Emphasis on early diagnosis and treatment is extremely important to prevent disease activity, duration and ultimately joint destruction. The American Rheumatism Association (ARA) criteria (Box 53.2) were principally designed for disease classification in patients with established disease and are not sensitive for patients in the early stages of rheumatoid arthritis (Arnett et al., 1988). The Disease Activity Score using 28 joint counts (DAS28) and American College of Rheumatology (ACR) response are some of the tools used by rheumatologists to assess disease activity and to monitor the patient’s response to treatment (see Boxes 53.3 and 53.4).

Box 53.3 Summary of DAS28 criteria in the assessment of rheumatoid arthritis

DAS28 is a composite formula. Four parameters are used to calculate a disease severity score:

1. Number of swollen joints out of a total of 28 specified joints

2. Number of tender joints out of a total of 28 specified joints

3. Erythrocyte sedimentation rate

4. Patient’s interpretation of wellbeing, with 0 being at their best and 100 their worst

Programmed calculators are used to determine the final DAS28.

DAS28 does not take into account other features of a patient’s disease, such as synovitis and other clinical symptoms.

High disease activity: DAS28 of >5.1

Moderate disease activity: DAS28 of >3.2 to 5.1

Low disease activity: DAS28 of 2.6–3.2

Remission: DAS28 of <2.6

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

Recommendations regarding the use of DMARDs in rheumatoid arthritis are summarised in Box 53.5 (NCCCC, 2009). Patients with a new diagnosis of rheumatoid arthritis should be offered combination DMARD therapy as first-line therapy as soon as possible, ideally within 3 months of the onset of persistent disease symptoms. The combination therapy should include methotrexate and at least one other DMARD, usually sulphasalazine and/or hydroxychloroquine. Evidence suggests that combination therapy appears to be superior in terms of benefits to symptoms, quality of life, remission rates and slowing of joint damage, when compared to monotherapy. Once sustained and satisfactory levels of disease control have been achieved, the doses of drugs should be cautiously reduced to levels that continue to maintain disease control.

Box 53.5 Key points regarding DMARD therapy (NCCCC, 2009)

Introduce DMARD therapy early (within 3 months ideally)

Use combination DMARDs involving methotrexate and at least one other DMARD

Use monotherapy where combination DMARD therapy is not appropriate, with rapid escalation to therapeutic dose

Withdraw cautiously when disease is stable to doses that maintain disease control

In patients where combination therapy is not appropriate, for example where there are contraindications to a drug due to existing co-morbidities, DMARD monotherapy should be started, placing greater emphasis on fast escalation to a clinically effective dose rather than on choice of agent (NCCCC, 2009).

There are many factors that influence the choice of DMARD: relative efficacy, severity of disease, convenience, monitoring requirements, patient co-morbidities, cost, time period to benefit, prescriber’s experience and success rates with the drug, side effects and patient adherence. Studies have shown that methotrexate has the best benefit to toxicity ratio. Both sulphasalazine and hydroxychloroquine are also favourable in terms of low incidence of serious adverse effects, although hydroxychloroquine alone does not slow radiological damage. Most patients started on a DMARD will not be taking it 3–4 years later because of adverse reactions or lack of efficacy. Despite promising results initially, some patients experience disease reactivation at a later stage and become unresponsive to treatment.

Methotrexate

Methotrexate is recognised as the gold standard DMARD in the management of rheumatoid arthritis. It is given as a once weekly dose and can be given orally or parenterally via the intramuscular or subcutaneous routes. Patients usually begin on oral therapy; parenteral methotrexate may be considered in those who do not respond adequately to the maximum tolerated oral dose, or in those who suffer from gastro-intestinal side effects. Doses used, whether administered by the parenteral or oral route, are similar, although bioavailability is greater with parenteral administration. Methotrexate is primarily excreted unchanged by the kidneys and so elderly patients or those with renal impairment may require lower doses. Methotrexate is a folic acid antagonist and acts by reversibly inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Concomitant administration of oral folic acid reduces adverse effects of methotrexate and improves continuation of therapy and adherence. Doses used range from 5 mg weekly to 5 mg daily except on the day of methotrexate administration.

