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GPs play a pivotal role in the diagnosis and long-term management of rheumatoid arthritis (RA), a progressive, inflammatory disease affecting about 1 per cent of the population. Symptoms typically include pain, stiffness and swelling of the joints. Early diagnosis of RA is crucial to improved patient outcomes. Standard treatment regimens use disease-modifying antirheumatic drugs (DMARDs), which include methotrexate (MTX) and biologics such as anti-tumour necrosis factor (anti-TNF) agents. RA is most effectively managed through an active collaboration between a GP and a rheumatology department.
Making the diagnosis
A diagnosis of RA should be considered when a patient reports symptoms consistent with the onset of RA (ie, onset of one or more swollen and/or tender joints, morning stiffness lasting more than 45 minutes, and joint pain). The history should include specific questions about the nature of the patient’s symptoms, for example:
Are you stiff when you get out of bed in the morning?
Are you slow to get going in the morning?
If so, how long does the stiffness last?
What time of day is the pain/stiffness at its worst?
Do you smoke?
Do you have a family history of RA?
How easily can you complete tasks such as brushing your teeth or picking up a kettle in the morning?
Do your symptoms improve with exercise or exertion?
A thorough physical examination should include a squeeze test.
A provisional diagnosis of RA includes a consideration of three criteria:
Swollen or tender joints: The number and location of swollen or tender joints is the most important indicator of possible RA. The likelihood of RA increases as the number of affected joints increases. Often, the small joints of the hands and feet are involved, and the squeeze test is a good, quick, and simple screening procedure. In the squeeze test, the metacarpals or metatarsals are squeezed. If the patient expresses discomfort or pain during the squeeze test, the test is considered positive. RA usually, but not always, affects joints symmetrically.
Duration of symptoms for six or more weeks: Insidious onset of symptoms over six or more weeks is more likely to be caused by an inflammatory arthritis, such as RA. Long-standing symptoms without obvious deformity suggests against the diagnosis of RA.
Laboratory tests: Certain laboratory tests are used to distinguish RA from other inflammatory arthritides. Whereas the presence of rheumatoid factor (RF) has long been used in the diagnosis of RA, anti-CCP antibodies are more specific than RF in discriminating RA from other diseases, while the presence of both anti-CCP and RF is highly indicative of RA. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are part of the acute-phase response that accompanies inflammation and are useful as serological measures of inflammation that are predictive of joint erosions and functional disability.
If any joints are swollen or tender, the squeeze test is positive, and/or any of these laboratory tests are abnormal, a provisional diagnosis of RA should be made and the patient referred to a rheumatologist for confirmation as soon as possible.
The patient may still have RA even if they do not meet any of these criteria, although this is less likely and reduces the urgency of specialist opinion. In these cases, it is important to rule out other potential causes of inflammatory arthritis (viral or crystal) and consider referral to a rheumatologist if the diagnosis remains unclear. Common diagnostic challenges include the presence of non-specific symptoms such as pain, stiffness, fatigue, depression, and inconclusive laboratory results.
Getting your patient seen
Rheumatologists want to see inflammatory arthritis, in particular, early inflammatory arthritis. Referrals that highlight antibody status (CCP and RF), inflammatory markers (ESR and CRP) and a short summary of clinical findings (early morning stiffness, positive squeeze test, steroid responsiveness) will be easier to prioritise for an early arthritis clinic. Large volumes of referrals come through rheumatology departments each day and it can be genuinely difficult to identify patients appropriate for early assessment because of the heterogeneity of referrals. There is a national arthritis referral form, which should be used where possible (www.isr.ie).
Bridging the gap to assessment
It is perfectly acceptable and in fact a good idea to start treatment as soon as possible if RA is clearly suspected. Once you have carefully documented objective findings, then steroids can be started. If you are comfortable to do so, then it is reasonable also to start MTX. You should not be concerned that you are hiding the objective findings from the rheumatologist by starting steroids.
Reducing the inflammatory burden as quickly as possible reduces joint damage and improves long-term outcomes (‘time is tissue’). Steroids can always be discontinued to allow for re-emergence of inflammatory change if necessary, for diagnostic confirmation at a later date.
Consideration at this point should be given to both gastroprotective therapies (proton pump inhibitors and similar) and glucocorticoid-induced osteoporosis prevention (bisphosphonates and similar). At a minimum, cholecalciferol (vitamin D) should be started (I prescribe 2,400 units/day). These aspects of management can often be overlooked at a first rheumatology visit when the focus is on diagnosis and education in terms of disease and drugs.
Starting MTX in the community
You should ensure a normal set of liver function tests (LFTs) and full blood count (FBC) prior to starting MTX. Most rheumatology departments have variations on a theme of how they prefer to initiate methotrexate but in general, it is reasonable to give a test dose of 7.5-10mg on the first week and then escalate over the next two or three weeks to 15-20mg once weekly. My practice is to check a repeat FBC and LFTs after the second, fourth and eighth doses of MTX.
Shared care is required once definitive therapy is in place and GPs have an important role in monitoring both response and assessing for adverse events. DMARDs form the basis of long-term RA management and are the most effective treatment option for altering the natural course of RA and reducing disease severity, disability and RA-specific complications.
