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My Approach to Difficult RA

May 19, 2017 12:11 am

Difficult RA - We see them, but don’t quite know what to do with them.

Patients are labeled as having “difficult RA" when: 1) we are frustrated, 2) it's too late, 3) we've run out of options or 4) the relationship is failing. 

RA is inherently difficult. By definition it is progressive and destructive, requires a dozen or more lifetime drug changes to control but not cure, and increases the risk of cancer, heart disease and serious infections.  All this occurs despite expert care by a rheumatologist.  

Have you looked at any of the algorithmic/pictorial depictions of treatment guidelines in the last decade?  Although meant to be instructive aids to teach the standard of care, they appear to be a dazed and confused map of equipotent choices in RA therapy. Guidelines won’t prevent difficult RA.

Even without “omics” to guide precision medicine, rheumatologists have been remarkably successful in managing this most challenging, elusive beast of a disease. In the last few decades we have achieved higher remission rates, lower rates of surgery and extraarticular manifestations, fewer cardiovascular deaths, reductions in mortality and historic evidence that RA is getting milder.

The experienced rheumatologist doesn’t need guidelines to knows what works in most RA patients. The average rheumatologist manages a total of 200-400 RA patients. Unfortunately there are too many who we would describe as hard, recalcitrant or unmanageable. 

Difficult RA is more than a swollen joint count or eye-popping lab value. The following equation quantifies difficult RA, by including the variables that drive the disease and its control. As such, management of any of the variables may be an unaddressed opportunity to improve patient outcomes.

After a lot of lectures and a lot of rumination on this topic, I’ve acquired an understanding and approach that analyzes the many sides and options for what may be “difficult”. 

- Wrong Diagnosis?  When your best therapies don't work, the problem may not be the patient or therapy: it may be the wrong diagnosis. We have all managed RA patients who, over time, revealed a truer or better diagnosis. Seronegative RA leads the way and is followed by numerous disorders that may masquerade as RA.

  • Masqueraders: tophaceous gout, psoriatic arthritis, erosive osteoarthritis, enteropathic arthritis, CPPD, hemochromatosis, another connective tissue disease, polymyalgia rheumatica, Still’s disease, infectious arthritis (TB, leprosy, chikungunya arthritis), multicentric reticulohistiocytosis, or neoplasia.

- Damage Done – Could it be that what you are treating isn’t fixable? Non-response to anti-inflammatory, DMARD or biologic therapies usually indicates your dealing with fibromyalgia, mechanical or degenerative disease. At some point the pain of inflammatory synovitis transitions to its consequences – damage, degeneration and pain. At either end of the spectrum is pain.  Three dictates for such patients include:

  • Don’t chase pain
  • Pain and damage mandates referral and a “team approach”
  • When unsure of pain or problem – get medical imaging

- Looking for the Next Best Thing – Most of us believe that therapeutic excellence has been fostered or driven by new drug development. The tipping points of change in RA care came with the introduction of methotrexate and, 15 years later, TNF inhibitors. If drug development was the answer to “difficult RA”, then this problem should have tailed off with the introduction of anakinra, rituximab, abatacept, tocilizumab and tofacitinib. But it has not.  Accordingly, I don’t believe future therapies (more Jak inhibitors, IL-6 inhibitors, biosimilars, etc.) will change the story appreciably. We don’t need newer therapies as much as we need new skills. Hence, the smart rheumatologist should be looking to: 

  • Smarter use of existing therapies
  • Changing rheumatologist behaviors and practice
  • Stop waiting for the holy grail “biomarker” and adopt changes that are innovative

- Optimize MethotrexateO’Dell analyzed 2009 claims data on 35,640 RA patients treated with MTX and shown by 2014 on 44% remained on MTX, 49% switched to a biologic and that only 7% switched from oral to injectable MTX. His point was that all too frequently we bail out on MTX and employ more expensive biologics without the certainty of greater efficacy.  Hence my tips on optimizing MTX include:

  • Dosing: once you are at 15 mg/wk or above, either switch to parenteral MTX or split oral dosing (e.g., 7.5 mg bid on Friday) to maximize MTX absorption
  • All patients must be on folate daily
  • Manage oral ulcers and nausea with vitamin A 8000 IU qd.
  • CNS “blahs” can be managed with dextromethorphan (i.e., Mucinex DM) given with MTX qhs and bid the next day.