Methotrexate is associated with lung, liver and bone marrow toxicities. As a consequence, strict monitoring is advised and alcohol intake should be minimised. Methotrexate pneumonitis is usually seen within the first year of treatment, but can sometimes occur after long-term therapy. Myelosuppression can cause significant falls in blood cell counts. It is more likely to occur in the elderly, patients with renal impairment or patients who are also taking anti-folate drugs. A clinically significant drop in cell count calls for immediate withdrawal of methotrexate, and folinic acid rescue therapy. Patients should be counselled to report any of the following warning symptoms immediately to a healthcare professional: blood disorders, for example sore throat, bruising, mouth ulcers; liver toxicity, for example nausea, vomiting, abdominal discomfort, dark urine; and respiratory effects, for example shortness of breath, persistent dry cough.

Following a number of patient incidents involving methotrexate toxicity, guidance on safe use was issued by the National Patient Safety Agency (Box 53.6). Methotrexate-monitoring booklets are routinely given to patients when therapy is initiated. The booklet contains information to reinforce counselling points such as warning symptoms and drug interactions, and has sections where prescribers can enter in dose details (in number and strength of tablets) and record blood results. Methotrexate tablets are available as 2.5-mg and 10-mg strengths; most pharmacies will dispense the 2.5-mg strength only for non-chemotherapy indications such as rheumatoid arthritis.

Box 53.6 Summary of recommendations for the safe prescription of methotrexate

All prescriptions must specify a dose

The term ‘as directed’ should be avoided on prescriptions

The strength of tablets supplied should remain consistent to avoid confusion regarding dose

Issue all patients with a methotrexate monitoring booklet

Counsel patient:

• Strength and number of tablets to take

• Monitoring requirements

• Warning symptoms of methotrexate, for example sore throat, persistent cough, vomiting

• To inform other healthcare professionals that he/she is taking methotrexate

Biological therapies

Over the past decade, there have been significant advances in the treatment of rheumatoid arthritis due to emerging biological therapies. The so-called biologics in rheumatoid arthritis are genetically engineered monoclonal antibodies which selectively target different parts of the inflammatory pathways (Fig. 53.3). Activated T-cells release pro-inflammatory cytokines including TNF-α, interleukin-1 and interleukin-6. Adalimumab, etanercept, golimumab, infliximab and certolizumab pegol target TNF-α, anakinra and tocilizumab target the interleukins, whilst abatacept and rituximab act on T-cells and B-cells, respectively.

Fig. 53.3 Biologic agents and their targets in the inflammatory pathway.

In current practice, biologics are used after a patient has failed DMARDs, although there is emerging evidence to suggest they should be used earlier in the disease. Combination DMARD therapy is increasingly advocated and may lead to earlier use of biologics. For example, a patient may now be trialled on two DMARDs, including methotrexate, over a period of 6 months and if the response is inadequate could be eligible for an anti-TNF agent within a year of diagnosis.

Anti-TNF agents

There are five anti-TNF agents available: adalimumab, etanercept, golimumab, infliximab and certolizumab pegol. All inhibit TNF-α which is an inflammatory cytokine found in high concentrations within the joint synovium of rheumatoid arthritis patients.

Infliximab was the first anti-TNF agent licensed for the treatment of rheumatoid arthritis. It is a chimeric human-murine monoclonal antibody that binds with high affinity to TNF-α, thereby neutralising its activity. Infliximab is the only anti-TNF agent which is given by intravenous infusion and must be given concomitantly with methotrexate. It is usually well tolerated, with the most common adverse effects being mild infusion reactions, such as headache and urticaria. Anaphylaxis and delayed hypersensitivity reactions have also been rarely reported. As infliximab is a part murine monoclonal antibody, it is thought to carry a higher risk of developing human anti-chimeric antibodies (HACAs). HACAs are associated with an increased frequency of infusion-related reactions and can be minimised by administering with an immunomodulatory therapy.

