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New Standards of Treatment for Difficult RA - Part 1


Just as we would not accept active disease in infections, asthma, cancer, hypertension, angina or diabetes, we should have a similar treatment paradigm in RA. Our aim should be no evidence of diseases (NED) because it is clear that active redness, warmth and swelling in a joint will, without control, lead to an erosion and the downstream deformities that follow it. How tightly we should control RA, using the phraseology of diabetes treatment? In diabetes, we need to balance between microvascular changes and glycosylation due to poor control and hypoglycemia due to overly tight control of glucose. In RA, do we have the medications to attain NED and, when they are used, are their side effects unacceptable? I would contend that we now do have medications to reach this goal, and their single or combined toxicities are acceptable, given our current concept of the aggressiveness and unpredictability of RA.

My treatment philosophy is to be equally aggressive to the aggressiveness of the patient's RA personality. Ideally, we should try to attain an infectious disease paradigm, in which we accept nothing less than complete control. Partial control that might be considered equivalent to an ACR 20 would be malpractice in the treatment of infections. While we may not be there yet in the treatment of RA, we need to see that as our eventual goal. When I give patients a DMARD, I let them know that I expect 70-80% control of their inflammation, in all of its components. They are 10/10 when they start the medication, and I want them, over the next 1-2 months, to improve by 80%, down to 2/10 in intensity (employing fatigue, pain, morning stiffness, functional limitation and work status as important outcomes to measure either as a global score or individual ones). If they have not attained that level of improvement, I optimize their medication dose (such as with methotrexate where I push them all to between 20 and 25 mgm/week po or subq) or add or switch to a new DMARD. All are also on the best NSAID that I can find for them, and many have received short courses of low-dose steroids for 3-4 days to re-set the thermostat of inflammation, so as to allow the other medications to attain their disease control better.

Your Basic Medication Armamentarium

What medications should the patient be refractory to before we deem them as having refractory RA? First, very few RA patients truly have refractory RA, meaning that the aggressive personality of that specific patient's disorder cannot be adequately controlled with any of the presently available therapies. My bias is that all RA patients need to be treated within a month of their diagnosis with some DMARD. I believe that the rapid advancement of therapy with more and more aggressive approaches to optimally match the therapy to the disorder- as you better understand the personality of that person's RA - will avoid extra-articular manifestations, erosive disease, atherosclerosis and osteoporosis.

The medications that one should try in full doses for the correct amount of time are (not in any specific order of recommended use):

  • hydroxychloroquine, sulfasalazine (to a maximal dose of 1,500 mg bid with meals), parenteral gold, minocycline;

  • methotrexate to 25 mg/week, with a switch to the subcutaneous route of administration if the clinical response is suboptimal;

  • leflunomide or leflunomide + MTX;

  • azathioprine to 3 mg/kg;

  • etanercept 25 mg twice weekly subq;

  • infliximab, with changes in doses or dosing of remicade to monthly (instead of the every 8 weekly dosing) and to doses of as high as 10 mg/kg (some patients do not respond to the 3 mgm/kg dose every 8 weeks but do respond adequately when the dose and frequency are changed to as high as 10 mg/kg every 4 weeks, although higher doses lead to increased costs, not all of which is covered by health plans);

  • adalimumab 40 mg subq every other week, or weekly if unresponsive;

  • anakinra 100mg subq daily;

  • combinations of DMARDs including:

  • hydroxychloroquine, sulfasalazine, + MTX;

  • MTX + cyclosporine;

  • Anti-TNF medications + MTX or leflunomide or other DMARDs;

  • Anti-IL-1 medication + MTX or leflunomide or other DMARDs.

Further, it is assumed that all of these patients will have been treated with short courses of prednisone to bring the inflammation under control in the window between starting the DMARD or DMARD combination and the likely response time. Common steroid courses are 10 mg prednisone bid for two days and then tapering by 5 mg every two days to zero. These short courses are optimal because, if they are given every 1-2 months, the side effects are minimal. Unfortunately, in refractory patients, chronic steroid therapy is often used in order to improve function and control the inflammation that has eluded the prior therapeutic regimens. Be aware of the fact that the institution of chronic steroid therapy places a great long-burden that involves the institution of a steroid-protection regimen for osteoporosis, atherosclerosis, infections with appropriate immunizations, diabetes, hypertension, emotional problems, thinning of the skin, cataracts, and glaucoma, etc.