- Defensive Prescribing – after your first DMARD or first biologic failure the next best options are usually dictated by either the comorbidities present or patient fears. Rather than choosing what you believe to be the next best therapy, you opt into drugs chosen defensively to minimize risk. In these situations, you need to know the real risks that allow you to have the fortitude to write the next safest prescription. The figure below shows your best or worst options given a few common impactful comorbid states:

- Common Prescribing Mistakes – most of these are omissions, misconceptions or wrongful practices.

  • Not considering anakinra, cyclosporine, or rituximab – they’re FDA approved and proven to be efficacious
    • Anakinra – it’s not just for Still’s disease.  RCTs showed it to yield ACR20 response rates of 42%; the same number as infliximab in the ATTRACT study.
    • Cyclosporine – in combination with MTX, CyA is quite effective. The dose is 2.5-4.0 mg/kg as a single or split daily dose. The monitoring pearl is to keep the serum creatinine within 30% of baseline (pre-treatment) creatinine levels. Hence, a baseline Cr = 0.9 is toxic if it rises to 1.2 while on CyA.
    • Rituximab – highly effective in RA; more so in those who are seropositive.  For many the concern is PML; but the risk of PML on RTX in RA is 1:30,000. This happens to be far lower than the PML risk in lupus or cancer patients.
  • Azathioprine – most rheumatologists under dose AZA; note that after checking TPMT levels, the target AZA dose is 2-3 mg/kg/day.  Thus, most adults should be on 150-200 mg qd, instead of most being on 50 or 100 mg qd.
  • Hydroxychloroquine – be careful to not give more than 200 mg daily to women
  • Methotrexate – failure to adjust delivery (sc, IM, split oral) when using doses >15 mg weekly.
  • Monotherapy – the quest for monotherapy should be reserved for the few, easily controlled RA patients. Do not be tempted to go it alone (monotherapy) with tofacitinib, tocilizumab, infliximab or adalimumab. Remember we are talking about “difficult RA” here.
  • Weaning – this has been a popular experiment in the last decade, largely driven by undeclared patient non-adherence and clinical trials. But the results are clear – weaning is unwise for most and has clinical disadvantages and radiographic risks. The 2015 ACR guidelines state that patients achieving:
    • LDAS – Continue therapy; do not discontinue or wean.
    • Remission - tapering DMARD, TNFi, non-TNF biologic, or tofacitinib. But strongly recommend not discontinuing all therapies

- Seven Drugs You Might-Could Consider - If you gone through the above and are left with uncontrolled synovitis despite your multiple-best efforts, there are options you’ve yet to consider.  These options are either FDA approved, but discarded (meaning you have almost no experience with these agents) options or tried and failed off-label treatment options.  My list includes: 

  • Anakinra, gold, cyclosporine, tacrolimus, cyclophosphamide, mycophenolate, and apremilast

- Ctrl-Alt-Del Option - when frustrated with your computer, it may be time to reboot by using the combined Ctrl-Alt-Del key.  Turns out the same keys can be applied to patients where the options seem few, conflicted or dangerous. 

  • Control – review with the patient which among all their meds afforded them the most relief and best control
  • Alternatives – what are the drugs that you’ve never used or considered in managing this difficult RA?  This may include either FDA approved and off-label agents (see above)
  • Delete – remove immediately all medicines the patient is allergic to or refuses to take. Also delete treatment options which you deem to be dangerous or risky to the patient.
  • What your left with is a reasonable list of useable therapies that can be combined or added sequentially to improve outcomes.

Lastly, ask the patient what they most want you to fix. You may be surprised by what they say.

I saw a “difficult RA” scenario this week.  It was difficult because I thought the patient was happy and very well controlled. Unfortunately, a difficult dialogue ensued when I inquired why she wasn't taking the medicine as prescribed. She said she was spacing out her treatments because of her fear of the many rare side effects seen on television advertisements. The discussion pitted arguements for whats best for you (mine) against what I'm afraid of (hers). I almost lapsed into a defense of my treatment choices and dosing, but realized instead of taking opposing positions, I needed to state my role, my strengths and what I believe to be irrefutable:

  1. I really want to be her rheumatologist and I want to earn her trust.
  2. I welcome shared decision-making – but only up to when my certainty clearly outweighs her concerns – then she will have to trust me or get a second opinion.
  3. I want her to read, research and be well-prepared, but that should not the basis for her making medical decisions alone. She must realize that my 30+ years of study, research and experience out-trumps a) what “people say…”, b) google, and c) advice from well-meaning friends, family, etc.
  4. She needs to be the CEO of her own health.
  5. She may be afraid of is the 1/1000 risk on the television, but I’m afraid of is the certain damage that uncontrolled inflammatory RA will bring upon her in the near future (the 800-lb. gorilla argument).
  6. The drug prescribed for her took $2 billion, 10 years and 2500 patients to develop; has been studied for 20 years and given to over 2 million patients worldwide; and that we know all we need to know about the efficacy and safety of this drug.  Thus, when I say this drug was built and designed for her, she needs to know the enormity and certainty behind that statement.




