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Fifty-two-year-old Mrs TH was referred to the early arthritis outpatient clinic by her GP. The GP’s letter stated that she had a four-week history of painful joints in her fingers and in the joints of her lower limbs. The patient reported “walking like a disabled person” and that she had never had this problem before. Blood tests performed by the GP showed a raised erythrocyte sedimentation rate (ESR). Her previous medical history included hypertension, uterine fibroids and iron-deficiency anaemia. Her medication consisted of:
- Amlodipine 5mg od
- Ferrous fumarate 210mg tds
- Diclofenac 50mg tds
- Co-codamol 8/500 ii qds prn
The medical registrar took a brief medical history and carried out an examination, which revealed active synovitis in the wrists, metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints of both hands and synovitis in both ankles. The patient complained of early-morning stiffness persisting for up to two hours each morning. The hands and wrists of both her arms had been tender and swollen for the past two months and she had found it difficult to walk due to swelling and pain in both knee joints and her feet.
The registrar performed a number of blood tests, including a full blood count (FBC), liver function tests (LFTs), urea and electrolytes (U&Es), inflammatory markers and antibodies associated with autoimmune inflammatory joint diseases. He also performed an infection screen to rule this out as a causative factor. The patient’s disease activity score 28 (DAS28) was calculated and she was sent for X-rays of her hands, feet and chest. The subsequent X-ray report showed early erosive change at the fifth metatarsal head but no other abnormalities.
A provisional diagnosis of rheumatoid arthritis (RA) was made and the patient was booked to return to the clinic in two weeks to start treatment with a disease-modifying antirheumatic drug (DMARD). She was given a depot intramuscular injection of 120mg methylprednisolone acetate and a prescription for:
- Naproxen 500mg bd
- Tramadol 50mg qds prn
What common symptoms are associated with RA?
RA is a chronic autoimmune condition. It presents as a polyarthritis, sometimes developing acutely over a few days or, more commonly, over weeks to months. Fatigue and diffuse musculoskeletal pain may occur before there is visible swelling of the joints.
The disease commonly presents with swelling, tenderness and stiffness in joints, usually those of the hands, wrists, knees, ankles and feet. Morning stiffness is a common early feature. Boggy synovial tissue may be felt on examination. However, RA is not purely a disease of the joints and extra-articular manifestations may affect the lungs, skin, blood, eyes and other organs. The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) use a score-based algorithm in diagnosing RA (see Panel 1).
Panel 1: Classification criteria
The scoring system consists of four categories. A score of at least 6 out of 10 is required for diagnosis.
1 Large joint 0
2–10 large joints 1
1–3 small joints (with or without involvement of large joints) 2
4-10 small joints (with or without involvement of large joints) 3
10 joints (at least 1 small joint) 5
Serology (at least one positive result is needed for classification)
Negative RF and negative ACPA 0
Low-positive RA or low-positive ACPA 2
High-positive RA or high-positive ACPA 3
Acute phase reactants (at least one abnormal result needed)
Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
< six weeks 0
≥ six weeks 1
Key: RF = rheumatoid factor; ACPA = anti-citrullinated protein antibodies; CRP = C reactive protein; ESR = erythrocyte sedimentation rate
What is the role of corticosteroids in managing RA?
Corticosteroids are often used as a bridging therapy to reduce symptoms and disease activity when waiting for the therapeutic onset of a DMARD or when changing from one DMARD to another. In addition they have been shown to be effective adjunct treatments to DMARD therapy to achieve more effectively the desired target (usually, clinical remission). They are also added at low to moderately high dose to DMARD therapy as an initial short-term adjunct. Oral corticosteroids should be tapered off as rapidly as clinically feasible.
Depending on the number of affected joints, corticosteroids may be injected directly into the joint (intra-articular) or given as an IM depot injection or as short-term oral therapy. They produce rapid relief of inflammatory symptoms and may have a role in disease modification, but their use, at high dose in particular, is restricted because of their long-term side effects, such as osteoporosis, peptic ulceration, diabetes mellitus and hypertension. Low-dose oral prednisolone may be used intermittently if the disease cannot be controlled by other means. For severe disease, particularly where there are extra-articular manifestations, pulsed V infusions of methylprednisolone may be given, although with the introduction of newer therapies this is now less common. Patients with repeated exposure to corticosteroids are at high risk of glucocorticoid-induced osteoporosis. The risks are highest during the initial stages of treatment. Consideration should be given to the need for bone protection with a bisphosphonate and calcium plus vitamin D supplementation.
Mrs TH takes her prescription to the hospital pharmacy. She asks the pharmacist if she should take these new medicines in addition to the painkillers she is already taking.
What are the important differences between the non-steroidal anti-inflammatory drugs?
The differences in anti-inflammatory effects of the various NSAIDs are small, but there is wide variation in the incidence of side effects. In addition, patients differ in their response. If a patient does not respond to one NSAID he or she might respond to another. However, it is important to give a chosen NSAID an adequate therapeutic trial before switching. Although pain-relieving benefits begin after the first dose, maximum analgesia takes up to a week to develop and anti-inflammatory action up to three weeks.
Gastrointestinal bleeding and perforation occur in approximately 1 per cent of patients and result in significant morbidity and mortality. Piroxicam, ketoprofen, indometacin, naproxen and diclofenac are all associated with an intermediate risk of gastrointestinal side effects; azapropazone is associated with the highest risk and ibuprofen the lowest. The cyclooxygenase-2 (COX-2)-selective agents etoricoxib and celecoxib are as effective as traditional NSAIDs but have a lower incidence of gastric side effects.
