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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

General principles and overview of management of

rheumatoid arthritis in adults
Authors: Larry W Moreland, MD, Amy Cannella, MD, MS, RhMSUS
Section Editor: James R O'Dell, MD
Deputy Editor: Philip Seo, MD, MHS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Mar 07, 2023.

INTRODUCTION

Management strategies for patients with rheumatoid arthritis (RA) are directed toward the
control of synovitis and the prevention of joint injury. Treatment approaches aim to achieve and
maintain remission or low disease activity by use of disease-modifying antirheumatic drug
(DMARD) therapy that is initiated early in the disease course. Common principles that guide
management have been developed based upon evidence from randomized trials and other
studies and from an increasing but incomplete understanding of the disease. (See
"Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and
"Pathogenesis of rheumatoid arthritis".)

The general principles and treatment strategies that should be applied to the management of
RA are reviewed here. The initial therapy of RA and the treatment of patients resistant to initial
and subsequent DMARDs are discussed in detail elsewhere. (See "Initial treatment of
rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of
rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to
initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid
arthritis in adults resistant to initial biologic DMARD therapy".)

GENERAL PRINCIPLES

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Our approach to treatment involves the timely and judicious use of several types of therapeutic
interventions and is based upon general principles that have been widely accepted by major
professional organizations and other expert groups [1-7]. The application of these principles
has resulted in significant improvements in treatment outcomes since the 1980s; such progress
may owe even more to the therapeutic strategies that have been adopted than to the
development and use of newer and more potent drugs [8].

These general principles, discussed in greater detail below, include:

● Early recognition and diagnosis (see 'Early recognition and diagnosis' below)
● Care by an expert in the treatment of rheumatic diseases, such as a rheumatologist (see
'Care by a rheumatologist' below)
● Early use of disease-modifying antirheumatic drugs (DMARDs) for all patients diagnosed
with rheumatoid arthritis (RA) (see 'Early use of DMARDs' below)
● Efforts toward tight control, utilizing a treat-to-target strategy, with a goal of remission or
low disease activity (see 'Tight control' below)
● Use of antiinflammatory agents, including nonsteroidal antiinflammatory drugs (NSAIDs)
and glucocorticoids, only as adjuncts to DMARD therapy (see 'Adjunctive role of
antiinflammatory agents' below)

MANAGEMENT STRATEGIES

Early recognition and diagnosis — Achieving the benefits of early intervention with disease-
modifying antirheumatic drugs (DMARDs) depends upon making the diagnosis of rheumatoid
arthritis (RA) as early as possible, before irreversible injury has occurred [5,8-10]. The diagnosis
and differential diagnosis of RA are reviewed in detail separately. (See "Diagnosis and
differential diagnosis of rheumatoid arthritis".)

Persistent synovial inflammation, which is associated with a proliferative and destructive

process in joint tissues, can lead to significant and irreversible joint injury as early as during the
first two years of disease. (See 'Early use of DMARDs' below and "Pathogenesis of rheumatoid
arthritis".)

Care by a rheumatologist — Patients with inflammatory arthritis who are suspected of RA and
those diagnosed with it benefit from ongoing care by an expert in the rheumatic diseases, such
as a rheumatologist [11,12]. Early and ongoing care of such patients by a rheumatologist,
compared with care rendered primarily by other clinicians, is associated with better disease
outcomes, including reduced joint injury and less functional disability [13-18].

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The initial rheumatology consultation allows the diagnosis to be made or reassessed, the
severity of disease to be estimated, and a plan of care to be developed and initiated. The
frequency of subsequent specialist care depends upon the severity of symptoms and joint
inflammation, the patient's response to treatment, the complexity of and risks associated with
the therapy, the preferences of the patient and primary care clinician, and the availability of
such care.

Early use of DMARDs — We suggest that all patients diagnosed with RA be started on disease-
modifying antirheumatic drug (DMARD) therapy as soon as possible, consistent with the
recommendations of major professional organizations [3,6]. There is widespread expert
consensus regarding this approach, which is based upon a number of observational studies
and a more limited number of randomized trials [3,6,9,19-25]. Our choice of drug therapies in
patients with RA and the evidence supporting these choices are described in detail separately.
(See 'Choice of therapy' below and "Initial treatment of rheumatoid arthritis in adults" and
"Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults".)

Much of the joint damage that ultimately results in disability begins early in the course of the
disease [26,27]. As an example, in a study from 1989, more than 80 percent of patients with RA
of less than two years' duration had joint space narrowing on plain radiographs of the hands
and wrists, while two-thirds had erosions [27]. The use of more sensitive imaging techniques,
such as magnetic resonance imaging (MRI) and high-resolution ultrasonography, can identify
even earlier damage than that which is recognized by radiography [28-30].

Better outcomes are achieved by early compared with delayed intervention with DMARDs in
patients with RA [9,19-25]. Some evidence suggests that the effect upon outcomes is not linear
with time, and that there may be an early "window of opportunity" for optimal DMARD
treatment benefit [25]. As examples:

● Disability is greater in patients for whom therapy is delayed. One study in Texas found that
low socioeconomic status (SES) was associated with a substantial delay in starting DMARD
therapy; and both the delay and low SES were independently associated with greater
disease activity, joint damage, and physical disability [24].

