Combination therapy for rheumatoid arthritis

The term ‘combination therapy’ refers to the use of more than one of the standard disease modifying anti-rheumatic drugs (DMARDs), with or without short-term steroids. This can refer to multiple drugs, with ‘triple therapy’ being a not uncommon approach. The term ‘monotherapy’, in contrast, refers to a DMARD being used on its own. Standard (or conventional) DMARDs are drugs such as methotrexate, sulfasalazine, hydroxychloroquine and leflunomide, as opposed to the newer, biologic drugs, which are not currently offered to recently diagnosed patients. The steroids recommended for short-term use with these drugs can be given as injections into muscle or inflamed joints, or in tablet form.

NICE (National Institute for Health and Clinical Excellence) published rheumatoid arthritis Management Guidelines in 2009 which recommend that in recently diagnosed, active rheumatoid arthritis, combinations of conventional disease modifying anti-rheumatic drugs (DMARDs), along with short-term steroids in some form or another, should be used. The guidelines are due to be revised, but currently this recommendation still stands. In this article, we have separated up the different parts of the recommendation to get an understanding of why this is currently being recommended for the treatment of rheumatoid arthritis.

What evidence is there to suggest that this is a good way to manage early rheumatoid arthritis?

There have been a number of trials that have looked at using two or more DMARDs combined together, and comparing this approach with taking a single DMARD, used alone. For most of these individual trials, the combination therapy has been more effective than a single DMARD, and just as well tolerated, with no more side effects than the single drug. When they are lumped together into what is referred to as a ‘meta-analysis’, there is a concern that there might be slightly higher rates of side effects on combination therapies, but these are out-weighed by the increased benefits.

An analysis was performed for the NICE RA Management Guidelines, which looked at the cost-effectiveness of different drug strategies, and this concluded that combination therapies were more cost effective than single drug approaches. Although more drugs in combination cost more money, the benefits to patients on combination therapies outweighs that of single drug approaches to the point that the extra expense is more than worthwhile in terms of extra relief of the burden of the disease.

The most important principle in controlling rheumatoid arthritis is to suppress inflammation quickly and sustain this improvement. All is well if this can be achieved with monotherapy, but for most patients with ongoing active disease, combination therapy will be necessary either from the start or at early follow up.

Which drugs will commonly be used in this combination therapy and why?

Methotrexate is mentioned in the recommendation as being the drug to which others should routinely be added. This is because this is the drug against which all other therapies should be judged, as it tends to be the one that patients stay on for longest. This suggests that the combination of benefits and possible side-effects for methotrexate is better for most patients than any other single DMARD. Consequently it is natural to use this drug as the “anchor” drug onto which other treatments could be added. It can be used in tablet or subcutaneous (meaning ‘under the skin’) injection forms, the latter often improving the effectiveness of the methotrexate, and decreasing side effects. Common drugs to be added in to methotrexate include sulfasalzine, hydroxychloroquine, leflunomide, and occasionally gold injections, used in combinations of two or three drugs. The blood tests and other monitoring requirements of these drugs are no greater than the individual drugs themselves. Some concerns have been expressed about the combination of methotrexate and leflunomide, with a few reports of serious adverse liver reactions. However, this combination is quite commonly used in the UK, and needs to be monitored closely by an experienced team, as with all DMARDs. Furthermore, more DMARDS means that potential interactions with other medications need to be even more closely avoided, and it is important for the professional team to know all the medication that the patient is taking.

What is the role of steroids in combination therapy?

All of the trials for combination therapy have also used steroids in some form or another (usually injected into muscles, or into inflamed joints, but by mouth in some trials). A study comparing steroids given in tablet form with an injection of steroids into the muscle showed no difference in effectiveness. The steroids themselves help to dampen down the inflammation in the joints quickly, and relieve the symptoms whilst waiting for the other DMARDs to hopefully take effect. It is good for people to feel better quickly to enable them to restore function to their joints, and keep up with important roles such as working in a job or looking after the home. The steroids also help to slow the disease down, not only helping with symptoms but also preventing damage to the joints. However, their long-term use should be avoided if at all possible, because their disadvantages can outweigh their advantages over time, with decreasing benefit to symptoms, and even low doses of steroids increasing the risk of infection and osteoporosis. If patients with early RA are struggling to get off steroids, other treatment strategies need to be considered, such as increasing the doses of other DMARDs, or introducing biological therapies such as anti-TNF drugs.

What is meant by “active” disease?

All of the trials have looked at patients with active RA. Unfortunately the different trials define “active” differently. Some have used tender and swollen joint counts, or measures of inflammation such as the ESR or CRP, or other indices for measuring disease activity, such as the DAS28. Therefore in putting the recommendation together, “active” disease could not be defined, and has to be left up to individual rheumatologists and teams to decide. A common approach is that a DAS28 more than 3.2 with three or more tender and swollen joints constitutes active disease. This is pitched at a much lower level than the NICE recommendations for anti-TNF (currently a DAS28 > 5.1), because we are keen to exercise a low threshold for dampening down inflammation as quickly as possible. In the early stages of RA, the disease can be very mild for some patients, or even intermittent, coming and going. At the moment we do not know how best to treat this type of milder disease, and trials are needed to determine whether single drug DMARDs would be most appropriate for such patients. This monotherapy is a common approach in clinical practice.