All NSAIDs, including the COX-2 inhibitors, are contraindicated in the presence of active peptic ulcer disease. Concomitant aspirin therapy greatly increases the gastrointestinal risks of NSAIDs and severely reduces any gastrointestinal safety advantages of COX-2-selective agents.
The options for reducing gastric side-effects due to NSAIDs are to avoid the use of NSAIDs and use simple analgesia; to use an NSAID with the fewest associated gastrointestinal side-effects and to use it at the lowest possible dose; to prescribe a gastroprotective agent (proton pump inhibitors are probably best); or to prescribe a selective COX-2 inhibitor.
Recent epidemiological studies lend support to the view that some increased cardiovascular risk may apply to all NSAID users, irrespective of their baseline risk, and not only to chronic users. The greatest concern relates to chronic users of high doses, especially of the COX-2-selective agents and diclofenac. Diclofenac should no longer be prescribed in patients with established ischaemic heart disaese, peripheral arterial disease, cerebrovascular disease or congestive heart failure (NYHA II-IV). Evidence suggesets that naproxen is associated with a lower thrombotic risk than both the COX-2 selective agents and diclofenac.
Patients should use the lowest effective dose and the shortest duration of treatment necessary to control their symptoms.
Evidence suggests that naproxen is associated with a lower thrombotic risk than the COX-2-selective agents. For ibuprofen the risk is low for doses below 1,200mg per day, but doses of 1.6–2.4 g daily are needed. All NSAIDs are contraindicated in severe heart failure and should be used with caution in patients with renal impairment.
It should be noted that although NSAIDs may inhibit the excretion of methotrexate (see later), leading to methotrexate toxicity, this usually remains a theoretical concern. NSAIDs are often prescribed with methotrexate but these patients are carefully monitored.
Are changes to Mrs TH’s pain relief appropriate?
In view of the patient’s history of hypertension it was appropriate to switch to an NSAID associated with a lower thrombotic risk such as naproxen.
The combination of tramadol with co-codamol 8/500 is inappropriate and needs to be discussed with the prescriber, as does the need for gastric protection.
Paracetamol used in combination with a weak opiate such as dihydrocodeine can provide simple pain relief. Although the combination has no anti-inflammatory properties and will not affect the disease process, such simple analgesic combinations do have a place in both early and late stages of RA.
The World Health Organization’s analgesic ladder is a good starting point for any decision on analgesia. Note that codeine in doses of 8mg, as in co-codamol 8/500, has not been shown to confer any additional benefit over standard paracetamol. Mrs TH may benefit from a prescription of paracetamol 1g qds combined with a separate weak opioid such as dihydrocodeine 30mg qds. It is important to avoid the co-prescription of two weak opioids, for example tramadol and co-codamol, because this is unlikely to provide any additional analgesia and will predispose the patient to unwanted side effects. Mrs TH might also require a laxative to prevent opiate-induced constipation.
On Day 14 Mrs TH returned to clinic to be reviewed by the rheumatology nurse specialist. The results from her blood tests were as follows:
- Haemoglobin 11.1g/dL (11.5–16.0)
- Red blood cells 4.85×1012/L (3.80–5.80)
- White blood cells 4.18×109/L (4.00–11.00)
- Neutrophils 2.22×109/L (2.00–7.50)
- Plasma viscosity 1.90mPa/s (1.50–1.72)
- Platelets 323×109/L (150–400)
- Mean cell volume 78fL (78–100)
- U&E and LFT levels and liver function were unremarkable.
- Urate 239mol/L (140–360)
- Infection screen negative.
- C reactive protein (CRP) 57mg/L (<10.0) • Rheumatoid factor (RF) 250IU/mL (<20)
- Anti-cyclic citrullinated peptide (anti-CCP) assay 318 (CCP quantitive result >10: positive)
- Anti-neutrophil cytoplasmic antibody (ANCA) screen negative
The nurse reviewed the results and examined her. Mrs TH still had a number of swollen and tender joints. The DAS28 was calculated and recorded (see Panel 2). Mrs TH stated that the injection and painkillers she had been given had reduced some of her pain and stiffness.
Panel 2: DAS28 and its significance
DAS28 is a disease activity score based on a 28-joint count. It is calculated from the number of tender and swollen joints, the patient’s ESR or CRP and a self-determined patient assessment of general health status according to a 100mm visual analogue scale. A score of more than 5.1 indicates high disease activity; ≥3.2 and up to 5.1 indicates moderate disease activity; between 3.2 and 2.6 indicates low disease activity while <2.6 indicates remission.
DAS28 is often used to determine when treatment with a biologic should be started, and to evaluate the patient’s response. An adequate response is defined as an improvement in the DAS28 of 1.2 points or more. A drawback associated with using DAS28 as an indicator for changing therapy is that some patients may not have particularly high inflammatory markers, but still have severe disease.
DAS28 may also be raised by the perception and reporting of pain by patients and the presence of pre-existing long-term damage. Variations in the score will be caused by different individuals making the assessment, and any sensory, communication or learning difficulties a patient may have.
