New Rheumatoid Arthritis Management Guidelines: A Quick and Easy Guide

(Cp nht: 24/09/2014 10:07:50)

The March issue of Annals of the Rheumatic Diseases includes updated recommendations
issued by the European League Against Rheumatism (EULAR) on the management of rheumatoid
arthritis (RA) with synthetic and biologic disease-modifying antirheumatic drugs (DMARDs). The new
guidelines were originally published online in October 2013 and update EULAR's 2010 RA management
guidelines.
The 14 recommendations included in the new document were developed by an international task
force that based its decisions primarily on findings from 3 systematic literature reviews and subsequent
expert consensus and voting. Some of the 2010 guidelines were removed, and others revised or divided,
in an effort to hone management guidance for rheumatologists and other clinicians involved in caring for
patients with RA. The following summary serves as a quick reference guide to the new guidelines,
reviewing both what was unchanged from the previous guidelines as well as what is new or revised.
Overarching Principles
As in the 2010 recommendations, the new guidelines were developed with the following 3
overarching principles in mind:
- Treatment of patients with RA should aim for the best care and must be based on a shared
decision between the patient and the rheumatologist;
- Rheumatologists are the specialists who should primarily care for patients with RA; and
- RA incurs high individual, societal, and medical costs, all of which should be considered in its
management by the treating rheumatologist.
Guidance documents of this type are important for several reasons. First of all, they codify
evidence-based expert opinion in this field. Second, they provide a starting point for practicing physicians
and for those who draft other guidance documents at the national or local levels. Finally, they inform
health care administrators, payer representatives, and policy-makers on the current state of therapeutics
in a particular area.
Having said that, several limitations must also be clearly understood. First and foremost, these
guidelines can never replace the individualized decision-making that must be at the center of the
patient/physician interaction, and physicians must have the possibility to 'deviate' from guidelines on the
basis of the specific circumstances for each individual. In addition, because guidance is based on
published literature and requires a lengthy process to develop, important recent insights may not be
sufficiently integrated into such a document.
Start DMARDs ASAP
The Basics:
- Start DMARDs as soon as an RA diagnosis is made.
- The 2010 American College of Rheumatology (ACR)/EULAR classification criteria should be
used to support diagnosis.
Changes: Whereas the earlier EULAR guidelines specifically mentioned the possibility of using biologics
as first-line therapy, this updated EULAR guidance no longer states that specifically. It does seem to leave
open this possibility by not specifying that the DMARD has to be "synthetic."
The Bottom Line: Both of these recommendations are quite sensible, but must of course be applied in the
context of individualized decision-making. In principle, RA should always be treated with true
antirheumatic therapies (DMARDs), both to provide the patient symptomatic relief and to prevent longterm damage. However, some patients with very mild disease or with multiple contraindications might not
be suitable for DMARD therapy. Classification criteria, which are intended primarily for research, can also
be used by the clinician as a helpful tool; however, the diagnosis must not be based on a strict application
of these, because they are always associated with a substantial rate of both false-positive and falsenegative results.

Target Remission or Low Disease Activity

The Basics:
- Treatment should focus on reaching remission or low disease activity.
- Use the current ACR/EULAR definition of "remission."
- Improvement in physical functioning and slowing or stopping of structural damage are implicit in
the definition of "remission."
- For patients in whom remission cannot be achieved, low disease activity defined by a composite
measure is a reasonable treatment goal.
Changes: The former recommendation 2 has been now divided into recommendations 2 and 3 to
emphasize the importance of defining a treatment target.
The Bottom Line: Clinicians need to train themselves to think in terms of the disease state that the patient
has to achieve. Simply achieving any improvement, or having a good feeling about the treatment result, is
no longer acceptable.
Monitor Disease and Adjust Therapy as Needed
The Basics:
- Monitor active disease every 1-3 months.
- If there is no improvement by 3 months from the start of treatment or the target is not reached
by 6 months, treatment should be modified.
- That said, monitoring should be performed as frequently as a patient's disease requires.
- Maximizing treatment efficacy includes reaching an optimal methotrexate (MTX) dose within "a
few weeks" and maintaining the maximal dose (25-30 mg/week) for at least 8 weeks.
- Maximal efficacy with most treatments may take up to 6 months to achieve in some patients.
Changes: To reiterate, recommendation 3 was formally grouped with recommendation 2. Whereas the
prior joint recommendation which "also dealt with follow-up and treatment adjustments that could be
interpreted or used differently than intended," the revised statement provides specific guidance.
The Bottom Line: Once a treatment has been selected, it is advisable to check the result after 3 months. If
some improvement has been achieved, it may be reasonable to wait another 3 months to make a final
assessment. After 6 months, a decision has to be made on the basis of whether the target has been
achieved. Because underdosing of MTX is very common, optimizing the MTX dose is clearly an important
step in treatment that must not be forgotten.
MTX in Active RA
The Basics:
- MTX should be part of the initial treatment approach in active disease, defined as a Clinical
Disease Activity Index (CDAI) score > 10, a Disease Activity Score 28 (DAS28) > 3.2, or a Simplified
Disease Activity Index (SDAI) > 11.
- MTX is highly effective both as a monotherapy and in combination with glucocorticoids,
conventional synthetic DMARDs (csDMARDs), and biologic DMARDs (bDMARDs).
- The recommendation implies that some patients with low disease activity may not need MTX.
- Important considerations include dose optimization, optimal folic acid use, and the recognition
that maximal MTX efficacy is attained only after 4-6 months.
- The optimal MTX dose (25-30 mg/week with folate, or less in the case of dose-limiting side
effects) should be maintained for at least 8 weeks.
Changes: None.
The Bottom Line: Clearly, MTX should be first-line therapy for most patients, and it must be administered
optimally in terms of dosing and use of folic acid.
MTX Contraindications

