Dr Catherine Sullivan outlines the latest treatment options
in rheumatoid arthritis
Rheumatoid arthritis (RA) is a common
inflammatory arthritis with a prevalence of 1 per cent worldwide. Left
untreated it results in irreversible deformity and disability, there is also
now ample evidence that delays in diagnosis and treatment results in poorer
outcomes. The incidence of RA in women is twice that of men and is most common
between the ages of 30 and 50 years. Patients with RA experience higher levels
of work disability and unemployment compared to the general population, which
has repercussions for mental health as well as ongoing societal costs. In
addition to joint damage caused by synovial inflammation, there are significant
potential extra-articular complications of RA, which contribute to both
morbidity and mortality. As well as the classic textbook lists of
extra-articular features it is now well recognised that patients with RA have a
higher incidence of cardiovascular disease compared to the general public and
that this accounts for their reported increased mortality rate. Ischaemic heart
disease, sudden death and cerebrovascular disease are all more common in
patients with RA compared to the general population. Thankfully, this mortality
gap is beginning to close reflecting recent changes in treatment strategies
that prioritise early aggressive treatment with a focus on achieving disease
remission rather than treating symptoms. Accompanying this, a reduction in
orthopaedic and plastic surgeries has been seen, with fewer joint replacements
and tendon surgery required in RA patients.
Presentation
The classic presentation of RA is that
of pain, swelling and stiffness in the small joints of the hands, wrists,
ankles and MTPs though it can affect any synovial joint. Occasionally RA
presents as a monoarthritis initially and progresses to a polyarticular pattern
over time. Pain and stiffness are usually worse in the morning time and early
morning stiffness can last for several hours. Symptoms can develop rapidly in
which cases the diagnosis is often straightforward; it may be more difficult to
identify where the onset is insidious or the presentation asymmetrical. It is
important to remember that about 30 per cent of patients will be negative for
rheumatoid factor and anti-CCP and so a negative antibody test does not exclude
a diagnosis. Additionally, normal inflammatory markers do not outrule RA and
patients with normal ESR and CRP should be referred on for specialist
assessment if the clinical suspicion is high. Plain x-rays are often normal in
patients with RA and specialist review should not be delayed while waiting for
these. Patients with RA will frequently complain of fatigue and other systemic
features such as weight loss, anorexia or fever.
Treatment
There is now a wide range of
pharmacological treatment options available to treat RA as well as other types
of inflammatory arthritis. While NSAIDs and steroids are useful in initial
symptom control the mainstay of long-term treatment is disease modifying
anti-rheumatic drugs (DMARDs) – both synthetic and biologic. The newer DMARD
treatments target specific inflammatory and immune pathways, blocking the
action of specific cytokines or binding to cell surface markers.
Methotrexate is a conventional synthetic DMARD with
no specific target and is the cornerstone of treatment for patients with RA; it
is the first-line synthetic DMARD used when not contraindicated. Methotrexate
is taken weekly either orally or as a subcutaneous injection with
supplementation with folic acid at a minimum dose of 5mg weekly. Side effects
of methotrexate include GI upset, headaches and mouth ulcers. Patients on
methotrexate need to have LFTs and FBC checked regularly and should avoid
alcohol intake to reduce the risk of hepatotoxicity. Methotrexate is
teratogenic and for pre-menopausal women counselling regarding the risk of
methotrexate and ensuring adequate contraception are important parts of the
consultation. Despite the daunting list of potential side effects and
toxicities, methotrexate is generally well tolerated and its evidence-base in
RA is robust. Extra folic acid can be used to reduce recurrent side effects if
necessary and the subcutaneous route of administration can help to avoid GI
intolerance. Previous concerns about lung disease secondary to methotrexate
have been largely disproven in recent large meta-analyses.
Plaquinal/hydroxychloroquine can be used as an adjunct to
methotrexate or as monotherapy. Taken daily either as a single or twice-daily
dose the side effects of most concern is that of retinotoxicity which is now
thought to be more prevalent than previously thought with an estimated 7.5 per
cent of long-term users potentially affected. It manifests as damage to the
retinal pigment epithelium and the development of bull’s eye maculopathy with
central visual loss. Plaquinal should be avoided in patients with pre-existing
macular disease and, if long-term use is planned, a baseline review by an
ophthalmologist should be carried out within six-to-12 months of starting
treatment.
Salazopyrin may again be used as part of
combination DMARD therapy or as monotherapy. It is taken orally, up to four
tablets a day and may be useful in patients who have contraindications to the
use of methotrexate. It can result in reversible azoospermia and infertility in
men.
Leflunomide is occasionally used but has a
significant rate of symptomatic GI side effects.
Azathioprine
and cyclosporin
are no longer used as first-line treatments of RA.
