- Focus on common clinical scenarios, not exceptional cases
- Cost is a consideration in these recommendations. However, explicit cost-effectiveness analyses were not conducted.
- Disease activity measurement using an ACR-recommended measure should be performed in a majority of encounters with patients with rheumatoid arthritis (RA).1
- Functional status assessment using a standardized, validated measure should be performed routinely for RA patients, at least once per year, but more frequently if disease is active. Examples of commonly used functional status measures include Health Assessment Questionnaire (HAQ), Health Assessment Questionnaire-II (HAQ-II), Multidimensional Health Assessment Questionnaire (MD-HAQ), Patient-Reported Outcomes Measurement Information System , Physical Function 10-item, PROMIS Physical Function 20-item, and PROMIS Physical Function Computerized Adaptive Tests (PROPFCAT).
- If a patient has low RA disease activity or is in clinical remission, switching from one therapy to another should be considered only at the discretion of the treating physician in consultation with the patient.
Arbitrary switching between RA therapies based only on a payer/insurance company policy is not recommended.
- A treatment recommendation favoring one medication over another means that the preferred medication would be the recommended first option. However, favoring one medication over the other does not imply that the non-favored medication is contraindicated for use in that situation; it may still be a potential option under certain conditions.
Table 1. Definitions
Key Terms and Definitions
- Adult RA patient
- Adults, 18 years and older, meeting the ACR RA classification criteria.2, 3
- Health Benefits and Harms
- Efficacy and safety of treatments including desirable and undesirable effects.
- Early RA
- RA with duration of disease/symptoms of <6 months, where âdurationâ denotes the length of time the patient has had symptoms/disease, not the length of time since RA diagnosis.
- Established RA
- RA with duration of disease/symptoms of â¥6 months OR meeting 1987 ACR RA classification criteria.a
- Disease activity
- Categorized as low, moderate, or high as per validated scales
(Table 3). Moderate and high disease activity categories were combined, as used previously for the 2012 ACR RA treatment recommendations.1
- RA remission
- A joint ACR-EULAR task force defined remission as a tender joint count, swollen joint count, C-reactive protein (mg/dL) and patient global assessment â¤1 each or a Simplified Disease Activity Score (DAS) of â¤ 3.3,4 one of 6 ACR-endorsed disease activity measures.b
- Optimal dosing of RA treatments
- Dosing to achieve a therapeutic target derived from mutual patient-clinician consideration of patient priorities, and
- Given for â¥3 months before therapy escalation or switching.
- DMARD failure
- Failure of traditional/conventional DMARD(s) due to lack of efficacy/desired response or side effects.
- Biologic failure
- Failure of biologic(s) due to lack of efficacy/desired response or side effects.
- Secondary biologic failure
- A biologic was efficacious initially but subsequently became inefficacious.
- Active hepatitis B infection
- Hepatitis B surface antigen positive, Hepatitis B surface antibody negative, Hepatitis B core antibody total positive (less important), AST/ALT typically increased, HBV DNA positive (if checked).
- Hepatitis C infection
- HCV antibody positive, HCV RNA positive, AST/ALT typically increased.
- NYHA class III and IV
- NYHA class III includes patients with cardiac disease resulting in marked limitation of physical activity with less than ordinary physical activity causing fatigue, palpitation, dyspnea, or angina, but no symptoms at rest.
- NYHA class IV includes patients with cardiac disease resulting in inability to carry on any physical activity without discomfort, symptoms of heart failure are present even at rest, and discomfort increases if any physical activity is undertaken.5
NOTE: All numeric superscripts refer to Source References on page 17. Alphabetic superscripts refer to footnotes at the end of figures and tables.
a New classification criteria for RA (ACR /EULAR collaborative initiative) were published in 2010.3 The definition of established RA is based on the 1987 ACR RA Classification criteria,2 since the 2010 ACR RA classification allows a much earlier diagnosis.
b Any of the ACR-recommended disease activity measures may be chosen, as described in Anderson
Table 2. Agents Used in Treating RA
Drug Category and Definitions
- Methotrexate (MTX)
- A disease modifying antirheumatic drug (DMARD)
Used either oral or subcutaneous
- Traditional/conventional DMARDs including hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate or sulfasalazine (SSZ) (excludes azathioprine,
cyclosporine, minocycline and goldb). It does not include tofacitinib,
which is considered separately.
- DMARD monotherapy
- Most often defined as the use of MTX monotherapy, but may also be SSZ, HCQ, or LEF
- Double DMARD therapy
- MTX SSZ, MTX HCQ, SSZ HCQ, or combinations with LEF
- Triple DMARD therapy
- MTX SSZ HCQ
- DMARD combination therapy
- Double or triple traditional/conventional DMARD therapy
- Oral synthetic small molecule
- TNFi biologic or non-TNF biologic (excludes anakinraa)
- Low dose glucocorticoid
- â¤10 mg/day of prednisone (or equivalent).