The Basics:
- In cases of MTX contraindications or early intolerance, sulfasalazine or leflunomide should be
considered as part of the initial treatment approach.
- Contraindications to MTX include hepatic or renal disease; MTX-induced lung disease is also a
concern.
- Optimal sulfasalazine dosing is 3-4 g/day as enteric-coated tablets; the usual leflunomide dose
is 20 mg/day.
- Antimalarials, including hydroxychloroquine and chloroquine, can be considered
monotherapy or part of combination therapy, primarily in patients with low disease activity.

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- MTX intolerance within 6 weeks should be viewed as a contraindication rather than treatment
failure.
Changes: MTX intolerance has been modified with the word "early" to indicate that intolerance to the drug
within 6 weeks should be viewed as a contraindication rather than a failure of treatment. The prior
recommendation 4 listed injectable gold salts as a possible MTX alternative. Although gold salts have
established efficacy on the basis of high-quality evidence, they have been removed from their formerly
prominent position among possible RA treatment because no study has evaluated intramuscular gold
since the previous systematic literature review was conducted.
The Bottom Line: Several other DMARDs can be used in lieu of MTX, either as monotherapy or in
combination.
Reach for the DMARDs
The Basics:
- In DMARD-naive patients, csDMARD monotherapy or combination therapy should be used,
irrespective of the addition of glucocorticoids.
- Data on the efficacy of csDMARD combination therapy vs MTX monotherapy are conflicting.
However, given that both approaches have supportive data, they are both included in the new guidelines
as possible treatments. It is also pointed out that patient preferences and adverse event expectations
should play a role in treatment selection.
- Data suggest that stepping up to bDMARD therapy from MTX monotherapy is more effective
than moving to csDMARD combination therapy.
-Combination csDMARD therapy should in general include MTX.
Changes: The 2010 recommendation favored csDMARD monotherapy in DMARD-naive patients,
irrespective of additional glucocorticoids, on the basis of the systematic literature reviews on which the
guidelines were established. The new guideline weighs monotherapy and combination csDMARD options
more equally, given recent data supporting the latter approach.
The Bottom Line: Here, some remarkable changes have been made. The use of combination therapy with
conventional DMARDs -- and especially the triple therapy of MTX, sulfasalazine, and hydroxychloroquine,
which was largely ignored in 2010 -- is here given as a reasonable option that is supported by several
trials, including FIN-RACo, Swefot, TEAR, and RACAT. The guidelines stop short of recommending
combination therapy for all patients, even though FIN-RACo, TEAR, and a recent trial (tREACH) all
showed significantly better results with combination than with monotherapy. Avoidance of overtreating
some patients still appears to be a very important consideration.
These recommendations do not include the first-line use of biologics, even though the previous
recommendations did suggest that possibility for patients with severe disease. Clinical trials done with
many biologics have demonstrated that the combination of a conventional DMARD (usually methotrexate)
and biologic as first-line therapy is superior at the group level to a DMARD (MTX) alone. However, using
such a combination might also lead to overtreatment in a lot of cases. Therefore, many experts feel that
the option of early treatment with biologics (usually in combination with MTX) should be available,
especially in patients with severe disease and a poor prognosis, but is to be used only in those cases. A
separate discussion is whether combinations of conventional DMARDs or glucocorticoids could be
equally effective (see the section "Consider Glucocorticoids," below).

