2015 ACR RA Guidelines Released– Finally! (Best of 2015: #2) Save

ACR 2015 RA treatment guidelines were published yesterday, nearly a year after they were preliminarily presented at the 2014 ACR meeting in Boston. After a year of review and revision these have been posted.

The following summarizes these guidelines for treatment as they apply to 1) Early RA; 2) Established RA; and 3) Patients with High-Risk Comorbidities. The level of evidence is also noted. Editors comments are added in italics.

Recommendations for Early RA Patients

The guideline committee recommends that early RA (ERA) patients be treated in the following manner:

• Use a “Treat-to-Target” strategy with the ideal target being low disease activity (LDA) or remission “as determined by the clinician and the patient”. Level of Evidence: Low. (It’s unclear if this is an argument against patient reported outcomes (e.g., RAPID3) as a means of assessment.)
•  DMARD-naïve ERA patients with:
  • LDA: should receive DMARD monotherapy. Level of Evidence: Low.
  • Moderate (MDA) or High Activity (HDA) should also receive DMARD monotherapy (over double or triple DMARD therapy). Level of Evidence: Moderate to High.
• Methotrexate (MTX) is the preferred initial therapy for most patients with early active RA.
• ERA patients with MD or HDA who have failed a DMARD: Combination DMARDs or TNFi or a non-TNF biologic should be used, with or without methotrexate (MTX) in no particular order. Level of Evidence: Low.
• Biologic therapy should be used in combination with MTX when possible, owing to superior efficacy.
• Low-dose glucocorticoids (prednisone ≤10 mg/day or equivalent) should be added in ERA patients who have moderate or high disease activity, despite any of the above DMARD or biologic therapies. Level of Evidence: Low. (It’s clear that low dose steroids will make most combination therapies better, but this particular recommendation should not advocate for steroids when a change in DMARD or biologic is indicated based on activity)
• Low-dose glucocorticoids may also be used as bridge therapy until the benefits of DMARD therapy are evident. 
• Steroid dosing should be low and the duration of therapy short. (Interestingly the guidelines suggest short-term steroids in ERA patients, but with established disease there is a provision for long-term steroids in active established RA patients (see below). Chronic steroid use is a practice employed by many. On average >60% of patients enrolling in clinical trials are on chronic prednisone 5-10 mg daily)
• Flares of RA: they recommend glucocorticoids ( 3 months of treatment) at the lowest possible dose for the shortest possible duration. Level of Evidence: Low.

Recommendations for Established RA Patients

• Use a “Treat-to-Target” strategy with the ideal target being low disease activity (LDA) or remission “as determined by the clinician and the patient”. Level of Evidence: Moderate.
• DMARD-naïve established RA patients with:
  • LDA: should receive DMARD monotherapy (over a TNFi). Level of Evidence: Low.
  • MDA or HDA should also receive DMARD monotherapy (over double or triple DMARD therapy and prefer DMARD monotherapy over tofacitinib). Level of Evidence: Moderate to High.
• MTX is the preferred initial therapy for most patients with established RA and active disease.
• Established RA patients with MD or HDA who have failed DMARD monotherapy (e.g., MTX): Combination DMARDs or TNFi or a non-TNF biologic or tofacitinib should be used, with or without MTX, in no particular order. Level of Evidence: Moderate to Very Low. (This is a significant departure from current practice where the next best treatment choice is either the addition of a TNFi (preferred by most practicing rheumatologists) or the change to combination DMARDs (e.g., triple DMARD therapy; this is preferred by managed care, fewer rheumatologists and patients with financial constraints).
• Biologics should be used in combination with MTX over biologic monotherapy, when possible. (Unlike EULAR RA guidelines, there is no exception for tocilizumab monotherapy that demonstrates efficacy comparable to tocilizumab with DMARDs)

For all scenarios for established RA patients below, treatment may be with or without MTX

• Active MDA or HDA patients on TNFi therapy alone (no DMARD) - one or two DMARDs should be added to the TNFi therapy. Level of Evidence: High.
• MDA or HDA despite a single TNFi therapy, they conditionally recommend changing to a non-TNF biologic. Level of Evidence: Low.
• MDA or HDA despite non-TNF biologic therapy, they conditionally recommend using another non-TNF biologic. Level of Evidence: Very Low.
• Patients failing multiple non-TNF biologics who have MDA or HDA and are TNFi-naïve should receive treatment with a TNFi.
• MDA or HDA who have been treated with a TNFi and at least one non-TNF-biologic (sequentially, not combined), they recommend first treating with another non-TNF biologic. If a non-TNF biologic is not an option, they conditionally recommend treatment with tofacitinib. Level of Evidence: Very Low.
• MDA or HDA patients who have used multiple (2+) TNFi (in sequence, not concurrently), they conditionally recommend non-TNF biologic therapy; or tofacitinib when a non-TNF biologic is not an option. Level of Evidence: Low.
• MDA or HDA patients with on any DMARD or biologic therapies, they conditionally recommend adding low-dose glucocorticoids. Level of Evidence: High to Moderate.
• Flares of established RA (while on DMARD, TNFi, or non-TNF biologics) should receive short-term glucocorticoids ( 3 months of treatment) at the lowest possible dose and for shortest possible duration. Level of Evidence: Very Low.
• Established RA in LDA (but not remission), they strongly recommend continuation of therapy rather than discontinuing medication. Level of Evidence: Moderate to High. (DMARD, TNFi, non-TNF biologic or tofacitinib).
• Established RA in remission, they conditionally recommend tapering DMARD therapy, TNFi, non-TNF biologic, or tofacitinib. But strongly recommend not discontinuing all therapies in patients with established RA in remission. Level of Evidence: Low. (The latter two recommendations basically say, weaning therapy is reasonable and prudent for established RA in remission, but discontinuation of DMARD or biologic therapy is not adviseable)