The author has no conflicts of interest to disclose related to this subject
Dr. Cush is the Executive Editor of and also Co-Edits the online textbook 
Dr. Cush's interests include medical education, novel drug development, rheumatoid arthritis, spondyloarthritis, drug safety, and Still's disease/autoinflammatory syndromes. He has published over 140 articles and 2 books in rheumatology.
He can be followed on twitter: @RheumNow

Rheumatologists’ Comments

David Theis

| May 19, 2017 11:46 am

One of your best articles Jack! If I may, I would add two pitfall points: 1) to avoid hasty permanent discontinuation of a particular DMARD after a single infection (whether it be sinusitis, zoster, or other), and; 2) to address RA flares with a brief pred taper before prematurely declaring that a csDMARD or bDMARD has "lost effect." There seems to be a particular springtime flare season happening each year, where a brief pred taper regains control for my pts and averts the risk of playing musical chairs with DMARDs.
David - thanks. 1) with the Ctrl-Alt-Del approach there is no negotiation. Why try to make the patient a believer in an option they have already painted as bad. After all your the doc who prescribed the drug that caused her infection(s). The reason for her distrust in a drug doesnt matter. The goal is to get optimisim and as many choices on your side. 2) One thing I didnt put in this talk (that is in the lecture) is that we need new Flare management approaches. Steroids are, in the end, still chronically dangerous and if you need a steroid taper to make a DMARD work then you likely do not have a good DMARD choice. Tis always the season for a flare in RA, and its not limited to spring. Flare management may enable better control and durability of a DMARD - but right now you're using the same drug your fathers, fathers rheumatologist used to manage flares in 1960. I agree with the goal of Steroid use for flares, I just dont like that its the only option, especially in Difficult RA patients who by definition end up playing DMARD musical chairs! Thanks for the thoughts! JC

Carlos Antonio Gusmão Guerreiro de Moura

| May 19, 2017 2:07 pm

As the consultations succeed, it is common to for us to focus the reasoning on what seems obvious: patient with rheumatoid arthritis and pain = disease activity = therapeutic optimization. This leads to a high and undue use of immunobiologicals. I always advise my residents: when something does not evolve as we expected, take a step back to see the forest and not just the tree. We must be very careful with numbers and with the mathematization of medicine, after all, the scientific evidences of today will not necessarily be those of tomorrow. Nice comment by David Theis too. Congratulations.
Very well said and all should learn from your comment - "take a step back to see the forest and not just the tree" JJC

David S Knapp

| May 19, 2017 9:40 pm

The is a huge "underground" of "sero-negative RA patients" who phenotypically act like sero-+ RA patients in regards to symptoms and steroid responsiveness, but often have more symptoms than signs. This group of patients are subjected to multiple biologic agents in a fruitless effort to meet the rheumatologists' needs for satisfaction and the patient's needs for QOL and functionality. Some type of clinical research is badly needed for this most difficult group, many of which are overtreated with dangerous and expensive medications (sometimes to pay the rent!)
Thank you for a great article. Love the MTX tips! Hi David!

Manish bavaliya

| May 23, 2017 11:23 pm

Sir, that's an excellent and extremely informative article. Thank you very much

James Smith

| Jul 25, 2017 10:38 pm

This is a great piece. I particularly agree with the damage done, avoiding looking for the next best thing, and optimizing methotrexate. I would add tobacco cessation. This is a real issue in the southeast.

Michael G. Blackmore MD FRCPC Int Med/Rheumatology

| Jul 06, 2018 10:16 am

Brilliant! BUT I have to comment...since entering into Rheumatology in '92 there has been A DRAMATIC CHANGE: in 2018 my patients with RA are not coming in with TKR's, Swan-neck or Boutonniere's, cervical ruffs, we must be doing "something" right. You're algorithm is "spot on".....for ONE MAJOR REASON: RA = [X] [Y] [Z] / Rx .....BUT the key is: the exponential factor of FM! So I applaud you for remains an essential component. Thank you!

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