Another remarkable and rather contentious change is the wording suggesting that the addition of
biologics to MTX is more effective than the addition of conventional agents. This was indeed supported by
the 1-year results of the Swefot trial and several secondary outcomes in RACAT. However, some experts
believe that the advantage of biologics over conventional combinations is small and does not justify the
greatly larger cost.
Consider Glucocorticoids
The Basics:
- Low-dose glucocorticoids should be considered as part of initial treatment plan (in combination
with 1 or more csDMARDs) for up to 6 months; they should be tapered as soon as clinically appropriate.
- "Low-dose" generally refers to 7.5 mg prednisone or its equivalent per day.
- Glucocorticoid monotherapy is not recommended, except in exceptional cases in which all
DMARDs have contraindications.
Changes: The previous recommendation read, "Glucocorticoids added at low to moderately high doses to
sDMARD monotherapy [or combinations of sDMARDs] provide benefit as initial short-term treatment, but
should be tapered as rapidly as clinically feasible." The new wording does not just suggest that
glucocorticoids may provide benefits, but rather that they should be considered as part of the initial
treatment strategy. The change is based on recent data on the efficacy of adjunctive glucocorticoid
therapy for initial RA management.
The Bottom Line: The revised guidelines give stronger support for the use of glucocorticoids as additional
therapy in RA. This is based on several trials, both older and more recent. Unfortunately, data are still
lacking on the true negative implications of long-term low/moderate-dose glucocorticoids. An interesting
option was not discussed in the guidelines: the use of multiple intra-articular glucocorticoid injections
rather than oral glucocorticoids, as studied in the CIMESTRA and OPERA clinical trials.
When the Treatment Target Is Not Achieved
The Basics:
- If the treatment target is not reached with the initial DMARD approach, in the absence of poor
prognostic factors, considering switching to another csDMARD approach.
- When poor prognostic factors exist, consider addition of a bDMARD.
- Risk factors for a poor clinical outcome include high disease activity, autoantibody positivity for
rheumatoid factor or antibodies to citrullinated proteins, and the early presence of joint damage.
- In patients with low risk for poor outcomes, another csDMARD strategy (with glucocorticoids) is
preferred; in those at high risk, consider adding a bDMARD.
Changes: Data on stepping up to combination csDMARD therapy vs the addition of a bDMARD are
conflicting, and the panel tried to find balanced wording to reflect this. The newly recommended treatment
sequence has been modified from the 2010 guidelines, to reflect the Task Force's stance that many
patients may not be at high risk after an initial DMARD strategy and that a rapid change in the csDMARD
regimen within 6 month may provide efficacy in a considerable percentage of patients. The word "change"
has supplanted "switch" to reflect add-on therapy vs swapping medications; the word "supported" has
been applied to this recommendation, reflecting the panel's acknowledgment that treatment decisions
should be individualized and opting for a bDMARD after a failed initial csDMARD approach in patients at
low risk for poor outcomes may occasionally be appropriate, whereas a subsequent csDMARD regimen
might sometimes be reasonable in high-risk patients.
The Bottom Line: The 1-year results of the Swefot trial demonstrated better efficacy with MTX plus antitumor necrosis factor (TNF) than with combined conventional DMARDs, and even the 2-year data
showed a numerical difference (as well as a significant radiographic benefit). Several secondary
outcomes in RACAT[8] also support this view. In contrast, the TEAR[6] trial and the primary outcome of
RACAT demonstrated noninferiority for combined DMARDs vs anti-TNF, especially when the options of
switching therapies were included (as would be the case in practice, of course). Many experts believe that
the advantage of biologics over conventional combinations is small and does not justify the greatly larger
cost.

Introducing Biologics
The Basics:
- If response to MTX or other csDMARD strategies, with or without glucocorticoids, fails to
achieve the treatment goal by 6 months or results in no improvement at 3 months, bDMARDs should be
initiated with MTX.
- bDMARDs include TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab,
infliximab, and approved biosimilars); abatacept or tocilizumab; and, under certain circumstances,
rituximab.
- Rituximab (currently the least expensive biologic) is approved in patients who have responded
insufficiently to TNF inhibitors, and may be considered a first-line bDMARD in the setting of the following
contraindications for other agents: recent lymphoma history, latent tuberculosis with contraindications to
chemoprophylaxis, living in a tuberculosis-endemic region, or a history of demyelinating disease.
- No preferential order of biologic selection is provided in the new recommendations, although the
Task Force acknowledges that there is more experience with TNF inhibitors than with other bDMARDs.
- Anakinra is not specifically mentioned, because interleukin-1 inhibitors have not shown strong
efficacy compared with other bDMARDs in meta-analyses; however, some patients may respond to the
agent.
Changes: The corresponding 2010 guideline stated that in cases of inadequate response to MTX and/or
another csDMARD, "current practice would be to start a TNF inhibitor," owing to the larger and longer
evidence base at that time compared with that for abatacept and tocilizumab. Although the evidence base
for TNF inhibitors still remains larger, abatacept and tocilizumab are now recommended equally with both
each other and the other approved bDMARDs. Also at that time, tocilizumab was not approved in the
United States for patients with inadequate response to csDMARDs; the same was true for abatacept in
Europe.
The Task Force also removed the former recommendation to consider combination therapy with
MTX plus a biologic in DMARD-naive patients with poor prognostic markers. This approach is now
strongly discouraged as the new recommendations still allow for introducing a biologic early in the
disease course (6 months).
The Bottom Line: Clearly, the choice of a first biologic is an important therapeutic decision. Because of
more extensive long-term data and much larger practical experience, anti-TNF has remained a natural
choice for many rheumatologists, but clinical trial data also support the use of several non-anti-TNF
biologics as the first biologic, and this is now reflected in the guidelines. This gives the clinician more
flexible options for each individual patient.
When the First Biologic Fails
The Basics:
- If the initial bDMARD fails, patients should be treated with a subsequent bDMARD. If the first
TNF inhibitor fails, patients can receive either another TNF-blocking agent or another biologic with a
different mechanism of action.
- Current evidence does not support any particular biologic over switching to another TNF
inhibitor when the initial anti-TNF agent fails.
- With multiple biologic biosimilar medications around the corner, the Task Force emphasizes that,
for example, an infliximab biosimilar should not be regarded as "another" TNF inhibitor in patients who do
not respond adequately to infliximab.
Changes: This recommendation was included as a consequence of the previous recommendation to
introduce biologics.
The Bottom Line: As more and more biologics have become available, clinicians have the option of
choosing between different ones as first, second, or third-line therapy. There is little data to support such
choices, and therefore the current guidelines do not support one biologic over another as a second-line
biologic. However, biosimilars should be regarded as equivalent to the original compound, as common
sense would also suggest.