Recommendations for RA patients with High-risk Comorbidities

• Congestive Heart Failure: established RA with MDA or HDA and NYHA class III or IV CHF, they conditionally recommend using combination DMARD therapy, a non-TNF biologic, or tofacitinib rather than a TNFi. Level of Evidence: Moderate to Very Low. (This recommendation flys in the face of evidence. While the product label for the TNFi state under “warnings” that congestive heart failure, worsening or new onset, may occur. And under precautions state “Physicians should exercise caution when using a TNFi in patients who also have heart failure, and monitor patients carefully”. This warning is based on the performance of etanercept and infliximab in heart-failure only patients. Multiple studies in RA patients have shown no higher rates of de novo CHF or cardiac event and no higher rate of worsening when receiving TNFi. To recommend therapies (DMARDs, non-TNFi biologics) that have NOT been studied in CHF patients is naïve and disregards the evidence.)
  • If such patients are treated with a TNFi and their CHF worsens while on the TNFi, we conditionally recommend switching to combination DMARD therapy, a non-TNF biologic, or tofacitinib rather than a different TNFi. Level of Evidence:  Very Low.
• Hepatitis B: established RA patients with MDA or HDA and evidence of active hepatitis B infection (HBsAg+ > 6 months) and are receiving or have received effective antiviral treatment, they strongly recommend treating them the same as patients without this condition. Level of Evidence: Very Low.
  • Those with natural immunity from prior HBV exposure (HB core antibody and HB surface antibody positive and normal liver function tests), we recommend the same therapies as those without such findings as long as the patient’s viral load is monitored.
  • For patients with chronic hepatitis B who are untreated, referral for antiviral therapy is appropriate prior to immunosuppressive therapy.
• Hepatitis C: established RA patients with MDA or HAD and evidence of chronic hepatitis C virus (HCV) infection, who are receiving or have received effective antiviral treatment, we conditionally recommend treating them the same as the patients without this condition. Level of Evidence: Very Low.
  • Rheumatologists should work with gastroenterologists and/or hepatologists who would monitor patients and reassess the appropriateness of antiviral therapy, especially given the recent availability of highly effective therapy for HCV.
  • Chronic HCV patients not requiring or receiving antiviral treatment, they conditionally recommend using DMARD therapy rather than TNFi. (Again, this is based on very little evidence and is expert opinion only. But, those who treat HIV patients prefer TNFi over other therapies to treat either RA, Psoriatic disease, etc)
• Malignancy
  • Previous Melanoma and Non-Melanoma Skin Cancer: established RA patients with MDA or HDA and a history of previously treated or untreated skin cancer (melanoma or non-melanoma), they conditionally recommend the use of DMARD therapy over biologics or tofacitinib. Level of Evidence: Very Low. (Most of the cancer risk ascribed to TNFi and biologics is exactly the same as the cancer risk associated with RA alone/without biologics. Unfortunately there is no data testing the efficacy and safety of DMARDs in patients with skin cancer. Conversely there is a plethora of reports about the use of TNFi [much less for other biologics] in these scenarios without damning effects).
  • Previous Lymphoproliferative Disorders: established RA patients with MDA or HDA and a history of a previously treated lymphoproliferative disorder, we strongly recommend using rituximab, rather than a TNFi and conditionally recommend using combination DMARD therapy, abatacept or tocilizumab rather than TNFi. Level of Evidence: Very Low. (This recommendation favors choices that have not been studied and disregards the hefty data of TNFi use in patients with lymphoma. Even though rituximab is approved for use in CD20+ B cell lymphoma, its’ efficacy and safety has never been tested in RA patients with lymphoma. This topic was previously address on RheumNow)
  • Previous Solid Organ Cancer: established RA with MDA or HDA and a previously treated solid organ cancer, we conditionally recommend that they be treated for RA just as one would treat an RA patient without a history of solid organ cancer. Level of Evidence: Very Low.
• Serious Infections: In established RA patients with MDA or HDA and previous serious infection(s), we conditionally recommend using combination DMARD therapy or abatacept rather than TNFi. Level of Evidence: Very Low.
• Vaccine Recommendations: RA patients on DMARD and/or biologic therapy
  • RA patients age >50 years, they recommend giving the herpes zoster vaccine before the patient receives biologic therapy or tofacitinib for their RA. (It’s a smart recommendation and coincides with the label, however the CDC/ACIP and insurers generally won’t pay for the zoster vaccine in patients under 60 years)
  • RA patients currently receiving biologics, they conditionally recommend that live attenuated vaccines such as the herpes zoster (shingles) vaccine not be given.
  • RA who are currently receiving biologics, they strongly recommend using appropriately indicated killed/inactivated vaccines.