A formal diagnosis of seropositive RA was made. The nurse explained what RA is and how it is managed. She gave MR TH a prescription for a DMARD and a form to have blood tests (FBC, U&Es, LFTs and inflammatory markers) in two weeks. Mrs TH was asked to return to clinic in four weeks.
What is the significance of the positive results for RF and anti-CCP?
RF and anti-CCP are antibodies directed against one or more of an individual’s own proteins. These autoantibodies may be detected in the blood of patients with RA and along with a other diagnostic tests, are used in the diagnosis of RA.
RF was the initial defining autoantibody in RA. It is an antibody against the Fc portion of IgG. RF and IgG combine to form complexes that contribute to the RA disease process. However, a positive result may be due to another cause and a negative result does not rule out a RA. Around 80 per cent of patients with RA will be positive for RF and this may precede symptom onset by several years. The presence of RF in RA is associated with a poorer prognosis. Other conditions associated with an elevated RF include chronic hepatitis, primary biliary cirrhosis, chronic viral infection, bacterial endocarditis, leukaemia, dermatomyositis, infectious mononucleosis, systemic sclerosis and systemic lupus erythematosus.
Raised anti-CCP (also known as ACPA) has been relatively recently recognised as a marker for RA. Post-transitional modification of arginine residues to citrulline is the antigen recognised and it has a higher specificity for distingushing RA from other rheumatic diseases. The presence of anti-CCP may precede symptoms of RA for many years and it is highly predictive of the future development of RA in healthy individuals and patients with undifferentiated arthritis. ACPA-positive RA is associated with increased joint damage and lower remission rates. ACPA-positive and ACPA-negative RA are associated with different genetic and environmental risk factors and are increasingly viewed as two distinct disease entities.
When should a DMARD be started and which are commonly used?
All patients with a confirmed diagnosis of RA should be commenced on a DMARD immediately. Several studies have shown that irreversible damage occurs in the first two years of RA with magnetic resonance imaging indicating that it happens within weeks.
Early therapeutic intervention with DMARDs can improve patient outcome and reduce disease progression. All patients with a confirmed diagnosis of RA should be prescribed a DMARD. They do not provide pain relief but do suppress the disease process. They also have a delayed onset of action — it can take six weeks before the patient starts to see a response, and up to six months before a full response is achieved.
Recommendations vary on whether a patient should be started on a single DMARD or whether it is more appropriate to prescribe combination therapy. Current National Institute for Healthcare and Clinical Excellence guidance recommends that all patients with newly diagnosed active RA should be offered a combination of two DMARDs as first-line treatment, ideally within three months of the onset of persistent symptoms. However, European guidance suggests that DMARD monotherapy may be more appropriate in DMARD-naive RA patients. This is due to a number of reasons, including variations in glucocorticoid use in trials comparing DMARD combination and monotherapy, which resulted in non-comparative treatment arms, plus difficulties in evaluating toxicity and efficacy when two DMARDs are started together. Physicians may, therefore, prefer to start with a single agent with close monitoring and rapid dose escalation, with early addition of a second agent where appropriate.
The precise mechanism of action of DMARDs is unclear. There is good evidence that they inhibit the activity of inflammatory cytokines. Certain cytokines have been shown to play an important role in the pathogenesis of RA. Activated T cells also play a role in the early induction of RA. Methotrexate and leflunomide have both been shown to inhibit T cells.
The agent of choice is methotrexate. This is highly effective in the management of RA, both as a monotherapy and on the basis of its ability to increase the efficacy of biologic medicines (see later). No other DMARD has shown superiority in terms of clinical efficacy and meta-analyses have confirmed Tumour necrosis factor inhibitor (TNFi) monotherapy is not superior to methotrexate in improving signs and symptoms of RA.
Methotrexate is generally used as a first-line agent (unless comorbidity precludes its use). It has an onset of action of about a month, and can be given orally or by subcutaneous or IM injection. It tends to be given by injection when patients are unable to tolerate oral doses because of gastric side effects, or where doses of 25mg or more are being given. The starting dose tends to be 7.5–10mg once a week, then gradually adjusted according to response and tolerance. Patients should be clearly counselled that methotrexate should only be taken once a week.
Common side effects include mouth ulcers (stomatitis) and nausea. Folic acid is commonly prescribed to counteract these. Folic acid tends to be given as a 5mg once daily, although other regimens are used. Most will, however, omit the dose on the day of methotrexate therapy to avoid any potential impact on the latter’s efficacy.
The use of methotrexate has been associated with haematological, hepatic and pulmonary toxicity. Because of the drug’s potential to suppress bone marrow and cause liver toxicity it is essential that certain blood tests are performed regularly. All patients should have the baseline FBC, U&E and LFTs and these should then be performed regularly throughout treatment.
Although methotrexate is considered the “anchor” drug in RA, its use may be contraindicated in some patients or therapy may have to be discontinued due to side effects. Other currently recommended DMARDs include sulfasalazine, leflunomide and injectable gold (sodium aurothiomalate). The antimalarials hydroxychloroquine and chloroquine may also be of use in milder disease. Although they show some efficacy as a monotherapy with respect to the signs and symptoms of RA, they have not been shown to inhibit structural damage sufficiently compared with other DMARDs. They may also be combined with other DMARDs in the management of RA, but it is not established if they confer additional efficiacy when used in this way.