Consider Tofacitinib
The Basics:
- Tofacitinib, a synthetic Janus kinase inhibitor and therefore not a bDMARD, can be considered if
biologic treatment fails; the Task Force recommends bDMARDs first, because "little is currently known
about [tofacitinib's] long-term safety."
- The authors point out that although the 5-mg dose of tofacitinib approved in the United States
and Japan just misses statistical significance for inhibition of joint damage suppression, it is still
recommended because data show significant radiologic differences at this dose.
Changes: The 2010 recommendations did not consider tofacitinib, because the agent was not approved
in the United States, Japan, and Russia until 2013.
The Bottom Line: The small-molecular oral agent tofacitinib has been approved only in a few of the
countries included in EULAR. In clinical trials, it demonstrated efficacy at par with anti-TNF (ORAL
Standard), and the US Food and Drug Administration and other agencies worldwide approved the drug for
various RA patient populations. Safety considerations appear to have been the main reason why the
Committee for Medicinal Products for Human Use did not approve this drug; among these, an increased
risk for infections and various laboratory abnormalities were noted. It remains somewhat unclear how the
drug compares with the approved biologics; most experiences to date suggesting that tofacitinib is
tolerated well by the majority of patients. Tofacitinib is priced similarly to biologics.
When to Taper
The Basics:
- If a patient is in persistent remission after glucocorticoids are tapered, consider tapering
bDMARDs, especially when combined with csDMARDs.
Changes: A similar recommendation was included in the 2010 guidelines; however, additional data have
since been reported supporting this approach.
The Bottom Line: For patients whose disease is in stable remission, it is natural to consider dose
reductions or discontinuation of these agents. Because of the cost implications, this has become an
important issue for biologics. Several important trials and studies, some of which were published very
recently and were perhaps not included in the literature review for the current guidelines, all support the
idea that such downward titrations of biologics can safely be implemented in many patients. In early RA,
many patients may be able to stop biologics entirely after stable remission (or low disease activity) has
been attained and continue with MTX alone, whereas patients with established RA may not be able to
stop the biologic altogether but might maintain their response with reduced dosages, at least for
etanercept and adalimumab.
Strategies in Long-term Remission
The Basics:
- In cases of sustained remission, consider careful reduction of the csDMARD dose; this should
be a collaborative decision between physician and patient.
- Recognize that stopping csDMARD therapy altogether in a patient with remitted RA results in
disease flares in up to 70% of patients -- twice as frequently as in those maintained on a regimen of any
kind.
Changes: Beyond replacing the word "titration" with "reduction," this recommendation remains the same.
The Bottom Line: Reductions of conventional DMARDs may also benefit the individual patient, especially
in terms of side effects or convenience; cost is no major issue in this case. Because of the slow action of
these drugs, such changes must be made more cautiously.
Therapy Adjustment: Factors to Consider
The Basics:
- If therapy needs adjustment, the following factors beyond just disease activity should be
considered: progression of structural damage, safety issues, and comorbidities.

- Reaching the outcome of low disease activity or remission is not always a prerequisite if the
above considerations are a factor; some patients with low disease activity may still develop progressive
radiographic joint damage and may require intensification of therapy.
Changes: None.
The Bottom Line: As always, therapeutic decisions must be individualized.