Eamonn Brady outlines the choices available in the pharmacy for treating what is primarily an inflammatory autoimmune disease of the joints
I have discussed rheumatoid arthritis (RA) in Irish Pharmacist on numerous occasions over the years and, previously, I discussed causes; prognosis; types; symptoms; diagnosis; and non-pharmacological treatment options. For this article, I focus solely on the pharmacological choices available to care for what is essentially an inflammatory autoimmune disease of the joints.
There is no cure for rheumatoid 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 diclofenic 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 disease-modifying anti-rheumatic drugs (DMARDs).
Pain control
Although DMARDs may be introduced at the time of diagnosis, they have a slow onset of actions 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 non-steroidal anti-inflammatory drugs (NSAIDs). The need for painkillers may be reduced once the DMARDs start to exert their effect after a few weeks.
Paracetamol
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. Therefore, a combination of paracetamol and NSAIDs may allow a reduction in dosage of the latter and therefore reduce the risk of their side effects.
Opioid analgesics
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 (eg, 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 NSAIDs use.
Corticosteroids
Corticosteroids such as 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; eg, a 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 (eg, 120mg methylprednisolone) may be given, while waiting for DMARDs to take effect. Oral corticosteroids should only be used in conjunction with DMARDs until the latter 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
NSAIDs reduce swelling and stiffness in addition to providing pain relief and, in most case, they improve the quality of life for those suffering 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 (eg 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.
Disease-modifying antirheumatic drugs (DMARDs)
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 for 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.
NSAIDs reduce swelling and stiffness, provide pain relief and, in most cases, improve the quality of life for those suffering with acute RA
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 methotrxate 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.
Immunosuppressants
Azathiaprine (Imuran®) and Ciclosporin (Neoral®) tend to be reserved for severe RA, when other DMARDs are ineffective or inappropriate. They tend to be the last line as they have many potential serious side effects, mainly due to their suppression of the immune system.
Biological DMARDS
Biological treatments include TNF-alpha inhibitors (etanercept, infliximab, adalimumab and certolizumab), rituximab and tocilizumab. Etanercept (Enbrel®) and adalimumab (Humira®) are the 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
JAK inhibitors are also known as targeted synthetic DMARDs (tsDMARDs) are a therapeutic class that inhibit JAK. JAK inhibitors authorised in Ireland include tofacitinib (Xeljanz®), baricitinib (Olumiant®) and upadacitinib (Rinvoq®); they come in oral form. They can be prescribed in addition to methotrexate or as monotherapy instead of methotrexate in patients who as 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 blocks this inflammatory pathway.
Advantages of JAK inhibitors
Although DMARDS results in disease suppression for many patients with RA, only about 30 per cent achieve complete remission, and most 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) could have taken several weeks to reach their full benefit. Maximum benefit from JAK inhibitors is seen with six months.
Side effects and monitoring
JAK inhibitors increase risk of infections (bacterial, fungal, viral). It increases 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 and can increase the risk of anemia, thrombocytopenia, and neutropenia. Pre-treatment screening and ongoing monitoring for TB and hepatitis B and of LFTs and FBC is required; periodic examination for skin cancer especially in those at risk; monitoring for infections including herpes zoster (especially the elderly) and lipids is advised. 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 bad effects.
The benefits of JAK inhibitors can be seen in as little as a few days to two weeks, whereas previous biologics (DMARDs) could have taken several weeks to reach their full benefit
Tapering therapy
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 (eg, 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 flare-ups within a year.
References upon request
Disclaimer: Brands mentioned in this article are meant as examples only and not meant as preference to other brands.
Author: Eamonn Brady MPSI (Pharmacist). Whelehans Pharmacies, 38 Pearse St and Clonmore, Mullingar. Tel 04493 34591 (Pearse St) or 04493 10266 (Clonmore). www.whelehans.ie. Eamonn specialises in the supply
of medicines and training needs of nursing homes throughout Ireland. Email ebrady@whelehans.ie