Sulfasalazine (enteric-coated) is indicated in mild to moderate disease. It has an onset of action of six to 12 weeks. In order to reduce nausea the dose is usually titrated upwards from 500mg od, increasing at weekly intervals to 1g bd. Haematological abnormalities have occurred with sulfasalazine and, although rare, patients should be counselled to report unexplained bleeding, bruising, purpura, sore throat, fever or malaise. Patients should also be warned that sulfasalazine can colour urine red and stain contact lenses. Baseline FBCs and LFTs should be performed and repeated intermittently throughout treatment.
Leflunomide inhibits the synthesis of pyrimidine nucleotides in response cells (particularly T cells) and reduces proinflammatory cytokines. Studies have shown it to be at least as effective as sulfasalazine and methotrexate, and for quality-of-life measures some evidence suggests superiority. When given as a loading dose of 100mg od for three days followed by a maintenance dose of 10–20mg daily its therapeutic effect starts after four to six weeks, and further improvement may be seen for up to six months. However, many centres do not use this loading dose regimen because patients are unable to tolerate the gastrointestinal side effects associated with it.
Leflunomide use has been associated with both haematological and hepatotoxic side effects. An FBC and LFTs must be performed before therapy is initiated, and then every two weeks for the first six months, followed by every eight weeks thereafter. When leflunomide and methotrexate are used in combination extra caution is advised. Leflunomide can also cause hypertension — blood pressure should be checked before commencing leflunomide and periodically thereafter — and men and women are required to use adequate contraceptive measures during treatment, and a washout protocol must be followed for any patient considering starting a family.
Although injectable gold (sodium aurothiomalate) has been shown to be efficacious in the management of RA, its use is limited due to its unfavourable side effect profile. Due to the risk of anaphylaxis an initial 10mg test dose should be given in the first week of treatment, followed by a maintenance dose of 50mg the following week.
Administration is by deep IM injection. Patients should be monitored for 30 minutes following each dose. FBC and urine (for proteinuria) should be checked after six days, just before giving the next full dose of 50mg IM. The maintenance dose of 50mg every week is given until the first signs of remission occur. At this point the interval between injections should be extended to two weeks until full remission occurs. The interval between injections can then be increased progressively to three weeks, four weeks and then, after 18 months to two years, to six weeks.
Penicillamine is no longer used in the management of RA due to its poor side effect profile and lack of efficacy compared with other agents. Azathioprine and ciclosporin may be used occasionally for progressive disease refractory to other DMARDs, or where a biologic is contraindicated.
Azathioprine may also be used for steroid-sparing. It is an oral purine analogue that inhibits lymphocyte proliferation. It becomes biologically active after metabolism by the liver to 6-mercaptopurine. Bone marrow suppression and liver toxicity are associated with its use and FBCs and LFTs should be performed during treatment. Renal function should also be monitored because the drug is renally excreted.
Ciclosporin works by impairing the function of B and T lymphocytes. Dose-related hypertension and nephrotoxicity are common side effects. FBCs should be performed during treatment and liver and renal function monitored. Ciclosporin drug levels are not routinely measured when it is used for the management of RA.
Mrs TH visited the outpatient pharmacy with a prescription for oral methotrexate 10mg once a week for two weeks, then 15mg once each week for two weeks in conjunction with folic acid 5mg daily except on the day the methotrexate was taken.
What counselling would you with regard to methotrexate?
Although methotrexate is a safe medicine when used appropriately, deaths have occurred as a consequence of patients taking it incorrectly. Mrs TH must understand how and when to take the medicine plus the need for regular blood monitoring. It must be clear that the medicine is taken only once a week. All patients prescribed methotrexate should be recounselled every time they are issued with a prescription, irrespective of how long they have been on treatment.
Important points to cover when counselling a patient prescribed methotrexate are listed in Panel 3. National Patient Safety Agency guidance recommends that all patients taking methotrexate should be issued with a core patient information leaflet and a hand-held methotrexate monitoring booklet. The prescriber should provide the patient with information about the benefits and risks of treatment with methotrexate. The term “as directed” should not be used and patients should be clear on the number of tablets they are taking and on which day of the week. There should also be consistency on the strength of the tablet issued. Iideally patients should be supplied with only the 2.5mg strength to avoid confusion. When issuing prescription it should be clearly explained which is the methotrexate container and which is the folic acid container, so the patient is able to differentiate between the two.
Panel 3: Advice with methotrexate
- Why the methotrexate is prescribed.
- How long it will take to work.
- The dose and the frequency.
- The importance of regular blood monitoring.
- Side effects, including warning symptoms that necessitate urgent referral to the doctor (eg, increased breathlessness, a dry persistent cough or vomiting and diarrhoea.
- Interactions with the medicine, including over-the-counter drugs and herbal remedies.
- The need for adequate contraception in males and females.
Patients taking methotrexate who are admitted to hospital should have a full medication review conducted by a pharmacist.
Mrs TH returned to clinic to see the nurse specialist. Bloods tests at two and four weeks showed no abnormalities. The nurse further increased the dose of methotrexate to 20mg once weekly. Mrs TH was to have repeat blood tests in 2 weeks. These tests indicated a raised alanine transaminase (ALT) of 60IU/L (< 40).