Adalimumab is a recombinant human monoclonal antibody that binds to and neutralises TNF-α. Etanercept is a human TNF fusion protein that binds to TNF cell surface receptors, thereby inhibiting interaction of TNF-α with its receptors. Certolizumab pegol is a pegylated antibody fragment which binds and neutralises TNF-α and is thought to have a relatively more rapid onset of action. Golimumab is the most recent addition to this family of agents and has the advantage of having a less frequent dosing schedule. (Table 53.3). Optimum clinical benefit is achieved when these drugs are used in combination with methotrexate. However, adalimumab, etanercept and certolizumab pegol can be used alone as monotherapy in patients for whom methotrexate is not appropriate or not tolerated.

Table 53.3 Biologic agents used in the treatment of rheumatoid arthritis and typical dose regimens in adults

Drug	Usual dose	Route
Adalimumab	40 mg every 2 weeks	Subcutaneous
Certolizumab pegol	400 mg at week 0, 2 and 4, then 200 mg every 2 weeks thereafter	Subcutaneous
Etanercept	25 mg twice weekly or 50 mg weekly	Subcutaneous
Golimumab	50 mg monthly	Subcutaneous
Infliximab	3 mg/kg at week 0, 2 and 6, then every 8 weeks thereafter	Intravenous infusion
Rituximab	1 g then 1 g 2 weeks later Max 2 courses/year	Intravenous infusion
Abatacept	750 mg at week 0, 2 and 4, then every 4 weeks thereafter^a	Intravenous infusion
Anakinra	100 mg daily	Subcutaneous
Tocilizumab	8 mg/kg every 4 weeks	Intravenous infusion

a For a patient weighing between 60 and 100 kg; dose modifications are necessary for patients outside this weight range.

Safety

The anti-TNF agents are generally well tolerated, with the main side effects being injection site reactions with the subcutaneous agents, and infusion-related reactions with infliximab. There are fewer monitoring requirements compared to the DMARDs and less frequent dosing, making these drugs potentially more appealing. However, the long-term safety of these drugs is being monitored in the UK by the British Society of Rheumatology Biologics Registry. This database collects data on efficacy and safety outcomes of all patients on biologics in a variety of rheumatological conditions including rheumatoid arthritis.

Patients using anti-TNF agents are more susceptible to serious infections such as sepsis, and opportunistic infections. A number of serious infections, including some fatalities, have been reported. Patients should not start anti-TNF therapy in the presence of infection. Those who develop infection whilst receiving treatment should stop and wait until the infection is controlled. The anti-TNF agents have long half-lives and temporary cessation of therapy should be considered prior to and after surgery. Reactivation of hepatitis B and latent tuberculosis has been reported. All patients should be screened for tuberculosis using appropriate tests, such as the tuberculin skin test and a chest X-ray. Active tuberculosis must be treated before an anti-TNF agent is initiated.

Malignancies, including lymphoma, have been reported in studies and post-marketing surveillance of the anti-TNF agents. Caution should be exercised with the use of anti-TNF agents in patients with previous malignancy.

All the anti-TNF agents except etanercept are contraindicated in New York Heart Association (NYHA) grade III/IV heart failure, and all should be used with caution in those with mild heart failure.

Place in therapy

Guidance on the use of adalimumab, etanercept, infliximab (NICE, 2007) and certolizumab pegol (NICE, 2010a) have been published, with the appraisal of golimumab pending. Adalimumab, certolizumab, etanercept or infliximab are recommended as treatment options in adults who meet the following criteria:

• Active rheumatoid arthritis with a DAS28 greater than 5.1 on at least two occasions, 1 month apart.

• Have undergone trials with two DMARDs, including methotrexate, unless contraindicated. A trial of a DMARD is defined as being normally of 6 months, with 2 months at standard dose, unless significant toxicity has limited the dose or duration of treatment.

Patients should be assessed for treatment efficacy using DAS28 every 6 months and continue treatment only if an adequate response is demonstrated 6 months after initiation. An adequate response is currently defined as an improvement in DAS28 of 1.2 points or more.

