-rheumatic drugs

Joint damage is known to occur early in rheumatoid arthritis and is largely irreversible. The need for early intervention with DMARDs as part of an aggressive approach to minimise disease progression has become standard practice and is associated with better patient outcome. Early introduction of DMARDs also results in fewer adverse reactions and withdrawals from therapy (NCCCC, 2009).

The DMARDs that are commonly used for rheumatoid arthritis and have clear evidence of benefit are methotrexate, sulphasalazine, leflunomide and intramuscular gold (O’Dell, 2004). There is less compelling evidence for the use of hydroxychloroquine, d-penicillamine, oral gold, ciclosporin and azathioprine, although these agents do improve symptoms and some objective measures of inflammation. The exact mechanism of action of these drugs is unknown. All DMARDs inhibit the release or reduce the activity of inflammatory cytokines, such as TNF-α, interleukin-1, interleukin-2 and interleukin-6. Activated T-lymphocytes have been implicated in the inflammatory process, and these are inhibited by methotrexate, leflunomide and ciclosporin.

Patients should be made aware that the DMARDs all have a slow onset of action. They must be taken for at least 8 weeks before any clinical effect is apparent, and it may be months before an optimal response is achieved. Whilst early initiation of DMARDs is crucial, it is important to ensure the patient is maintained on therapy to maintain disease suppression. This itself is a challenge, due to the toxicity profiles of the majority of these drugs (see Table 53.2). The majority of the DMARDs require regular blood monitoring. Guidelines are available on the action to take in the event of abnormal blood results (Chakravarty et al., 2008).

Table 53.2 DMARDs used in the treatment of rheumatoid arthritis