What action should be taken following an abnormal ALT result? The dose should be reduced back down to 15mg once a week and blood tests repeated in two weeks. However, other factors which could have caused a raised ALT in conjunction with methotrexate should be excluded. These include use of NSAIDs; the addition of new medicines, including OTC and herbal remedies; increased alcohol consumption; and concomitant illness. If there are no other contributing factors the patient should be kept on 15 mg methotrexate weekly. If this is insufficient to control her RA a second DMARD will probably need to be added.
Mrs TH’s dose of methotrexate is stable. Her GP is asked to take responsibility for prescribing and monitoring. An outpatient appointment was made for the patient to return to clinic in three months.
The patient was seen by the registrar in the early arthritis clinic. Despite having been on methotrexate for three months Mrs TH still suffered from early morning stiffness and a number of swollen and tender joints in her hands and feet. The registrar administered a depot IM injection of 120mg methylprednisolone acetate and gave Mrs TH an outpatient prescription for sulfasalazine EC 500mg on for a week, then 500mg bd for week 2, followed by 500mg om plus 1g on for week 3, then 1g bd. Mrs TH was asked to return to clinic in four weeks. She was given forms to have blood tests taken two weeks after starting the sulfasalazine.
Mrs TH returned to the clinic. Her blood tests after two weeks of sulfasalazine therapy had been normal. Her medication was as follows:
- Methotrexate orally 15mg once weekly
- Folic acid 5mg od except on the day methotrexate was taken
- Sulfasalazine EC 1g bd
- Paracetamol 1g qds
- Dihydrocodeine 30mg qds
- Naproxen 500mg bd
- Lansoprazole 15mg od
- Amlodipine 5mg od
- Ferrous fumarate 210mg tds
She was reviewed in clinic by the nurse specialist. Repeat bloods were taken and her DAS28 calculated. An appointment was made for reviewed in a further three months. It was decided that the RA was still not adequately controlled her therapy would be escalated.
When is it appropriate to start a biologic and what is first-line? Government guidance (NICE) in England recommends that patients with active RA and a DAS28 of >5.1 who have failed an adequate trial of at least two DMARDs, including methotrexate (unless contraindicated), may be started on a biologic medicine. An adequate trial for a DMARD is defined in the guidance as a treatment period of six months, with two months at standard dose, unless significant toxicity has limited the dose or duration of treatment.
Recent international recommendations (“treat to target”) encapsulated the approach to the treatment of RA: namely, to aim towards achieving clinical remission or at least low disease activity if remission is not achievable (due to more established disease, for example) through frequent monitoring of disease activity with responsive titration of pharmacotherapy until the target is reached. NICE guidance is not entirely harmonious with its RA management guidelines which also state remission should be the desired goal of treatment. Patients who fail to achieve this on conventional DMARDs then have to demonstrate further severe disease activity to qualify for biologic therapy. Both the British Society for Rheumatology (BSR) and EULAR recommend that biologic medicines should be considered in patients with a lower DAS28 score. Current BSR guidance suggests initiating a biologic agent in patients with a DAS28 of greater than 3.2 in patients with three or more tender and three or more swollen joints who have undergone an adequate trial of at least two DMARDs, including methotrexate unless contraindicated. In patients with poor prognostic markers, such as very active disease or early structural damage accompanied by the presence of positive RF and/or ACPA, current European guidance would recommend starting a biologic first line in combination with methotrexate.
Studies of TNFi as first-line therapy in early RA have demonstrated the potential for high remission rates, with studies illustrating their ability to induce remission and maintain it following biologic withdrawal. There are a number of studies aiming to compare the aggressive treat to target conventional DMARD therapy (± later TNFi) approach with the use of TNFi as first-line therapy.
TNFis have the largest array of safety information. Current licensed TNFis available in the UK for the management of RA are:
More recently, two non-TNFi, tocilizumab and abatacept, have gained licences in the UK for moderate to severe active RA following DMARD failure. The practice of selecting a TNFi as first-line biologic agents of choice may change as more clinical experience is gathered on the use of newer non-TNF agents. NICE guidance in England approved the use of tocilizumab and abatacept first-line (both with concomitant methotrexate) following DMARD failure in accordance with the recommendations for TNFi.
TNF- and IL-1 are proinflammatory cytokines present in the synovial fluid and tissue. In RA they are produced in excess. Blocking of TNF-α by TNFi agents results in dampening of the inflammatory cascade and the blocking of IL-1 activity. TNFi therapy has been shown to reduce the signs and symptoms of RA, improve physical function and slow the progression of joint damage.
Adalimumab is a recombinant human monoclonal antibody that binds specifically to TNF- and neutralises its biological function by blocking its interaction with cell surface TNF- receptors. Due to it being a fully humanised monoclonal antibody it is less likely to provoke an immune response in the recipient than agents that contain non-human or artificial sequences. It is used with methotrexate in patients with moderate to severe active RA who have had an inadequate response to DMARDs, including methotrexate. It can also be used as monotherapy in patients who are intolerant to methotrexate, or where methotrexate is contraindicated. Adalimumab is administered as a 40mg subcutaneous injection every other week.