Changes in eligibility criteria have been suggested (Deighton et al., 2010) which recommend patients should have tried two DMARDs, but those with DAS28 > 3.2 and at least three or more tender joints and three or more swollen joints should be eligible for an anti-TNF agent. Whether NICE will adapt their guidance accordingly is unclear.

Use of the anti-TNF agents above their starting doses as listed in Table 53.3 is not advocated. According to their product licences, doses of adalimumab and infliximab may be escalated according to response, but this does not generally occur in practice.

Generally, the least expensive anti-TNF agent should be used although patient aspects may also affect choice of drug. There are differences between dosing frequencies of the anti-TNF agents, which should be discussed with the patient to ensure drug administration is easily incorporated into their lifestyle, thereby improving adherence. The subcutaneous agents are also available in pen formulations, making it easier for self-administration in patients who have problems with manual dexterity. Patients who are unable to self-administer the subcutaneous anti-TNF agents may choose to receive infliximab as a hospital day case. As infliximab is only licensed to be used in combination with methotrexate, adalimumab, certolizumab and etanercept are favoured in patients where methotrexate cannot be taken.

Rituximab

Rituximab is a chimeric human-murine monoclonal antibody which binds to the C20 antigen on B-lymphocytes to mediate B-cell lysis. It causes depletion of peripheral B-cells which play a role in the pathogenesis of rheumatoid arthritis. Recovery of B-cells appears to occur 6 months after treatment, with some patients showing prolonged B-cell depletion persisting up to 2 years after treatment (Emery et al., 2004).

Rituximab in combination with methotrexate is licensed for the treatment of severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to other DMARDs including one or more anti-TNF agent. Rituximab is also licensed for non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia, both using a different dosing schedule to that of rheumatoid arthritis. A course of rituximab consists of two intravenous infusions administered as a day case in hospital: 1000-mg infusion followed by a second 1000-mg infusion 2 weeks later. The course may be repeated every 6 months depending on patient response. Disease response varies between patients in that some achieve disease remission after one course and do not require re-treatment, whilst others require further repeat infusions every 6–12 months.

Rituximab is generally well tolerated, and the most common adverse effects are infusion-related reactions including fever, changes in blood pressure and rash. Minor infusion-related side effects can be managed by reducing the rate of infusion and giving treatment for relief of symptoms such as paracetamol. The incidence of adverse effects is minimised by pre-medicating with methylprednisolone, paracetamol and an anti-histamine 1 h prior to the infusion. Hypersensitivity reactions and anaphylaxis are rare but serious side effects.

As with the anti-TNF agents, rituximab increases the risk of infections and should not be used in the presence of active or severe infections. Use has been associated with progressive multifocal leukoencephalopathy. It may also exacerbate existing cardiac conditions such as angina pectoris and atrial fibrillation. Patients with a known history of cardiac disease should be closely monitored during treatment administration for changes in blood pressure and pulse. Anti-hypertensives may be omitted 12 h prior to the infusion. HACAs have been reported in some patients after the first course of rituximab. The presence of HACAs may be associated with worsening of infusion or allergic reactions, and possibly failure to deplete B-cells on further treatment.

In practice, rituximab is used in line with its product license, i.e. after failure of, or intolerance to, DMARD therapy including at least one anti-TNF agent. Patients may continue on rituximab therapy with infusions no more frequent than every 6 months, provided they demonstrate an adequate response of a DAS28 improvement of 1.2 points or more (NICE, 2010b).

Abatacept

Abatacept acts by blocking the full activation of T-cells thereby inhibiting the release of inflammatory cytokines. It is licensed for use in combination with methotrexate in the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs including at least one anti-TNF agent and who cannot receive rituximab because they have a contraindication to rituximab, or when rituximab is withdrawn due to an adverse event (NICE, 2010a).