- High dose glucocorticoid
- >10 mg/day of prednisone (or equivalent) and â¤60 mg/day with a rapid taper
(e.g., COBRA regimen6)c
- Short-term glucocorticoid
- <3 month treatment
a Anakinra was considered but not included in these guidelines due to its infrequent use in RA and lack of new data since 2012.
b Azathioprine, cyclosporine, minocycline and gold were considered but not included in these guidelines due to their infrequent use in RA and/or lack of new data since 2012.
c Regimen based on that described in the Combinatietherapie Bij Ruematoide Artritis (COBRA).5
Table 3. Instruments to Measure Rheumatoid Arthritis Disease Activity and to Define Remissiona
|Patient Activity Scale (PAS) or PASII7||Remission: 0â0.25|
Low activity: >0.25â3.7
Moderate activity: >3.7â<8.0
High activity: â¥8.0
|Routine Assessment of Patient Index Data 3 (RAPID3)8||Remission: 0â1.0|
Low activity: >1.0â2.0
Moderate activity: >2.0â4.0
High activity: >4.0â10
|Clinical Disease Activity Index (CDAI)9||Remission: â¤2.8|
Low activity: >2.8â10.0
Moderate activity: >10.0â22.0
High activity: >22
|Disease Activity Score (DAS) 28|
erythrocyte sedimentation rate (ESR)10, b
Low activity: â¥2.6â<3.2
Moderate activity: â¥3.2ââ¤5.1
High activity: >5.1
|Simplified Disease Activity Index (SDAI)11||Remission: â¤3.3|
Low activity: >3.3ââ¤11.0
Moderate activity: >11.0ââ¤26
High activity: >26
a These six measures were endorsed by the ACR in 2012. Other measures are now available to clinicians, but they were not included in this guideline because it was beyond the scope of this review.
b Adapted from Anderson J et al.1
Table 4. Recommendations for Patients with Symptomatic Early RA
|Recommendations||Level of Evidence|
1. Regardless of disease activity level, use a treat-to-target strategy rather than a non-targeted approach.
2. If the disease activity is low, in patients who have never taken a DMARD:
3. If the disease activity is moderate or high, in patients who have never taken a DMARD:
4. If disease activity remains moderate or high despite DMARD monotherapy (with or without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with or without MTX, in no particular order of preference), rather than continuing DMARD monotherapy alone.
5. If disease activity remains moderate or high despite DMARDs:
6. If disease activity remains moderate or high despite DMARD or
|biologic therapies, add low-dose glucocorticoids.||Low|
7. If disease flares, add short-term glucocorticoids at the lowest possible dose and for the shortest possible duration.
|See Table 9 for explanation of the Green and bolded and Yellow and italicized recommendations.|
Table 5. Recommendations for Patients with Established RAa
|Recommendations||Level of Evidence|
1.Regardless of disease activity level, use a treat-to-target strategy rather than a non-targeted approach.
2.If the disease activity is low, in patients who have never taken a DMARD, use DMARD monotherapy (MTX preferred) over a TNFi.
3. If the disease activity is moderate or high in patients who have never taken a DMARD:
4. If disease activity remains moderate or high despite DMARD monotherapy, use combination traditional DMARDs or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without MTX, in no particular order of preference), rather than continuing DMARD monotherapy alone.
|Moderate to Very Low|
5. If disease activity remains moderate or high despite TNFi therapy in patients who are currently not on DMARDs, add one or two DMARDs to TNFi therapy rather than continuing TNFi therapy alone.
6. If disease activity remains moderate or high despite use of a single TNFi:
|Low to Very Low|
8. If disease activity remains moderate or high despite use of multiple (2 ) sequential TNFi therapies, first use a non-TNF biologic, with or without methotrexate, over another TNFi or tofacitinib (with or without methotrexate).
9. If the disease activity still remains moderate or high despite the use of multiple TNFi therapies, use tofacitinib, with or without methotrexate, over another TNFi, with or without methotrexate, if use of a non-TNF biologic is not an option.
10. If disease activity remains moderate or high despite use of at least one TNFi and at least one non-TNF-biologic:
11. If disease activity remains moderate or high despite use of DMARD, TNFi, or non-TNF biologic therapy, add short-term, low dose glucocorticoid therapy.
|High to Moderate|
12. If disease flares in patients on DMARD, TNFi, or non-TNF biologic therapy, add short-term glucocorticoids at the lowest possible dose and the shortest possible duration.
13. If the patient is in remission:
14. If disease activity is low:
15. If the patientâs disease is in remission, DO NOT discontinue all RA therapies.
|see Table 9 for explanation of the Green and bolded and Yellow and italicized recommendations.|
a The definition of established RA is based on the 1987 ACR RA Classification criteria,2 since the 2010 ACR/EULAR RA classification allows classification of a much earlier disease state.3
b No studies were available, leading to very low quality evidence, and the recommendation was based on clinical experience.
c Tapering means scaling back therapy (reducing dose or dosing frequency), not discontinuing it. Tapering should be considered an option and not be mandated. If done, tapering must be conducted slowly and carefully, watching for increased disease activity and flares. Even for RA patients whose RA is in remission, there is some risk of flare when tapering.
d Evidence is rated low quality or moderate to very low quality because some evidence reviewed for this recommendation was indirect and included studies with discontinuation rather than tapering of therapy or since studies involved patients achieving low disease activity rather than remission.