Certolizumab pegol consists of a portion of a recombinant, humanised monoclonal antibody (fab fragment) bound to polyethylene glycol (PEG). The PEG portion increases the half-life to approximately 14 days, which is that of a whole antibody, and is much longer than the half-life of unconjugated fab fragments. The formulation was developed to address concerns that some of the toxicity associated with infliximab and adalimumab might be due to the effects of the Fc portion of the antibody causing complement activation and antibody-dependent cell-mediated cytotoxicity. Certolizumab, used with methotrexate, is indicated for the treatment of moderate to severe active RA in adult patients when the response to DMARDs, including methotrexate, has been inadequate. Certolizumab can be given as monotherapy in the case of intolerance to methotrexate, or when continued treatment with methotrexate is inappropriate. The recommended starting dose for adults with RA is 400mg (as two subcutaneous injections of 200mg each on one day) at weeks 0, 2 and 4, followed by a maintenance dose of 200mg every two weeks. In certain countries the manufacturer of certolizumab operates a patient access scheme where the first 12 weeks of treatment are provided free of charge. Data from clinical trials suggest that full clinical response to certolizumab should be achieved within the first 12 weeks of treatment. If the desired response has not been achieved then treatment should be discontinued.
Etanercept is a recombinant human soluble TNF- receptor. It competitively inhibits the activity of TNF- by binding to its cell surface receptors. It can be used as monotherapy or in combination with methotrexate for the treatment of moderate to severe active RA. It is given by subcutaneous injection, either 25 mg twice weekly or 50 mg once weekly.
Golimumab is a human monoclonal antibody that forms high-affinity, stable complexes with both the soluble and transmembrane bioactive forms of human TNF-, thus preventing the binding of TNF-α to its receptors. It must be administered in combination with methotrexate and it is licensed for the treatment of moderate to severe active RA following an inadequate response to DMARDs or following failure or intolerance to other TNFi. In randomised controlled trials (RCTs) it has demonstrated efficacy in RA patients who have failed with 1–2 previous TNFi. Clinical response is usually seen after 12–14 weeks of treatment. It requires less frequent administration than the other subcutaneous TNFi and is given once a month. The starting dose is 50 mg by subcutaneous injection once a month. Patients who weigh more than 100 kg should have their dose increased to 100 mg per month if they have not achieved an adequate response after three or four doses. If an adequate response is not achieved following administration of three or four doses of 100 mg, then treatment should be discontinued.
Infliximab is a chimeric human–murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of TNF-α, leading to inhibition of its functional activity. It is used in combination with methotrexate in patients with active disease who have failed to respond to other DMARDs, including methotrexate. Infliximab is given as a 3 mg/kg IV infusion. The initial infusion is given over a 2-hour period; subsequent infusions are given 2 and 6 weeks after the first. The patient is then maintained on 8-weekly maintenance infusions.
What checks should be performed before starting a biologic?
TNFi therapy has been associated with an increased incidence of infection and reactivation of latent tuberculosis (TB). TNFis may also exacerbate heart failure. A minority of patients have developed lupus-like symptoms or neurological complications as a result of demyelination. Before therapy all patients should be screened for the presence of infection. A chest X-ray should be taken plus blood tests for the presence of TB and hepatitis B/C infection. In addition, it is advisable that blood tests for autoantibodies linked to the development of SLE should be performed at baseline for future reference.
The risks and benefits of commencing a TNFi in certain patient groups should be carefully considered. TNFi therapy should be avoided in circumstances such as patients with: chronic leg ulcers; septic arthritis in a native joint within the past 12 months; sepsis in a prosthetic joint in the past 12 months (if the joint remains in situ); persistent or recurrent chest infections; indwelling urinary catheter; bronchiectasis associated with recurrent chest infection. Although data from RCTs and the British Biologic Registry failed to demonstrate an increase in treatment-related serious infections, data from the meta-analysis of RCTs and the German and Spanish registries suggest that TNFi use is associated with an approximate doubling of the risk of serious infections, particularly early on in therapy. An increased incidence of opportunistic and fungal infections has also been associated with treatment.
There is a well-established increased risk of TB associated with TNFi therapy, with UK and French registry data demonstrating a greater risk associated with TNFi monoclonal antibodies as opposed to a fusion protein.
Any active mycobacterial infection needs to be treated before aTNFi can be started. Where there is evidence of potential latent TB prophylaxis should be considered. Patients should continue to be monitored for the development of mycobacterial infections during treatment and for six months after stopping.
Conflicting data exist on the effect of TNFi on cardiac function in pre-existing heart failure. In initial trials involving TNFi there was worsening of moderate to severe cardiac function. Severity assessment of cardiac function should be performed in all patients with pre-existing cardiac failure before considering treatment with a TNFi. Treatment is contraindicated in moderate to severe impairment (New York Heart Association (NYHA) class III/IV) and should be used with caution in patients with mild heart failure (NYHA class I/II). Treatment with a TNFi should be discontinued in patients who develop new or worsening symptoms of congestive heart failure.
Rare cases of lupus and vasculitis (ANCA-associated) have been reported in association with anti-TNF treatment. SLE symptoms occurred three to six months after starting therapy and included fever, malaise, arthritis, discoid lupus rash, erythematous facial rash and hypertension. These symptoms resolved six to 14 weeks after stopping therapy. TNFi therapy should be stopped if symptoms of an SLE-like syndrome develop.
There are a number of reports of demyelination and acute neurological complications associated with TNFi therapy, although registry data have not led to a clear signal. Nevertheless, because of this, TNFi therapy should not be given to patients with a history of demyelinating disease and should be carefully considered if there is a strong family history of demyelination. Therapy should be stopped if patients develop signs or symptoms suggestive of demyelination.