What are the ACR RA classification criteria and why are they important?

All of the trials looked at people who fulfilled the 1987 American College of Rheumatology classification criteria for RA. These were designed to help researchers to define precisely what RA is, and to aid communication between researchers. Although they were not designed for clinics, they have influenced the way we think about the disease. The 1987 criteria were developed by looking at disease in people with well established RA, and therefore do not perform well in identifying patients with early inflammation of the joints in whom the diagnosis is uncertain (sometimes called undifferentiated inflammatory disease) that may go on to develop into RA. The criteria were updated in 2010 to make them more sensitive to early disease, and are now known as the ACR/EULAR criteria. However, what we do know is that patients who fulfil the 1987 and 2010 criteria are likely to have worse outcomes than those who do not. Consequently this recommendation focuses on those people who fulfil these criteria, because this is where the evidence lies, and these are the patients who are likely to have the worst outcomes if their disease is not treated promptly and intensively. We need more research to look at the best ways of treating people with persistent inflammation in joints that do not fulfil the ACR/EULAR RA classification criteria.

What are the monitoring requirements for newly diagnosed RA patients?

Another key recommendation of the NICE guidelines is the need to monitor newly diagnosed RA patients closely, with monthly follow-ups checking the levels of inflammation with a sensitive blood test such as CRP, and measures of disease activity like the DAS28. If the disease is not as well controlled as the patient and clinician would like, then further adjustments to treatment need to be undertaken, such as increasing the doses of drugs, changing the way the drug is administered (such as swapping oral methotrexate to subcutaneous injections, which can make it better tolerated for those people with side effects, and also more effective in treating the disease), or giving steroid injections into muscle or joints to control the disease activity rapidly. As was mentioned above, the most important aspect of managing RA in the early stages is to ensure rapid disease control, aiming for the lowest possible level of disease activity. Regular follow ups to monitor disease activity, and further interventions to ensure better control where necessary, are much more important principles than the specific drugs used to achieve this.

Conversely, if a patient is doing well, with the aim to eradicate disease whenever possible and get into remission, then consideration can be given to decreasing drug dosages, or even stopping them. However this needs to be done very slowly and cautiously. I often say to my patients that we are involved in a marathon not a sprint.

At the slightest hint of the disease activity returning, drugs need to be returned to a controlling dose, and patients need rapid access to the multidisciplinary team if they have a flare-up of disease. It is difficult to know how long most patients will need to be on combination therapy. If the disease was deemed to be sufficiently severe to need an aggressive multiple drug approach in the first place, then it is likely that such a patient will require DMARDs in some form indefinitely. However, if the disease is spotted quickly, and the inflammation dampened down rapidly, this may allow some patients to drop down to single drug approach within their first year of disease. It all depends on the response of individual patients. Guidelines cannot address every eventuality, which is why all patients need ongoing contact with their specialist team.

What are the disadvantages of combination therapy?

If side-effects do develop with combination treatments it can be tricky to determine which of the drugs is responsible. This is one of the many advantages of having methotrexate as the “anchor drug”. Because it is just given once a week, if the person develops side-effects (such as nausea for example) then it is sometimes easy to work out that this is responsible for the problems. However, if a person develops more persistent problems, such as mouth ulcers or rashes, then it can be impossible to work out which drug is responsible, with stopping drugs to see if side-effects subside often being the only tactic available. This then wastes time, when disease needs to be suppressed. However, your consultant will decide the best approach for you, taking into account various factors such as other medications you may be taking.

In conclusion, combinations of DMARDs (with steroids in some form) are usually more effective in treating early active RA than the use of single drugs, though the important principle is to reduce inflammation quickly and keep it under tight control, however this is achieved for each individual patient. Combinations for most patients have no more side effects, and only require the monitoring that would normally be provided for the individual drugs. They should be provided as part of a package of regular review to ensure that early disease is being suppressed. If the disease can be hit hard and early, emerging evidence shows that this can lead to long term improvements in outcomes. If patients with active RA are not at an early stage given the opportunity to be on combination therapies, it is very reasonable to ask “Why not?”

Further reading:

Understanding NICE guidelines RA

NRAS article on osteoporosis

NRAS information on DMARDs

Electronic Medicines Compendium (EMC) site, to search for drugs and their side-effects

NRAS information on DAS

References available on request

Dr Chris Deighton, NRAS Medical Advisor and consultant rheumatologist, Derbyshire Royal Infirmary

Original article: 29/08/2009 
Reviewed: 02/10/2015 
Next review due: 02/10/2018

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