Anakinra

Anakinra blocks the binding of interleukin-1 to its receptor, thus inhibiting the inflammatory effects of interleukin-1. The evidence of its benefit in rheumatoid arthritis is weak and it is considered modestly effective. There are no trials directly comparing anakinra with other biologic agents; adjusted indirect comparisons suggest that anakinra may be significantly less effective at relieving the clinical signs and symptoms of rheumatoid arthritis than anti-TNF agents in combination with methotrexate. Anakinra is not cost effective in the treatment of rheumatoid arthritis and availability for routine use in the NHS has not been supported (NCCCC, 2009).

Tocilizumab

Tocilizumab acts by binding to interleukin-6 receptors. Interleukin-6 is a pro-inflammatory cytokine produced by a variety of cells including T- and B-cells, and has been implicated in the pathogenesis of rheumatoid arthritis and other inflammatory diseases. Tocilizumab is licensed for use in combination with methotrexate in the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs including at least one anti-TNF agent. It is given as a monthly intravenous infusion at a dose of 8 mg/kg and requires regular monitoring of liver function tests and full blood count.

Tocilizumab is recommended for the treatment of rheumatoid arthritis in patients who fulfil the following criteria (NICE, 2010c):

• The patient has not responded adequately to one or more anti-TNF agents

and

• The patient cannot receive rituximab due to a contraindication or

• The patient cannot receive rituximab as they have experienced an adverse effect to treatment or

• The patient has not responded adequately to rituximab treatment.

Which biologic?

More biological therapies for the treatment of rheumatoid arthritis, with new mechanisms of action and targets in the inflammatory pathway, are expected to become available in the near future. Cost is a major factor in the use of biologics with many costing in the region of £10,000 per patient per annum. The decision as to which agent to use is further confounded by the absence of clinical trials that directly compare efficacy between the different biologics.

At present, anti-TNF agents remain the first-line biological therapy. Following failure or intolerance to one anti-TNF agent, patients should then be treated with rituximab. However, if patients cannot receive rituximab due to a contraindication, adverse effect, or intolerance to methotrexate, there remains a number of treatment options (see Fig. 53.4).

Fig. 53.4 Algorithm following introduction of an anti-TNF agent in the management of rheumatoid arthritis.

Rheumatoid arthritis and pregnancy

The management of rheumatoid arthritis during pregnancy is a common challenge, with disease activity improving in approximately 70–80% of patients. Disease activity usually decreases in the first trimester, and this lasts for a number of weeks to months into the postpartum period. Subsequently, 90% of patients will then experience a flare usually during the first 3 months.

Although case control studies of pregnancy outcome demonstrate a slight increase in spontaneous abortion in women with rheumatoid arthritis, most reports have failed to show an increase in fetal morbidity. Medication may potentially increase this risk, for example, steroids may restrict intrauterine growth. Women with active rheumatoid arthritis or other types of inflammatory arthritis may have children with lower birth weights.

None of the available drug treatments for rheumatoid arthritis are absolutely safe in pregnancy. A prescriber must carefully assess the risks and benefits of treatment in consultation with the patient. In patients with active rheumatoid arthritis during pregnancy, prednisolone is recommended at the lowest dose (below 20 mg daily if possible) to control the disease. Sulphasalazine and hydroxychloroquine are considered safe to prescribe by most obstetric physicians. Many of the DMARDs are contraindicated in pregnancy as they are known teratogens, and some require a washout period before conception, such as leflunomide.

Patient care

Patient education and counselling are vital aspects in the management of rheumatoid arthritis. Patients should be encouraged to engage actively in their pharmacological and non-pharmacological treatment, and take responsibility for ensuring their medication regimen is safe and effective. Medicine information sheets are available from the Arthritis Research UK with further information available on their website (http://www.arthritisresearchuk.org/). Monitoring of the potentially toxic DMARDs is essential as non-adherence with the monitoring schedule may have serious consequences. Patients should be reminded of the warning symptoms that must trigger them to contact a healthcare professional. They should also be counselled to inform healthcare professionals of all the medication they are taking before starting a new medicine, and this includes use of over-the-counter products such as ibuprofen or aspirin.