Concerns have previously been raised about the increased risk of cancer associated with TNFi therapy. It is important to be aware that RA itself, and continued disease activity, is associated with a greater risk of cancer (particularly lymphoma) than in the general population. Overall there is no conclusive evidence for an increase in solid tumours or lymphoproliferative disease with the TNFi therapies above the level which would be expected for the rest of the RA population; however, this issue continues to be monitored closely. There does appear to be an increased risk of non-melanoma skin cancers with TNFi therapy and patients should be counselled on appropriate skin protection.
Limited data are available on certolizumab pegol and golimumab, but information collected so far suggests that their side effect profile does not differ significantly from the older agents.
Mrs TH returned to clinic, having taken sulfasalazine for three months. Despite dual therapy she still had a DAS28 of 5.3. A decision was made to initiate a subcutaneous tumour necrosis factor inhibitor (TNFi).
Which TNFi would you recommend?
There have been no direct comparative trials of TNFi agents in patients with RA. Selection is based on several factors which include: clinical phenotype (serology profile, concomitant pathology); comorbidity; the ability to self-inject; co-prescription with methotrexate; as well as prescriber preference.
The treatment of RA must be based on a shared decision between the patient and rheumatologist. Not all patients are able to tolerate methotrexate and the TNFi agents golimumab and infliximab are required to be given with methotrexate. Other patients may be needle-phobic. In such cases consideration would be given to a TNFi which could be administered by infusion (infliximab) or a subcutaneous TNFi which only needs to be given monthly, such as golimumab. Patients may also have other autoimmune diseases in association with the RA, such as psoriasis or inflammatory bowel disease, in which case consideration would be given to selecting an agent licensed for both indications.
Mrs TH presented an outpatient prescription for etanercept prefilled pens 50mg by SC injection once weekly. The sulfasalazine was stopped in clinic and she was told by the nurse specialist to continue with the methotrexate. Following dispensing the patient was to return to clinic so that she could be trained by the nurse on the administration of etanercept. Mrs TH asked the pharmacist what would happen if this medicine did not work.
Are there any options if Mrs TH does not respond to treatment with etanercept?
Patients who have had only a partial or no response to a single TNFi may respond to an alternative. Other agents which may be considered following failure with a TNFi include another TNFi, abatacept, rituximab and tocilizumab. Evidence from RCTs has shown that abatacept, golimumab, rituximab and tocilizumab are all effective in patients in whom a TNFi has failed. At present there is insufficient evidence to support preference for a particular agent when switching.
If patients experience an adverse drug reaction to their first TNFi, which is not a class effect (eg, demyelination or TB), it is standard practice to switch them to an alternative TNFi to ensure he or she has had the opportunity of a good trial of TNFi. Where there is a primary non-response to the first TNFi, consideration may be given to switching to a TNFi with an alternative structure and mechanism. For example, if the patient has failed with a fusion protein such as etanercept then consideration could be given to switching to a monoclonal antibody such as adalimumab. Some patients may have a good response to their first TNFi, but then may subsequently lose this, usually due to development of antibodies to the medicine. In such cases another TNFi can be tried. Due to the costs associated with these therapies some countries may restrict the number of biologic medicines a patient can be treated with over a period and the sequence these agents can be used in. For example, current guidance in England recommends switching to rituximab following treatment failure with the first TNFi provided there are no contraindications.
Rituximab is a genetically engineered monoclonal antibody which binds to CD20, a protein expressed on B lymphocytes. It is licensed for use with methotrexate to treat severe active RA in patients who have had an inadequate response or intolerance to other DMARDs, including one or more TNFi therapies. It works by a variety of mechanisms, including depleting B cells and affecting B and T cell interaction, antigen presentation and cytokine production. In RA, B cells can be found in the synovium. They produce antibodies that contribute to the disease and inflammatory cytokines. B cells also affect the function of other cells and cause inflammation. Trial data and experience suggest that patients with seronegative arthritis may respond less well to rituximab than seropositive patients. A recent meta-analysis suggested that the association of seropositivity and response was most marked in the REFLEX study, which evaluated rituximab in patients who had failed with a TNFi. A recent consensus update on rituximab use in RA also suggested that in seronegative patients alternative biologic therapies may be considered in preference to rituximab. Rituximab is given as two 1g infusions two weeks apart and may be repeated after six months if the patient has a detectable B-cell count. Methylprednisolone is given in conjunction with each infusion to prevent infusion reactions. Patients may also require pretreatment with paracetamol and an oral antihistamine.
Abatacept is a recombinant human fusion protein that binds to proteins naturally expressed on the surface of activated T cells, causing attenuation of T-cell activity by blocking a co-stimulatory signal. T cells are central to the immune response and are found in the synovium of patients with RA. In the synovium T cells express activation markers, secrete cytokines and stimulate macrophages, thereby contributing to the development of inflammation and joint destruction. Abatacept, in combination with methotrexate, is indicated for the treatment of moderate to severe active RA in adult patients who responded inadequately to previous therapy with one or more DMARDs, including methotrexate or TNFi. It does not differ in therapeutic response between seropositive and seronegative patients and may therefore be considered in place of rituximab in seronegative patients who have failed on TNFi therapy. It is administered as an IV infusion according to weight (<60 kg = 500 mg; ≥60 to ≤100 kg = 750 mg; >100 kg = 1000 mg). Following the initial infusion it is given two and then four weeks later, then every four weeks thereafter.
