Eamonn Brady MPSI looks at the clinical considerations in treating rheumatoid arthritis
Arthritis is a general term used for the condition; however, there are over 100 types of arthritis. The two most common types of arthritis are osteoarthritis and rheumatoid arthritis (RA). RA is one of the most debilitating forms of the condition.
Estimates show that the condition effects 0.5-to-1.5 per cent of the world’s population, being more prevalent in the West than in developing countries. Arthritis Ireland estimates there are as many as 40,000 individuals (1.22 per cent) with rheumatoid arthritis in Ireland and that 70 per cent of the rheumatoid arthritis affected population are women. RA occurs because of the body’s immune system attacking the joints and causing inflammation of the lining of a joint and the tissues surrounding it. While 1 per cent of the population suffers from rheumatoid arthritis, about 80 per cent of sufferers develop it between the ages of 35 and 50, therefore predominantly affecting individuals of working age. About one-in-20 of affected people have a severe form of it, with many joints affected. Up to half of all patients are unable to work within 10 years of diagnosis.
Rheumatoid arthritis and work
Some of the figures below show the extent to which RA has a dramatic impact on the working population.
- Approximately 75 per cent of new diagnoses are of individuals who are working at the time of diagnosis.
- The ability to work is affected in around 50 per cent of individuals within five years of diagnosis, with every third individual diagnosed with RA becoming completely work-disabled.
- Up to 85 per cent of individuals with RA who can work will experience an average of 40 lost work days annually due to the condition.
- A report in 2002 indicated that 22 per cent of individuals diagnosed with RA will stop working altogether within five years due to their condition.
- A further 18 per cent will cease to work within five years of diagnosis due to a combination of RA and other factors, such as depression.
The factors shown above present a significant annual cost to the State’s economy. Research by Arthritis Ireland in 2008 estimated the annual indirect cost of lost production time due to all forms of arthritis to be €1.6 billion and found that 70 per cent of individuals diagnosed with RA in Ireland were not able to work outside their home.
As of 2020, rheumatic and musculoskeletal diseases (RMD) are known to affect up to 60 per cent of the 120 million EU citizens, at an estimated cost of €240 billion, with direct costs of 2 per cent of EU GDP. In Ireland, approximately 40,000 people have RA, with an estimated cost of €19,596 per patient/year, and overall economic cost of approximately €544 million. While there have been significant advances in the treatment of RA, there are no cures, therefore patients require life-long treatment.
What is RA?
Arthritis means inflammation of the joints. The condition can progress swiftly to become severe and disabling in a short period of time. The disease primarily affects the synovial joints, resulting in pain, deformity and eventual functional limitation. RA also increases the risk to sufferers of development of other diseases together with a significantly increased risk of premature death. RA is an autoimmune disease. Usually, the body’s immune system produces white cells and proteins called antibodies to destroy foreign substances such as viruses and bacteria. With autoimmune diseases, the immune system mistakes the body’s own tissue as foreign and attacks it, leading to inflammation.
Symptoms of RA
Symptoms can initially develop quite slowly and can occur either as a single episode of stiff and painful joints which may last some months, or as an aggressive and destructive condition which progresses rapidly.
Atypically, it starts with the small bones of the hands and feet, with discomfort and some swelling often being the first symptoms. Stiffness, especially in the morning, is a classic symptom of RA; this stiffness often reduces during the day (for osteoarthritis, the symptoms tend to get worse as the day goes on). The hands, wrists, feet, ankles, and knees are affected in over 80 per cent of cases. The symptoms are often symmetrical, meaning that both sides are affected equally, ie, both knees affected equally. In advanced cases of the condition, most joints are become affected.
Rheumatoid nodules may develop; these are fleshy lumps resulting from synovitis that usually appear on hands, feet, and elbows. These are not painful, but they can cause difficulty using hands. Up to 30 per cent of patients may present with non-arthritis type symptoms without obvious joint swelling, such as malaise (general feeling of being unwell), weight loss and myalgia (muscle pain). Depression can be a feature of RA. RA is thought to be associated with an increased rate of cardiovascular disease and there is evidence of an increased mortality rate from heart-related problems in RA patients.
In summary, the main symptoms of RA are:
- Joint swelling.
- Pain/stiffness (commonly in morning and lasting more than one hour).
- Weight loss.
Causes of RA
The exact cause is unknown but there is a genetic link, as RA tends to run in families. RA is three times more common in women than in men. It is common for the symptoms of RA to improve during pregnancy — this suggests that hormones and the immune system may be involved in triggering the condition. Certain lifestyle aspects such as obesity and smoking can be factors, with the risk of developing rheumatoid arthritis being almost twice as high in smokers compared to non-smokers. For reasons unknown, RA onset is twice as common in winter than in other seasons.