Shared care agreements between secondary and primary care are often employed for DMARD therapy. This involves a primary care clinician continuing to prescribe and monitor drug treatment which has been initiated by a hospital specialist. Clear guidelines stating responsibilities of both parties, and the action required in the event of toxicity is defined within the document. The main advantage of shared care is that the patient will not be required to attend regular hospital appointments for blood tests and will be managed in primary care.

Some of the common therapeutic problems that are encountered in the management of rheumatoid arthritis are outlined in Table 53.4.

Table 53.4 Examples of therapeutic problems encountered in the management of rheumatoid arthritis

Problem	Solution
NSAID not providing adequate symptom control	Consider alternative NSAID
	Review DMARD dose
	If patient has been on DMARD for a sufficient time period but with no improvement, consider alternative disease-modifying agent, i.e. another DMARD or a biologic agent
	Consider short-term systemic steroids for rapid relief of symptoms
Patient non-adherent with DMARD monitoring regimen	Education and counselling
	If patient still unwilling to comply, the safest option would be to consider swapping to DMARDs that require less stringent blood monitoring, for example hydroxychloroquine or sulphasalazine
	However, relative drug efficacy must also be considered
Nausea and vomiting with methotrexate	Ensure patient is taking folic acid
	Add anti-emetic therapy
	Change to parenteral methotrexate
Disease flares when trying to withdraw systemic steroids	Use a slower withdrawal regimen, for example decrease by 1 mg each month
Disease flares when trying to withdraw systemic steroids	If patient cannot be withdrawn completely from steroids, consider reducing to lowest dose possible as maintenance treatment
Side effects of long-term steroids	Aim to use steroids for short-term treatment only
Side effects of long-term steroids	Ensure concomitant treatment of PPI, bisphosphonate and calcium and vitamin D preparations are prescribed where appropriate
Patient cannot tolerate stinging at injection site associated with adalimumab or etanercept administration	Consider switching to infliximab

Osteoarthritis

Osteoarthritis is a chronic disease and the most common of all rheumatological disorders. It particularly affects individuals over the age of 65 years and is the major cause of hip and knee replacements in developed countries.

Osteoarthritis was previously thought to be the consequence of ageing, thereby leading to the term degenerative joint disease. However, it is now thought to be the result of a complex interplay of multiple factors including joint integrity, genetic predisposition, local inflammation, mechanical forces and cellular and biochemical processes.

Epidemiology

The prevalence of osteoarthritis increases with age. Generally, osteoarthritis is uncommon under the age of 35 years with 0.1% of people affected between the ages of 25–34 years, but 80% of people affected above the age of 55 years. It occurs in all populations irrespective of race, climate or geographical location. Obesity is the strongest modifiable risk factor and has been shown to particularly affect the knees. Trauma or injury due to diseases, such as rheumatoid arthritis, will predispose a joint to developing osteoarthritis.

A strong genetic component is thought to be present, particularly in women with hand involvement. An inherited defect in type II collagen genes is linked to the development of early-onset polyarticular osteoarthritis.

Pathogenesis

The pathogenesis of osteoarthritis has been classified into four stages:

1. Initial repair

2. Early-stage osteoarthritis

3. Intermediate-stage osteoarthritis

4. Late-stage osteoarthritis

Initial repair is characterised by proliferation of chondrocytes synthesising the extracellular matrix of bone. Early-stage osteoarthritis results in degradation of the extracellular matrix as protease enzyme activity exceeds chondrocyte activity. There is net degradation and loss of articular cartilage. Intermediate osteoarthritis is associated with a failure of extracellular matrix synthesis and increased protease activity, further increasing cartilage loss. Finally, late-stage osteoarthritis may result in complete loss of cartilage with joint space narrowing in the most severe of cases. Bone outgrowths (osteophytes) appear at the joint margins, and there is sclerosis of the adjacent bone. Deformity is common at this stage.