Tocilizumab is the first IL-6 blocker (acting as an IL-6 receptor antagonist) to become licensed in Europe for the management of moderate to severe RA with or without methotrexate. IL-6, like TNF-α, is a multifunction, pleiotropic cytokine that has a wide range of biological activities in various target cells and regulates immune responses, drives CRP (acute-phase reactants), haematopoiesis and bone metabolism. Because IL-6 is involved in a number of important physiological roles, deregulated overproduction of IL-6 causes various conditions, including autoimmune, inflammatory and lymphoproliferative disorders. In RA, elevated production of IL-6 is observed in the synovial fluid and blood with levels correlating with disease activity. Some of the clinical aspects of RA, such as overproduction of acute-phase proteins, raised platelet counts, anaemia, induction of osteoclasts, production of autoantibodies and decreased albumin, can be explained by activities of IL-6. At present, it is the only biologic agent which, when used as monotherapy, has demonstrated superiority over methotrexate in RCTs. Its licence permits use first-line following DMARD failure or following treatment failure with other biologic agents. Administration has been associated with abnormal LFTs and blood dyscrasias. Patients receiving treatment with tocilizumab should have regular FBCs and LFTs. Treatment has also been linked to an increase in lipid levels: such changes are not unique to tocilizumab and have been observed with TNFi and other biologic therapies, and are thus likely to reflect moderation of the inflammatory state. Patients receiving tocilizumab should have their lipid parameters checked 4–8 weeks following initiation of tocilizumab therapy. The standard dose regime for tocilizumab is 8 mg/kg given by IV infusion every 4 weeks (maximum dose 800 mg).
What is the long-term prognosis in RA?
The primary target for treatment of RA should be a state of clinical remission. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease. Unfortunately, in long-standing disease there may be considerable pre-existing joint damage and several prior treatment failures. In this patient group low disease activity is a more realistic goal.
Patients with RA have a shortened life expectancy and an increased risk of cardiovascular disease. A poorer prognosis is associated with a positive RF, raised inflammatory markers, early radiographic joint damage and the presence of tender/swollen joints. Early referral to a rheumatologist is essential. DMARDs should be commenced as soon as possible to prevent joint damage and increase life expectancy. The patient’s disease activity should be regularly assessed and therapy adjusted accordingly in a timely manner, in order to achieve the agreed target of (ideally) clinical remission in line with the ‘treat to target’ approach to management.
Previous editions of this chapter were co-authored by David Bryant. The author would also like to thank Dr M Buch, Consultant Rheumatologist, Leeds Teaching Hospital NHS Trust, for reviewing and commenting on this chapter.
- Buch MH, Smolen JS, Betteridge N et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70: 909.
- Cohen SB, Emery P, Greenwald MW Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks (REFLEX). Arthritis Rheum 2006; 54: 2793–2806.
- Deighton C, Hyrich K, Ding T et al. BSR Clinical Affairs Committee & Standards, Audit and Guidelines Working Group and the BHPR. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology 2010; 49: 1197–1199.
- Ding T, Ledingham J, Luqmani R et al. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology 2010; 49: 2217–2219.
- Emery P, Fleischmann R, Filipowicz-Sosnowska A et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial (DANCER). Arthritis Rheum 2006; 54: 1390–1400.
- Fleischmann R, Vencovsky J, van Vollenhoven RF et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic: the FAST4WARD study. Ann Rheum Dis 2009; 68: 805–811.
- Genovese MC, Becker JC, Schiff M et al. Abatacept for rheumatoid arthritis refractory to tumour necrosis factor-α inhibition. N Engl J Med 2005; 353: 1114–1123.
- Hjardem E, Østergaard M, Pødenphant J et al. Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor? Ann Rheum Dis 2007; 66: 1184–1189.
- Keystone E, Van Der Heeijde D, MasonJr D et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two week, phase III, multicentre, randomized double-blind, placebo-controlled, parallel-group study (RAPID 1). Arthritis Rheum 2008; 58: 3319–3329.
- Kremer JM, Genant HK, Moreland LWP et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis. Ann Intern Med 2006; 144: 865.
- National Collaborating Centre for Chronic Conditions. Rheumatoid Arthritis: National Clinical Guideline for the Management and Treatment in Adults. Royal College of Physicians, London, 2009.
- National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 247. Tocilizumab for the Treatment of Rheumatoid Arthritis (rapid review of technology appraisal guidance 198). NICE, London, 2012.
- National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 195. Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of RA after the Failure of a TNF Inhibitor. NICE, London, 2010.
- National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 130. Adalimumab, Etanercept and Infliximab for the Treatment of Rheumatoid Arthritis. NICE, Lndon, 2007.
- Scott DL, Wolfe F, Huzinga TW Rheumatoid arthritis. Lancet 2010; 376: 1094–1108.
- Smolen J, Kay J, Doyle MK et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomized, double-blind, placebo-controlled, phase III trial. Lancet 2009; 374: 210–221.
- Smolen J, Landewe´ RB, Mease P et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomized controlled trial. Ann Rheum Dis 2009; 68: 797–804.
- Smolen JS, Landewe´ R, Breedveld FC et al. European League Against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: 964–975.
- Smolen J, Aletaha D, Bijlsma JWJ et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: 631–637.
- Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. Br Med J 2011; 342: c7086.