Q: How do you manage the patient with RA who appears to be biologic refractory or is otherwise difficult to treat? 

First, I make sure that I have the correct diagnosis. I want to understand why my patient is not responding to therapy, so one of the first things that I do is to consider other explanations for the patient’s seemingly refractory RA symptoms. This might include evaluating for other causes of arthropathy, such as a crystalline arthropathy (eg, calcium pyrophosphate deposition disease, or pseudogout), or looking for other sources of persistent pain, such as fibromyalgia. When patients with RA are not responding to treatment, their compliance with the prescribed treatment should also be explored. This is particularly true for adolescents, especially when they leave home for college. There are also patient factors that make it more difficult for them to respond to standard treatment. Patients with obesity, for instance, tend to have a decreased response to disease-modifying therapy in RA; this might reflect the inflammatory contribution of obesity or perhaps that we are underdosing these patients (ie, weight-based dosing of RA treatments is uncommon in adults, whereas it is the standard of care in pediatric patients). I have also found that, for whatever reason, there are more adults with refractory disease, as opposed to children and adolescents. This may be, perhaps, because we are more aggressive in treating aggressive disease earlier in younger age groups. In any case, for those who appear to be truly refractory to their initial biologic medication, it comes down to being persistent with trying new therapies until we find one that works. Choosing the next medication is not standard and should be customized to the patient, considering patient preferences and patient characteristics. Most practitioners start biologic treatment with anti–tumor necrosis factor (anti-TNF) agents. I will typically try 2 different anti-TNF agents before moving on to other biologic or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Fortunately, there are now a number of other options for the treatment of RA, including B-cell depletion, T-cell inhibitors, interleukin 6 inhibition, and Janus kinase inhibition. Some are infusions, subcutaneous injections, or oral medications. It is important to discuss these options with your patients, as they may have preferences that should be considered.

Assuming that we have the correct diagnosis and that we are aware of clinical entities that could potentially cloud the picture, such as fibromyalgia, it is important to determine exactly how refractory the patient’s RA is. Often, individuals who are called refractory have received suboptimal doses and duration of methotrexate (MTX) followed by 1 or 2 biologic(s). In my experience, many patients who might be considered refractory have not had adequate trials of conventional medications, particularly MTX. When the dose and route of administration (ie, subcutaneous) are optimized, the percentage of those who are truly refractory markedly decreases. It is also unusual to see seropositive patients who are truly refractory, as the majority of individuals who are refractory are seronegative. So, we need to take a closer look at these patients to make sure that we are not missing something and that they are really taking their medications. We also want to take care to sort out the various sources of pain. Many patients are experiencing what I refer to as “birthday arthritis,” which is simply the normal aches and pains associated with aging. You do not want to be treating all of these aches and pains with biologic therapy. The bottom line is that you want to get your patient’s disease under control. If you fail to do so, RA can be a horrible—even fatal—disease. Thus, if the patient still has active disease despite the best use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), then he or she should definitely be on a biologic.

We often use a number of adjunctive treatments for those patients whose disease is well controlled but still have persistent pain, perhaps from osteoarthritis. For example, we will prescribe treatments such as diclofenac topical gel. I prefer to use topical nonsteroidal anti-inflammatory drugs (NSAIDs) because I am trying to get away from the use of systemic NSAIDS, as they are associated with several toxicities. Sometimes we use duloxetine or small doses of tramadol in certain patients with back and knee pain. I agree that seronegative patients are the most challenging to treat. These individuals often have joint damage on magnetic resonance imaging, and you have to carefully consider which treatments you can use to get their disease under control. These are the patients who should be on MTX or some csDMARD in combination with a biologic or a tsDMARD to at least control the symptoms because we know that, even if they are not achieving a true clinical response, they will experience some future joint protection. It is also important to ask whether patients or any individuals residing with them smoke because these individuals do not respond as well to therapy. In fact, reflecting on my experience with the Karolinska Institute in Stockholm, Sweden, the clinicians there did not treat patients unless they quit smoking. Patients were often enrolled in an aggressive smoking cessation program first, as this proved to be cost effective for the health care system. We still see some patients with RA who smoke here in the United States, one of the reasons being that smoking cessation treatments are often not covered by insurance.