Diagnosis of RA
It is important to start treatment of RA early because the earlier it is started, the more effective it will be. However, there are several challenges to achieving this early diagnosis. If not treated, the condition may lead to serious disability. It can be difficult to diagnose RA because many other conditions may make the joints painful. People may feel the symptoms are minor or may be simply normal signs of ageing. The National Audit Office in the UK suggests that around 50-to-75 per cent of individuals with RA do not visit their GP until their symptoms have been present for more than three months, with as many as 20 per cent waiting a year or more before seeking medical advice.
Symptoms are a good indicator of the condition. However, x-rays of joints and blood tests such as testing for the presence of a ‘rheumatoid factor’ or an ‘anti-CCP antibody’ can be more conclusive in diagnosing the condition.
Formal diagnosis is based on the American College of Rheumatology (ACR) diagnostic criteria.
According to the ACR criteria for diagnosis of RA, at least four of the following symptoms must be present:
- Morning stiffness in affected joints lasting at least one hour.
- Soft tissue swelling of at least three joint areas.
- Swelling of finger, hand, or wrist joints.
- Symmetrical swelling, ie, equal both sides.
- Rheumatoid nodules.
- Presence of rheumatoid factor (rheumatoid factor is an autoantibody which shows up in blood tests and is an indicator of arthritis).
- Erosion of bone which shows up in x-rays, particularly in hand, wrist, or feet joints
RA can be rapidly progressive in some patients. In these cases, treatment must be started early to prevent irreversible joint and other damage. Indications that the disease is rapidly progressing include high ESR or C-reactive protein levels (indicators of inflammation in blood tests), early erosive damage on x-rays, increasing number of affected joints, disability early in the condition, high levels of rheumatoid factor and the presence of extra-articular features at diagnosis. Extra-articular features include non-joint symptoms of RA such as damage to skin, heart, lungs, and eyes.
Treatment of RA
- Find a balance between exercise and rest. Swimming is an excellent activity because it strengthens muscles and joints without putting any strain on them.
- Losing excess weight will reduce the pressure on joints.
- Try to eat a healthy, balanced diet and cut down on saturated fats.
- A hot water bottle is useful when joints feel stiff and painful; try an ice pack if they are hot and irritated.
- Omega 3 fish oil has been proven to have a mild anti-inflammatory effect.
The aim of physiotherapy is to reduce pain and stiffness, prevent deformity, maximise function and to improve independence and quality of life. On presentation, the physiotherapist will conduct a functional assessment (transfer status, gait analysis, activities of daily living, etc), range of movement of all joints, strength, posture, and respiratory status to establish an individual’s current position. This then forms a solid platform to measure progress going forward.
The physiotherapist will generally recommend activities that can be either active (such as education and exercise), or passive (isometric or range of movement exercises, thermotherapy, electrotherapy such as Transcutaneous Electrical Nerve Stimulation (TENS) or ultrasound therapy) or a combination of both. They may also refer patients to occupational therapy for a more ‘work based’ assessment of individual needs.
Exercise and physiotherapy are used to maintain or to improve muscle tone to prevent or correct deformities and to maintain or increase joint mobility and function. Exercise has been shown to be particularly beneficial to people affected by rheumatoid arthritis, as they are often physically inactive. This is where a physiotherapist is important, as they can assess the person’s limits to ensure they are not under- or overdoing exercise, depending on the extent of the condition and other factors.
Evidence suggests that almost all rheumatoid arthritis suffers will experience problems with the bones of the feet, and that this is a significant cause of pain, mobility impairment and functional limitation. For 25 per cent of individuals with RA problems, their feet are the main cause of their walking impairment, with 75 per cent reporting that the effect of the condition on their feet contributes to their functional limitation. A consultation with a podiatrist can help. Through examination, they will be able to make recommendations regarding footwear and orthoses to aid comfort and improvement. Custom-built shoes and insoles have been shown to be considerably more effective than those that are mass produced (and therefore cheaper).
Irrespective of medical advances in the treatment of RA, there will be a number of affected individuals who will nonetheless develop irreversible joint or tendon damage. For these individuals, surgery can provide a return of functional ability, a decrease in symptoms and pain, and avoid deformity and disability, helping them return to a ‘normal’ life. Typically, surgical interventions involve joint replacement, (commonly hip, knee, shoulder, elbow, and hand joints). Evidence shows that a higher success rate is achieved if early consideration is given to surgery, before substantial joint damage has occurred, or disability has developed.
There is no cure for arthritis, however medicines can relieve symptoms and reduce progression. In brief, the treatment options for RA are as follows:
- Painkillers such as paracetamol may help to relieve pain, although they will not affect the progression of arthritis.
- Anti-inflammatory medicines, known as non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and diclofenac, reduce inflammation and so relieve pain and swelling.
- Disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and methotrexate work to slow down the disease process and delay joint damage.
