Advice on Multi-Drug Failures in RA Save

What’s your next best approach to the rheumatoid arthritis (RA) patient who has failed several DMARDs and biologics?  In such cases you have to either reconsider the diagnosis (especially if seronegative) or reach into your bag of tricks.  

As many of us struggle with multi-drug failures in RA, I reached out to the RA therapy mavens, trialists and teachers and asked, “Can you write a few words on  Multi-drug failures in RA.” 

I wanted to share with you the expert’s approach on managing those RA patients we all struggle with.  I didn’t define this as “difficult to treat RA”; just multi-drug failures, as I too have been frustrated, challenged and puzzled with this scenario.

I asked for a few sentences or few hundred words on their insights, rules, quotes, algorithms, or go-to drugs.  The experts responded in force, with more than I asked for. Their responses were well thought out, full of tenets, options, and occasional pearls.  I underlined what are thought were valuable pearls and insights, for your attention. In reading below, you’ll see common themes emerge.

• Make sure you have the right diagnosis
• Have a methodical approach to your choices
• Focus on the difference between pain and inflammation
• Steroids are last ditch and fraught with problems

Roy Fleischmann, MD (Dallas, TX)

When faced with a patient who is a “multi-drug failure” one needs to consider prior therapy. Did the patient have an adequate and appropriate trial of prior medications - high enough dose for a reasonable time such as MTX 20-25 mg a week for 3 months and continued MTX (or another csDMARD(s) when taking a bDMARD or tsDMARD? Have the patients been true primary failures to a bDMARD or were they a secondary failure – if a primary failure was there a switch in MOA which would be reasonable or another med with the same MOA with a secondary failure? Have all alternatives been utilized including other csDMARDs, TNFi, IL-6i, a co-stimulatory blocker and a B cell therapy given appropriately?  If the answer is yes to all, I would consider a trial of anakinra which can be effective in these circumstances. If all have been tried, then the best option would be a well-designed clinical trial of an RA medication in development with a different MOA. If all else fails, what I would not do is treat with high dose GC or opiate analgesics for obvious reasons.

Jeffrey Curtis, MD (Birmingham, AL)

Make sure you are treating the right disease. Your new referral (sometimes from another rheumatologist!) for ‘refractory seronegative RA’ may be something else instead, like polyarticular gout. Question all assumptions. Not all ‘drug failure’ is created equally. Often for a medication that the patient ‘failed’, if they cannot recall a specific side effect nor that it didn’t work well enough despite an adequate trial (e.g., at least 3 months), I may prescribe it (again) and sometimes the patient does well. Occasionally they just gave up too quickly.

Richard Conway, MD (Dublin, IR)

The spectre of a patient with rheumatoid arthritis with severe ongoing symptoms despite cycling through multiple biologic DMARDs is one which haunts all practicing rheumatologists. I have three key questions I ask myself when faced with this scenario:

1. Is the diagnosis correct? Is this really RA?
2. Are the current symptoms due to inflammatory RA? Or are they something which I should not necessarily expect to respond to immunosuppression (e.g., fatigue, fibromyalgia)?
3. Am I remembering the response rates to biologic agents? These drugs are wonderful and we all like to think they are perfect, but they are not. 60-70% of patients responding well, with decremental efficacy as we increase the number of failing medications. It is to be expected that some patients do not respond to standard treatments. We should not give up in this situation, but acknowledge it and try a different approach. We should be more honest with ourselves and our patients about the true efficacy of these superstar medications.

Elena Myasoedova, M.D., Ph.D. (Rochester, MN)

In our tertiary referral practice, I see a lot of patients who inadequately responded to multiple treatments. Before assuming this is a “refractory RA”, my approach is to: 1) ensure the correct diagnosis: i.e., does patient have RA? if the main concern suggestive of non-response is pain, is pain explained by inflammatory arthritis or there can be other non-inflammatory causes of pain (central sensitization, neuropathic pain, etc.) that need different management; 2) rule out common scenarios that mimic non-response: e.g. non-adherence, inadequate dosing/ escalation/ route (especially with MTX), insufficient duration of treatment; 3) If there is a non-response to multiple drugs, it is time to step back and reconsider diagnosis and treatment.

Optimizing dosing regimen of methotrexate can do wonders with treatment response.  Abatacept works great in some patients, has good safety profile and is frequently overlooked. Recent work suggests that HLA-DRB1*04:05 allele was independently associated with abatacept treatment response (Scientific Reports | (2023) 13:15250).  My favorite quotes (for such patients): 

• Primum non nocere – first, do not harm.
• Do what you can, with what you have, where you are (Roosevelt).
• Success is not final; failure is not fatal: it is the courage to continue that counts (Churchill).

John Tesser, MD (Phoenix, AZ)

A lot of thoughts:  1) make sure the patient has RA; review the differential diagnosis; could it be peripheral joint AxSpA, crystal arthritis? 2) make sure the patient’s symptoms are from RA: by exam, CRP/ESR (maybe helpful), US for synovitis/new erosions, VECTRA (if you believe in such things) and not from a chronic pain issue (FM, etc.).  3) Assuming it’s active RA not responding to MTX and biologics or JAK inhibitors, consider going back to the csDMARD basket and add/change anchor drug (MTX and leflunomide is a good and effective combo) Determine if any of the previous meds had worked for a while and consider a return to it. If several meds, then could try rotating through them again.  4) Try other biologics: TNFs of course, but also inhibitors of IL-6, T-cells (abatacept), and rituximab; In seronegative RA patients consider inhibitors of IL-17 or IL-23.  Also consider a clinical trial (if available). When things get desperate, consider mycophenolate mofetil, azathioprine, auranofin, anakinra:   IM gold and penicillamine are not available. Oh well, when everything fails - prednisone.