In
patients who have an inadequate response to methotrexate treatment, triple DMARD therapy may be used, that is
methotrexate/hydroxychloroquine/salazopyrin. There is, however, a significant
pill burden associated with this, which can lead to challenges in compliance
compared to injectable biologic agents.
Biologics
Anti-TNF agents are often the first biologic agents to
be used in RA, either in combination with methotrexate or as a monotherapy.
These are either monoclonal antibodies to TNF or receptor antagonists and the
majority are subcutaneous with one, infliximab, given intravenously. Depending
on the drug chosen these are self-administered with pre-filled pen devices
weekly, fortnightly or monthly. There is now a large body of safety data for
this class of biologic with over 20 years of clinical experience and registry
data. TNF inhibitor therapy is contraindicated in patients with TB,
decompensated heart failure, active malignancy and demyelination. They are safe
to use in early pregnancy but it is recommended that they are discontinued in
the third trimester, this is not due to toxicity but rather antibodies
transferred across the placenta may render the new-born immunosuppressed. The
exception to this is certolizumab, as the pegylated molecule does not cross the
placenta. TNF inhibitors are also widely used to treat psoriatic arthritis
(PsA).
Tocilizumab is an anti-IL-6 agent delivered
subcutaneously once a week and is licensed for the treatment of both RA and
giant cell arteritis. Lipid levels, LFTs and WCC need to be monitored and doses
may need to be adjusted accordingly.
Abatacept is a T-cell blocking agent that
prevents the co-stimulation signals required for T-cell activation. It is also
self-administered by subcutaneous injection once a week and is licensed for
both RA and PSA. There are some studies to suggest a better safety profile in
terms of infection risk and this may be a consideration when treating older
patients, or those with co-morbidities such as COPD or diabetes.
Rituximab targets the B-cell pathway via CD 20
in RA and is delivered intravenously every six months; it is also used to treat
some forms of vasculitis.
Tofacitinib is a Janus kinase (JAK) inhibitor with
is approved for treatment of both RA and PsA where methotrexate therapy has
failed or is contraindicated. It is a targeted synthetic DMARD and has a side
effect profile similar to that of the biologic DMARDs, in addition there
appears to be a modest increase in the risk of developing herpes zoster
infections while on treatment. In high-risk patients, vaccination for shingles
should be considered prior to commencing treatment.
Monitoring precautions
A full biochemistry profile and FBC
should be carried out before starting any DMARD; in addition a viral hepatitis
screen and chest x-ray is prudent before commencing methotrexate. A history of
chicken pox should be sought and if the patient has no history of infection
varicella, titres should be checked to establish immunity. Prior to biologic
DMARD treatment, and JAK inhibitors, all patients must be screened for TB with
a chest x-ray and Quantiferon test. Patients must be advised of an increased
risk of infection on DMARD therapy but reassured that the benefit generally
outweighs the risk, however they should be told to seek medical attention if
unwell and to discuss with their GP or rheumatologist whether DMARD therapy
needs to be held temporarily. All patients on DMARDs should receive the flu and
pneumonia vaccination, if not contraindicated, at the recommended intervals.
Patients who smoke are known to be at an increased risk of infection and
cardiovascular disease, it is now increasingly recognised that cigarette
smoking increases the risk of developing RA and may decrease response to
therapy and drug survival. Advice and treatment options for smoking cessation
should be introduced to the patient early in the diagnosis as an integral part
of the treatment pathway. Screening for osteoporosis should also be strongly
considered in patients diagnosed with RA, particularly in patients who have
other risk factors such as smoking, low BMI, thyroid disease, coeliac disease,
family history and women who are post-menopausal.
In summary
Ideally, patients
with suspected RA should be seen by a specialist within six weeks of symptom
onset to optimise outcomes and prevent structural damage. Research has
demonstrated a significant reduction in remission rates in patients treated
early, representing a window of opportunity for improving long-term health in
this patient cohort.
In the early stages of treatment, patients need to be
seen regularly to ensure treatment efficacy, particularly those with features
which predict a poorer outcome – positive RF or anti-CCP, high CRP, erosive
disease and a large number of swollen joints. While the array of
pharmacological therapies is better than ever, we have not yet reached the holy
grail of personalised medicine and cannot predict which treatment option with
work for each patient. As most therapies take a number of weeks, and often
months, to reach full efficacy it is important not to discard any particular
therapy as failed too early in the course of treatment.
Many factors feed
into the decision about drug treatments in RA; patient factors such as other
chronic illnesses, infection risk, liver function and renal disease and
lifestyle issues such as alcohol intake, family planning and patient preference
need to be considered. Drug cost may also place a significant burden on
patients and their families while the risk of work disability secondary to
untreated disease needs to be factored in. The single best intervention for our
patients with RA is early suspicion of disease, early referral to a specialist
and early
aggressive treatment.
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