- Biological medicines including infliximab, etanercept, adalimumab and rituximab have been developed in recent years. These are only used if other treatments are unsuccessful.
- JAK Inhibitors are a newer class of oral medicines that can be prescribed where the options above are unsuccessful.
Current guidelines recommend early diagnosis and early referral (ideally within three months of symptom onset) to a rheumatologist for the introduction of DMARDs.
More details on medicines used
Although DMARDs may be introduced at time of diagnosis, they have a slow onset of action and can take weeks for an improvement. Therefore, DMARDs have little or no impact on acute pain. Most patients will require at least initial courses of analgesics or NSAIDs. The need for painkillers may be reduced once the DMARDs start to exert their effect after a few weeks.
Paracetamol on its own is seldom sufficient to control acute pain in RA; however, there is evidence that regular dosing of paracetamol enhances the painkilling effects of NSAIDs in RA. Therefore, a combination of paracetamol and NSAID may allow a reduction of the NSAID dosage and therefore reduce the risk of side-effects of NSAIDs.
Opioid analgesics such as tramadol may be used during acute attacks of RA, especially in elderly patients who may not be able to tolerate NSAIDs. Their continuous/long-term use is not recommended due to the risk of addiction, cognitive impairment (ie, memory loss, confusion), constipation and respiratory depression. Paracetamol/opioid combinations such as Solpadeine or Ixprim are sometimes used in acute RA patients, especially in those at risk of developing problems with excessive NSAID use.
Corticosteroids, such prednisolone, are useful in the management of acute pain and have disease-modifying properties. Over the short-term, they exert an effect on the symptoms of RA, but their efficacy diminishes over time. The preferred method of administration of corticosteroids is intra-articular injection (directly into the joint), ie, Depo-Medrone injection. This produces rapid symptom relief and does not cause the side-effects of oral corticosteroids, such as stomach irritation. However, the effects of intra-articular steroid injections can wear off within a month, so they are not a long-term solution. Where there are multiple joints involved, local injection directly into the joints is not possible, so an intramuscular injection (ie, 120mg methylprednisolone) may be given while waiting for DMARDs to take effect.
Oral corticosteroids should only be used in conjunction with DMARDs until the DMARDs take effect or for flare-ups in between. Long-term use of even low-dose corticosteroids may result in osteoporosis and other steroid-related side-effects such as weight gain, thinning skin, easy bruising, and high blood pressure.
NSAIDs reduce swelling and stiffness in addition to providing pain relief, and they improve quality of life in most cases with acute RA. However, side-effects include gastric irritation, kidney damage, fluid retention and skin reactions, as well as evidence linking selective COX-2 inhibitors (ie, Etoricoxib, Celecoxib) to increased risk of myocardial infarction. Also, the European medicines watchdog issued a warning in July 2013 stating that diclofenac can significantly increase the risk of heart problems such as heart attack and stroke in those already at risk of these problems. Long-term use of NSAIDs is not recommended, especially in patients with known cardiovascular and gastrointestinal problems and only one NSAID should be used at any one time.
DMARDs help to ease symptoms and slow down the progression of RA. When antibodies attack the tissue in the joints, they produce chemicals that can cause further damage to the bones, tendons, ligaments, and cartilage. DMARDs block the effects of these chemicals. The earlier a DMARD is started, the more effective it will be. They must be started by a consultant rheumatologist; therefore, it is important to seek treatment with a rheumatologist early if showing signs of RA.
The most used DMARDs include methotrexate, hydroxychloroquine, and sulfasalazine. These are often known as conventional DMARDs since the advent of biological DMARDs in recent years. Similar efficacy has been reported for methotrexate and sulfasalazine in studies of up to 12 months. The response of DMARDs is usually monitored every one-to-three months initially until symptoms improve.
Methotrexate is often the first choice DMARD for RA. It can be taken on its own or in combination with another DMARD. The most common side-effects of methotrexate are sickness, diarrhoea, mouth ulcers, hair loss or hair thinning, and rashes on the skin. Regular blood tests to monitor blood count and liver are required, as methotrexate can cause potentially very serious liver and blood count problems.
Very rarely, it can affect the lungs, so chest x-rays and possibly breathing tests are performed when starting methotrexate. This is to provide a comparison if the patient develops shortness of breath or a persistent dry cough while taking methotrexate. Most people tolerate methotrexate well and more than 50 per cent of patients take it for at least five years. Methotrexate improves symptoms by 50-to-80 per cent, slows the rate of joint destruction (as seen on x-ray) and improves function and quality of life.