Reaching Beyond

If the physician has used all of the basic medications in our armamentarium in the correct way, maximizing doses, employing combinations, allowing for the appropriate time for that specific medication or combination to kick in and the patient still has active disease and significant functional limitation, what alternatives are available for that small but very needy group of patients?

  • Pulse steroids - 1-3 days of 250-1,000 mg intravenous methylprednisolone (the dose and number of days should be guided by the severity of the flare or status of the RA). This is very helpful in re-setting the inflammatory thermostat and not only improves the patient's disease but allows other medications to get a foothold into the disease activity. It can be repeated every month, until disease control is attained.

  • Cyclophosphamide - This is the true "terminator" and, in the 1970s-80s, was the first and one of the most powerful DMARDs. Unfortunately, its alkylating agent dark side outweighed its positives and cyclophosphamide was relegated to use in severe, refractory RA and RA vasculitis. Sometimes, it needs to be taken off the dusty shelf and used to calm down a very active RA. The positive is that it can be used for 3-6 months and then, once disease control is attained, you can switch to another DMARD that previously was unable to bring about disease control to allow for maintenance (i.e. as in oncology where you induce remission with one drug and then maintain control with another drug or set of drugs). In this way, you get out quickly from the oncogenicity of cytoxan and yet control the disease process. The regimen is usually oral cyclophosphamide at a dose of 2-3 mg/kg/day, but no study strongly states that you cannot use IV monthly cyclophosphamide at a dose of 0.5-1.0 g/m2 which has, overall, fewer side effects. This drug is particularly good in the setting of RA vasculitis but may be replaced with TNF antagonists.

  • Chlorambucil - This oral alkylating agent can also be effective is difficult situations such as severe, refractory RA, although it also was relegated to the historical recycle bin because of its oncogenicity. The oral dose is 2 mg/day.

  • Rituximab - This anti CD-20, used for the treatment of non-Hodgkin's lymphoma and refractory ITP, is being studied for SLE, RA and other autoimmune disorders. (See Rituximab in the treatment of rheumatoid arthritis, systemic lupus, and other autoimmune diseases: past, present, and future.) It may be difficult to get the insurance to pay for the use of this in RA.

  • Prosorba Column - This Staph A column has been around for many years, initially for the treatment of refractory thrombocytopenia. More recently, it has been resurrected for refractory RA. It is cumbersome, costly, demands a plasmapheresis unit, and has many potential side effects, but sometimes can get your patient out of a jam.

  • Bone marrow transplantation - Many have been performed, mostly in Europe, and some in the USA. At times, it works miraculously in very difficult situations but it does have significant costs in toxicity,mortality and financially. The main issue is to define the correct indications to avoid giving it to patients who are already overly immunosuppressed or sick and likely not to tolerate the preparative or transplant phases of the procedure. Autologous stem cell transplantation is the gentlest of the procedures but runs the risk of transplanting T cells that have been active in the disease process, thus setting up the possibility of a return of the disease in 2-3 years. If you use T cell depleted autologous stem cell transplant, you get away from the issue of bad seed T cells but increase the risk of EBV-related lymphoma. As time goes on, this procedure may become safer, cheaper and better indications and timing will have been defined.

  • Gene therapy - This has been performed locally wherein IL-1Ra is genetically programmed into fibroblasts and then injected into a joint. It not only improves inflammation in that specific joint but there may be a broader effect in other joints, as if there is a spread of the gene outside of the chosen joint. So far, no systemic gene therapy has been performed but we are probably not far away.



Headshot of Stephen A. Paget, MD, FACP, FACR
Stephen A. Paget, MD, FACP, FACR
Physician-in-Chief Emeritus, Hospital for Special Surgery
Stephen A. Paget Rheumatology Leadership Chair

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