Robert Schoen, MD (New Haven, CT)

When RA patients fail multiple drug therapies, diagnostic reassessment is often appropriate. For the seropositive patient with classic joint involvement, it is relatively easy to continue trying new options compared to the more clinically ambiguous seronegative patient. But success in treating these challenging patients can be very gratifying. Yesterday, I followed up with an obese RA patient with involvement primarily of knees and hips. I was fortunate that my decision to escalate to a biologic after failure of multiple non-biologics DMARDs was successful, resulting in a satisfactory visit for both the patient and for me.

Ted Pincus, MD (Chicago, IL)

In my experience, almost all "multidrug failures in RA" are a result of joint damage and/or patient distress manifested as anxiety, depression, and/or fibromyalgia, which can be detected on an MDHAQ.  I also think that the way we go about treating RA is incorrect, and the opposite of how oncologists’ approach for which we showed more than 40 years ago the prognosis of rheumatoid arthritis and other rheumatic diseases may often be as poor or poorer.  We need induction therapy rather than failure- based therapy.  Please remember that when I was a medical student there was no such thing as a coronary care unit and the only reason one went to a hospital for a heart attack was to get pain medication.  We need to change the strategy for treating inflammatory diseases. That is why I contacted you with the idea that treat-to-target should involve a target of early treatment rather than an index of disease activity, which is raised and 50% of people in moderate or high "activity" by joint damage fibromyalgia, anxiety, and/or distress.

Robert B.M. Landewé (Amsterdam, NL)

I am just old enough (59) to remember the sense of gratitude of those poor, crippled RA patients on our waiting list to receive their first miracle anti TNF-infusion at the end of the previous millennium. Some of them still use their first biological 25 years later, not thinking one second about changing it to a newer compound, since they know what they risk to lose.

Nowadays, many RA-patients who start a biological (or JAKi) respond far better and with lower residual joint counts and CRP than their predecessors, but still report more pain, fatigue and subjective discomfort; While being better off objectively, subjectively they feel worse.

Does this mean the treatment has failed?  No! We call this ‘reference shift’. Our modern drugs are perfectly suited to deliver what they should do: suppression of inflammation, and with almost no toxicity! 

What can we learn from this?  Suppression of inflammation is not always the same as reduction of pain, improvement of fatigue and feeling happier! Our drugs can promise suppression of inflammation and preservation of joint integrity and function, that’s it. They are not a panacea for happiness!

Tell your patient that they may expect fewer joints being inflamed, less joints being destructed, and a better prognosis over all. Tell them too that a happy life is more than what one expensive drug can deliver. Do not cycle drugs too easily!

Stanley Cohen, MD (Dallas, TX)

Refractory RA or multidrug failure RA remains one of the greatest challenges in disease management. The actual definition of refractory RA is controversial and various experts/professional societies have used different definitions making interpretation of data difficult. There is no roadmap regarding management of these patients and treatment is purely empirical after initial biologic failures. We have some data that suggests that seropositivity for CCP might enhance treatment response to therapies such as rituximab or abatacept and biomarkers are being developed that may predict nonresponse to TNF inhibitors. However refractory RA is quite complicated as there are numerous features that may play a role in lack of response to treatment. Multiple studies have demonstrated that patients who are less educated and lower social economic status tend to be less responsive to treatment as well as those with structural damage. Obese patients are less responsive to treatment. Additionally a significant number of patients with rheumatoid arthritis have central somatization which can be confused by the provider as increased disease activity resulting in modification of treatment that may not be necessary.  How these features interplay and result in lack of adequate response to treatment is not yet clear but certainly need to be considered as we grapple with this treatment resistant group of patients. With the advances over the last 30 years that have resulted in dramatic improvement in patient outcomes for RA patients this subset of refractory RA is now receiving the proper research attention with efforts such as the NIH AMP initiative and Arthritis Foundation funding which has resulted in the identification of synovial pathotypes that may be associated with poor response to treatment. Identification of the heterogeneity in synovial pathology may result in novel targeted treatments that might improve outcomes in these more difficult to treat patients.  A little more than 2-3 sentences, but this is a very complicated area.

Glenn Hazelwood, MD (Calgary, CA)

• Carefully review prior DMARD use and reason for failure; could an effective drug that was stopped for a possible/questionable AE be re-tried?    
• Can a prior biologic used as monotherapy be re-introduced with optimization of MTX/csDMARDs?
• -Consider drug/anti-drug Ab levels (TNF therapy)
• Adding in low-dose prednisone
• IM Gold: Never used it myself, but have heard from others that some people achieve a deep and lasting remission. 

Dan Furst, MD (Los Angeles, CA)

It is relatively clear that there are not great differences in efficacy among the biologic DMARD’s (Biologics and conventional synthetic DMARD’s).  Therefore, the choice of which medications to use for which patient must rely on other factors. I examine the complementarity (different and complementary) mechanisms of action, clinical pharmacology and, as much as possible, major adverse events among these medications. For example, there is logic to using an IL-6 inhibitor, a calcineurin inhibitor and an antimalarial together as they have different mechanisms of action, different pharmacokinetics and generally nonoverlapping adverse events. I have found this approach to be useful in patients who have tried and “failed” multiple medications.  I have found that tacrolimus is often an overlooked and underutilized drug in patients such as those described. This calcineurin inhibitor has been shown to be effective in rheumatoid arthritis, is well and fully understood, has positive kinetics (less renal excretion than cyclosporine, convenient oral dosing (daily)) and is frequently a medication not previously used by these difficult patients.

General rules I use:

1. Understand the drugs I use, the other drugs. the patient uses and the individual differences among patients.
2. Involve the patient in the difficult decisions being made and be sure they understand the upsides and downsides of the decisions.
3. Emphasize that “you never get something for nothing.”