Clinical manifestations

Osteoarthritis is traditionally classified by aetiology into idiopathic and secondary forms. Idiopathic can be further divided into localised and generalised depending on the number of joints involved. Localised osteoarthritis most commonly affects the hands, feet, hip, knees and spine, and less commonly the shoulder, temporomandibular, sacroiliac and wrist joints. Pain is increased by movement and loading on the joint, and may radiate beyond the joint itself, as in leg pain associated with spinal disease, and knee pain radiating from the hip. Stiffness in the early morning lasts for less than 30 min, unlike that due to rheumatoid arthritis; it may also occur after periods of rest and throughout the day.

In the hands, the most commonly affected joints are the distal interphalangeal joints or Heberden’s nodes, the proximal interphalangeal joints (Bouchard’s nodes) and the base of the thumb, the first carpometacarpal joint. Hip pain is particularly felt in the groin. Unlike rheumatoid arthritis, there is no extra-articular disease.

Investigations

Osteoarthritis is primarily diagnosed by its clinical presentation. Confirmation and progression can be achieved by radiography with the presence of joint space narrowing, bone sclerosis, cysts and deformity. There is a lack of conformity between symptoms and radiological findings. On arthroscopy normal cartilage is smooth, white and glistening, while osteoarthritic cartilage is yellowed, irregular and ulcerated. Synovial fluid analysis should be carried out if one suspects infection or crystal arthropathy such as gout or pseudogout. Blood tests usually reveal a normal ESR and CRP.

Treatment

The aims of treatment are pain relief, optimisation of function and minimisation of disease progression. There are three core interventions which should be considered for every person with osteoarthritis where possible:

• Education, advice and access to information

• Strengthening exercises to improve muscle strength and aerobic fitness training

• Weight loss if overweight or obese

Guidelines are available for the management of osteoarthritis (NCCCC, 2008). If the three core interventions are not sufficient, paracetamol and topical NSAIDs can be added in to the treatment regimen. Paracetamol and topical NSAIDs are deemed ‘relatively safe pharmaceutical options’ compared to other available agents such as oral NSAIDs, opioids and intra-articular steroids. Other interventions which may also be considered include joint arthroplasty, transcutaneous electrical nerve stimulation (TENS), supports and braces, or manual therapy involving manipulation and stretching.

Paracetamol is the first-line drug treatment and should be used alongside core treatment. Regular dosing may be required as ‘when required’ administration may lead to reduced efficacy.

Topical NSAIDs, capsaicin and rubefacients are widely used for local relief of pain and inflammation. Topical treatments are perceived as self-management, and this has a positive effect on a patient’s perception of their disease.

Due to the recent safety concerns with non-selective NSAIDs and COX-2 inhibitors, treatment regimens have moved towards opioids for uncontrolled pain. This should be balanced against adverse effects such as constipation and drowsiness, particularly in the elderly population.

There is a large amount of evidence supporting the efficacy of NSAIDs in reducing pain and stiffness in osteoarthritis. However, there is no strong evidence to suggest a consistent benefit over paracetamol. Non-selective NSAIDs or COX-2 inhibitors may be considered in patients where paracetamol and/or topical NSAIDs do not provide adequate pain relief, based on careful consideration of the patient’s risk factors, as discussed earlier in the chapter. This does not include etoricoxib which is associated with a greater risk of causing fluid retention and aggravating hypertension. NSAIDs should be used at the lowest dose for the shortest period of time possible, and patients should also be prescribed a PPI.

Intra-articular steroids may be of benefit in reducing pain and inflammation in joints. Evidence suggests that they provide short-term reduction in pain, although improvement in function is less clear. They should be considered as an adjunct to core treatment for the relief of moderate to severe pain in osteoarthritis.

Hyaluronan is an endogenous molecule found in the synovial fluid. Its key functions are to increase viscosity of synovial fluid and lubrication within the joint. Synthetic intra-articular injections of hyaluronan are thought to provide pain relief and improve joint function, although there is limited evidence to support this. The synthetic hyaluronans are expensive and not currently recommended.

Nutraceuticals is a term which describes food supplements believed to have health benefits. The most widely used of these agents in osteoarthritis are glucosamine and chondroitin. They are available in a multitude of preparations, combinations, strengths and purities and can be purchased over the counter and via the internet. There is, however, little available evidence of efficacy to support their use.

Case studies