Doses of methotrexate up to 20mg weekly may be needed. Parenteral administration (SC, IM, starting at 7.5-10mg weekly) may be considered in severe acute RA if oral treatment is ineffective or in those unable to tolerate oral methotrexate. It takes six-to-12 weeks for methotrexate to start working. Methotrexate may also be combined with biological treatments. It is very important to emphasise that methotrexate is a weekly dose. Giving it daily is a potentially serious medication error. Sulfasalazine has a slow onset of effect (one-to-three months). Patients may need to discontinue long-term treatment of sulfasalazine due to gastrointestinal complaints.
Hydroxychloroquine takes several weeks to exert its effect. It has been reported to be less effective than the other DMARDs but is well tolerated; therefore, it may be useful in mild disease or in combination therapy. However, it can cause eye damage, so regular eye checks are needed. It is important to keep taking DMARDs, even if there is no improvement at first. Many patients must try two or three types of DMARD before finding the one that is most suitable for them. Once the most suitable DMARD is found, the patient will usually have to take it long term.
Azathioprine (Imuran) and Ciclosporin (Neoral) tend to be reserved for severe RA, when other DMARDs are ineffective or inappropriate. They tend to be last-line, as they have many potential serious side-effects, mainly due to their suppression of the immune system.
Biological treatments include TNF-alpha inhibitors (etanercept, infliximab, adalimumab and certolizumab), rituximab and tocilizumab. Etanercept (Enbrel) and adalimumab (Humira) are most prescribed biological treatments for RA in Ireland. In general, use of biological agents is reserved for patients with moderate-to-severe active RA where conventional DMARDs have failed. They are usually taken in combination with methotrexate or sometimes with another DMARD. They work by stopping chemicals in the blood from activating the immune system to attack the lining of joints. They are given by subcutaneous injection.
Side-effects from biological treatments are usually mild and include skin reactions at the site of injection, infections, nausea, fever, and headaches. They should be used in caution in patients who have had tuberculosis (TB), septicaemia and hepatitis B in the past. There is a slight risk that biological treatments can reactivate these conditions and, in rare cases, trigger new autoimmune problems.
JAK Inhibitors are also known as targeted synthetic DMARDs (tsDMARDs) and are a therapeutic class that inhibit JAK. There are two JAK inhibitors authorised in Ireland, tofacitinib (Xeljanz) and baricitinib (Olumiant), and they come in oral form. They can be prescribed in addition to methotrexate or as monotherapy instead of methotrexate in patients who are not getting sufficient benefit from or are intolerant to methotrexate. Concurrent use of JAK inhibitors with biological DMARDs is contraindicated and JAK inhibitors should not be used with live vaccines.
How JAK Inhibitors work
Janus kinase (JAK) are intracellular enzymes that transmit signals from cytokines binding to receptors on the cell surface to signal transducers and activators of transcription (STATs), which drive pro-inflammatory cellular responses. JAK inhibitors block this inflammatory pathway.
Advantages of JAK inhibitors
Although DMARDs result in disease suppression for many patients with RA, only approximately 30 per cent achieve complete remission, and the majority of patients treated with biologics experience disease exacerbation following cessation of treatment. The route of administration is also an important consideration, with the results of two studies suggesting that patients with RA may prefer therapies taken orally rather than those taken by injection. The benefits of JAK inhibitors can be seen in as little as a few days to two weeks, whereas previous biologics (DMARDs) can take several weeks for full benefit. Maximum benefit from JAK inhibitors is seen within six months.
Side-effects and monitoring
JAK inhibitors increase risk of infections (bacterial, fungal, viral) and increase the risk of the likes of tuberculosis and herpes zoster (shingles). They increase cancer risk through their suppression role on the immune system. As with DMARDs, JAK inhibitors can affect blood counts so can increase risk of anemia, thrombocytopaenia, and neutropaenia.
Pre-treatment screening and ongoing monitoring for TB and hepatitis B and of LFTs and FBC are required; periodic examination for skin cancer, especially in those at risk; monitoring for infections, including herpes zoster (especially in the elderly) and lipids is advised; and patients are advised to seek medical attention if symptoms suggestive of infections occur. JAK inhibitors have a shorter half-life than other DMARDs, so negative symptoms can be reversed relatively quickly if they need to be stopped due to negative effects.
Current guidelines suggest that rheumatologists should consider tapering treatment six months after achieving the treatment target. The suggested order of tapering is:
1) Glucocorticoids, such as prednisolone;
2) Biological DMARDs; and
3) Conventional DMARDs such as methotrexate. Glucocorticoids should be dose-reduced and discontinued typically within six months initially. When tapering a biological DMARD, the dose should be reduced rather than stopped suddenly, due to the significantly higher rate of flare-ups with sudden discontinuation. Therapy with the conventional DMARD (ie, Methotrexate) should continue while the biological DMARD is being reduced; patients should be educated on the need for urgent re-evaluation by their rheumatologist at the early signs of an RA flare-up. In general, medication-free remission is not sustained in patients with RA; two out of three patients who stop all treatment, including methotrexate, experience flares within a year.
References on request