Traditional DMARDs (eg, MTX, leflunomide, sulfasalazine) have been used successfully for decades to treat RA, and most require a minimal level of monitoring that includes an FBC and LFTs. Biologic DMARDs differ from conventional DMARDs in their ability to target specific components of the immune response involved in the pathophysiology of RA, such as TNF, T cells, B cells, and interleukin-6 (IL-6). Because biologics alter immune function, it is important to be vigilant for signs of infection. Additionally, anti-TNF therapies confer an increased risk of TB (even where pre-screening was negative). Different departments will have different protocols, which may include questionnaires, Mantoux, QuantiFERON-TB Gold and chest x-rays.
Escalation of treatment
Escalation of therapy can be conducted in a primary care setting and generally involves oral pulses of steroid with either an increase in an existing DMARD (eg, MTX) or addition of another DMARD (eg, hydroxychloroquine). In the case of the commonest DMARD, MTX escalation above doses of 15mg once weekly can be frustrated by the poor oral bioavailability at higher doses. I generally encourage transition to subcutaneous MTX once doses over 15mg once weekly are required.
Treat to target
Treating RA to a target has changed the approach to assessing how we determine what constitutes active disease and also provides rationales for pursuing states of minimal disease activity. Obviously, the goal of treatment is to achieve remission, but how is that defined? DAS-28 is a well-known composite measure of RA activity but unfortunately, we know from ultrasound studies that patients can still have active inflammation in their joints, despite a DAS-28 score indicating remission.
Having said that, it is important to define a target and pursue it, rather than simply trying to achieve a state of ‘looks and feels better’. I personally use point-of-care, high-resolution ultrasound for all my rheumatoid patients but I would suggest that you identify and familiarise yourself with whichever composite measure your local rheumatology department utilises.
It can sometimes be difficult to manage an RA patient through a particular set of circumstances, or you may have a particular query, which although not urgent, you would prefer dealt with before the next routine scheduled rheumatology outpatient appointment.
An example might be that your patient requires routine surgery and you are looking to know what to advise around perioperative MTX or biological drug use. Or you may wonder about vaccinating a young RA patient (on the same medicines) who plans on travelling to areas requiring live vaccinations. A great tip would be to contact the rheumatology nurse in your patient’s rheumatology department. They generally have telephone helplines (the patient will have been given the details at the time of their education session) and respond to queries promptly. They will often know the answer to your question immediately and if they do not, can usually get you a response within 24 hours. Rheumatology nurses are a tremendous resource to patients and rheumatology departments and can provide a great liaison service between GPs and rheumatology consultants.
You may encounter a first-degree relative of a patient who has been diagnosed with RA who is wondering whether they can be screened for RA and what they can do to prevent getting RA. We know that positive anti-CCP antibodies predict development of RA. However, testing asymptomatic individuals is not advised, as it will likely confer a degree of anxiety and there is no clear role for treatment in the pre-symptomatic state. The increasing understanding of the role of the gut microbiota in health and disease suggests that diet could affect RA and other inflammatory diseases by altering the composition of the microbiome and the downstream production of immune-modulating metabolites. There appears a clear role for eating oily fish and consuming eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in both reducing the risk of RA and also ameliorating inflammation in active early RA.
Other dietary recommendations can all be contradicted and generally reflect the personal beliefs of the practitioner or the status quo (eg, RCTs showing that Mediterranean diets are superior to Western diets in terms of inflammation and physical function are contradicted by data from the Nurses Health Study, showing no association with a Mediterranean diet and incident RA development). Despite RCT evidence of positive findings in relation to Lactobacillus casei in RA, the ingested micro-organisms are destroyed by the low pH of the gastric environment, suggesting that probiotics have little or no plausible biologic benefits.
Another presentation is the person who for some reason had a positive anti-CCP antibody discovered as part of a routine check-up and is looking for advice. I would firstly reassure the patient that not all antibody positivity necessarily leads to the disease, but to advise on what to watch out for. Depending on the patient, you could simply tell them to present if they develop symptoms (fatigue, stiff joints or spine, especially after rest or inactivity) or schedule them for regular follow-ups.
I would then advise on risk minimisation. Smoking is strongly associated with the development of RA in this cohort and stopping it could lead to a reduction in the risk of RA development. Alcohol is less clearly related, with some studies showing moderate alcohol consumption lowering the risk of RA. There is mounting evidence for the association of periodontal disease and RA, enough that I advocate twice-daily flossing in all RA patients as well as those who are asymptomatic, but who are looking to reduce their risk of developing it.
In general, patients receiving immunosuppressive drugs should not receive live vaccines. Use of killed virus or polysaccharide vaccines (eg, influenza and pneumococcal vaccines) is appropriate for RA patients whose disease and DMARD treatment puts them at higher risk for serious infection.
Influenza vaccine should be given to all RA patients who are going to be or are already treated with immunosuppressive drugs, regardless of when the drugs are initiated, unless the patient was vaccinated during the previous influenza season.
Pneumococcal vaccine should be given to all RA patients who are going to be or are already treated with immunosuppressive drugs, and a single re-vaccination is warranted if ≥five years have elapsed since the first vaccination.
Hepatitis B vaccination, where possible, should be given before MTX and biologic DMARDs if risk factors for hepatitis B are present, such as a history of multiple sexual partners in the last six months, household contacts with hepatitis B, intravenous drug abuse, or if they work in healthcare.