Answer: A patient’s history of painful and swollen joints, as well as positive serology, are highly indicative of a rheumatoid arthritis (RA) diagnosis.¹ Laboratory results for this patient reveal he is significantly positive for rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), but upon examination, he does not have synovitis. In fact, the rest of the examination is normal, and there is no other significant past medical history.

The revised criteria for diagnosis of RA from the American College of Rheumatology (ACR) require that synovitis is present in at least 1 joint;¹ however, the fact that we don’t find any synovitis during examination doesn’t exclude any swelling within the past 6 months, and simply asking the patient if he experienced swelling can be unreliable. Patients are generally very good at assessing their tender joints, but not as reliable when assessing synovitis/swelling. In addition, this patient’s positive serology with high values for rheumatoid factor and anti-CCP antibodies makes it highly likely that he has RA. He has had symptom onset within the 12-month “treat-to-target” window of opportunity, wherein therapy could potentially change the natural course of the disease (ie, prevent long-term damage).^1-3, Based on these criteria, this patient should be started on disease-modifying antirheumatic drug (DMARD) therapy because his symptoms have progressed over 6 months, even though at the time of this visit he doesn't have active synovitis. The ultimate treatment target set forth by ACR and the European League Against Rheumatism (EULAR) is remission for all patients, although if a patient has comorbid conditions, this target can be modified to low disease activity.

So this patient is a candidate to start DMARD therapy with methotrexate (MTX), possibly combined with low-dose prednisone, depending on the local practice patterns of this patient’s rheumatologist. When initiating MTX therapy, the patient’s baseline disease activity also has to be assessed, using any one of the tools recommended by the ACR; I recommend DAS28, CDAI, SDAI, and RAPID 3 (Figure 1).^4,5 Other first-line DMARDs include hydroxychloroquine or leflunomide.⁶

These are all validated assessment tools and can be used interchangeably, depending on physician preference. Such tools establish a baseline activity level, which needs to be re-assessed at least every 3 months while the patient is receiving therapy in order to evaluate therapeutic response. The use of these assessment tools allows the rheumatologist to make sure the patient is either achieving, or getting close to achieving, that ACR/EULAR treatment target; if not, the rheumatologist needs to change therapy as needed.

Once we’ve initiated MTX therapy for this patient, the goal is to increase the dose to 20-25 mg/wk with the first 2-3 months of treatment. Once the patient has reached a dose of 20-25 mg/wk after 3 months, if he hasn’t achieved low disease activity, we would have to add a biologic agent to his treatment plan.⁶

When choosing biologic therapy, rheumatologists have several efficacious options. Among the available agents, the tumor necrosis factor (TNF) inhibitors etanercept, adalimumab, and infliximab can all be used in the first-line setting, as can abatacept, a T-cell signal inhibitor. The TNF inhibitors certolizumab pegol and golimumab now have data that suggest that they could be used first-line; the same is true for the targeted agents rituximab and tocilizumab. Once the first biologic is added, we should allow 3-6 months for the maximal response to be achieved. After 6 months, it is very unlikely that any further improvement will be achieved, and so if the patient has not reached remission or low disease activity by 6 months, then it is time to consider an alternative therapy. Some experience does suggest that switching from one TNF inhibitor to another has a similar degree of effectiveness as that of switching to an entirely different mechanism of action (MOA; eg, T-cell inhibition), but switching MOAs provides better drug survival.⁷ So if this patient was started with anti-TNF therapy and didn’t achieve low disease activity after 6 months, then we would try a different targeted agent—the idea being that we cycle through different MOAs until we achieve our desired response.

The treatment options for RA management have evolved over the past 10-15 years, which has had a positive impact on patient outcomes. However, rheumatologists also need to recognize that they have to treat patients early and aggressively, using outcome measures to define their targets. Just as we automatically check patients’ blood pressure at every visit, we should also be checking patients’ disease activity levels as part of our routine clinical practice so that we have a better grasp on how patients have responded and how much further they have to go in order to achieve the ultimate goal of remission or low disease activity.

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Answer: This patient should switch therapies, but is concerned about potential side effects—especially given what she has heard on the television and read on the internet. She does not tolerate leflunomide (LEF) or MTX and is also sulfa-allergic. The problem in this scenario is that this patient’s RA is not controlled, putting her at risk for all the side effects associated with the disease, including increased mortality. In fact, RA decreases patients’ lifespan by approximately 8-10 years when not adequately controlled,⁸ making it a deadlier condition than some malignancies, such as Hodgkin’s lymphoma.

In general, RA affects nearly every organ system in the body and can be associated with a bevy of conditions, such as cardiovascular risk and increased cardiovascular death,^9,10, as well as increased rates of joint replacement surgery.¹¹ Patients have increased disability and decreased functional quality of life. This, in turn, can result in loss of work, high medical and social costs, as well as further morbidity.¹² Therefore, when weighing treatment side effects, patients have to be informed about the prevalence of comorbidity associated with uncontrolled disease, which is close to 100%. So this patient needs to understand that if her RA remains untreated, she will experience side effects in the form of substantial comorbidity (Figure 2).

In the same vein, rheumatologists have to be frank and realistic when communicating risks to their patients—with treatment comes the risk of potential side effects. However, not all patients experience side effects and only a minority of patients will experience serious side effects. This means that the majority of patients will never experience such toxicity, no matter how long they are on biologic therapy. By positioning the safety risks associated with biologic therapy in such a way, patients should hopefully reassess what they’ve seen or read online, which is largely unscientific information.

Coming back to this patient scenario, the preferable course would be start her on another biologic, ideally with a different MOA, and re-evaluate her disease activity level in 3 to 6 months. Among the available biologics, we have 4 different MOAs (5 if you include anakinra, but that agent is not often used for adults) (Figure 3). There is no single MOA that is superior to the others, although again, there may be benefit if you switch MOAs rather than cycling through the same MOA with various agents.^7,13,14,

For my patients today, I take the time to clearly explain the safety and risk-benefit profile of potential therapeutic options, so that they not only have a better understanding of what to expect, but also so that they’ll hopefully be more adherent to therapy, and therefore achieve better response rates. When we factor in the treatment options and combination regimens we now have available with the assessment tools we should be using to treat to target, we’ll be able to provide earlier and more aggressive care for our patients, culminating in better RA outcomes.

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