● There may be a limited period of several months following symptom onset during which
RA is most susceptible to intervention with DMARDs. The effect on the likelihood of
DMARD-free sustained remission of symptom duration prior to DMARD therapy was
examined in two large European cohorts [25]. The symptom durations that optimally
discriminated between greater and lesser likelihood of remission were between 11.4 and

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19.1 weeks, depending upon the cohort and whether patients were anti-citrullinated
peptide antibody (ACPA) positive.

● Response rates to drug intervention decrease over time. An observational study of 1435
patients involved in 14 trials, primarily of methotrexate (MTX) or other nonbiologic
DMARDs, found a progressive decrease in the likelihood of a significant response to
DMARD therapy with increasing disease duration [19]. Response rates were higher in
patients with no more than one year of disease than in those with one to two years of
disease, and response rates were lowest in the group with greater than 10 years of
disease (53 versus 43 versus 35 percent).

Tight control — Tight control treatment strategies help to quickly minimize inflammation and
disease progression; our therapeutic target is remission or a state of minimal disease activity,
without compromising safety. As an example, in patients resistant to initial DMARD therapy (eg,
MTX), we usually treat with a combination of DMARDs (eg, MTX plus sulfasalazine [SSZ] and
hydroxychloroquine [HCQ] or MTX plus a tumor necrosis factor [TNF] inhibitor), while also
treating the active inflammation with antiinflammatory drug therapy. In patients with disease
exacerbations despite a preceding period of better control of disease activity (a "disease flare"),
a temporary increase in antiinflammatory therapies, including the use of glucocorticoids, may
be required (see 'Drug therapy for flares' below). A description of our treatment approach and
the evidence supporting use of particular medications in patients with active disease despite
initial DMARD therapy are discussed in detail separately. (See "Treatment of rheumatoid
arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Tight control strategies involve frequent periodic reassessment of disease activity using a
quantitative composite measure, usually at least every three months; adjustment of DMARD
regimens every three to six months, if needed, as the primary tool to achieve treatment goals;
and administration of antiinflammatory therapies (eg, nonsteroidal antiinflammatory drugs
[NSAIDs] and oral and intraarticular glucocorticoids) as an adjunct to DMARDs as bridging
therapies to maintain control of disease activity until DMARD therapies are sufficiently effective
to discontinue glucocorticoids or reduce their use to an acceptably low level. Treatment
protocols based upon this general approach are associated with improved radiographic and
functional outcomes compared with less aggressive approaches [5,31-40]. (See 'Assessment and
monitoring' below and 'Adjunctive role of antiinflammatory agents' below.)

This approach is supported by American College of Rheumatology (ACR) and European Alliance
of Associations for Rheumatology (EULAR; formerly known as European League Against
Rheumatism) treatment recommendations and in the recommendations of an international
task force that were presented in 2010 and updated in 2021 [1,2,5,6,11,40-45].
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● Efficacy of treat-to-target strategy – The treat-to-target strategy, more than the specific
agents used, results in better outcomes for patients with RA [46]. A number of randomized
trials and related studies illustrate the range of medications and approaches that
demonstrate the efficacy of a treat-to-target approach, with excellent treatment responses
being achieved with a wide variety of nonbiologic and biologic DMARDs and with
regimens that combine either nonbiologic DMARDs alone or nonbiologic DMARDs with a
biologic agent [31-37,47-49].

The benefits of tight control have been shown in a meta-analysis of six heterogeneous
trials that evaluated tight control strategies in comparison with usual care for RA [50].
Greater improvement from baseline to one year in the Disease Activity Score derivative for
28 joints (DAS28) composite measure of disease activity was seen in the patients randomly
allocated to tight control strategies compared with usual care (mean difference in
reduction in DAS28 of 0.59, 95% CI 0.22-0.97). A greater reduction compared with usual
care was observed in the trials in which tight control was achieved with protocolized
treatment adjustments compared with trials without such protocols (mean difference in
DAS28 of 0.91, 95% CI 0.72-1.11, versus 0.25, 95% CI 0.03-0.46). Four of the six trials
analyzed compared functional ability in the two treatment arms using the Health
Assessment Questionnaire (HAQ). Greater improvement in HAQ scores in the tight control
groups were seen in two of these trials, while improvements in the HAQ scores did not
differ significantly between the treatment arms in the other two trials. (See "Assessment of
rheumatoid arthritis disease activity and physical function", section on 'Health Assessment
Questionnaire (HAQ)'.)

Examples of individual trials supporting this approach include the BehandelStrategieën

voor Reumatoïde Artritis (Dutch for "treatment strategies for rheumatoid arthritis" or
BeSt) trial [31,32]; the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial
[34-36,47]; the New Finnish Rheumatoid Arthritis Combination Therapy (NEO-RACo) trial
[48]; the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial [49]; and the Tight
Control of Rheumatoid Arthritis (TICORA) trial [37].

● Role of imaging to detect joint injury and/or inflammatory disease activity – The use
of sensitive imaging techniques, including either MRI or musculoskeletal ultrasound
(MSUS), may be better than the clinical exam for diagnosing joint involvement and
predicting disease relapse [51]. However, these imaging modalities do not appear to
provide greater clinical benefit and may be associated with increased adverse effects and
potentially with greater cost [52-54]. As an example, in a randomized trial involving 200
patients in clinical remission on conventional DMARDs, patients assigned to receive

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protocol-driven treatment adjustments every four months that were guided by MRI
imaging (for bone marrow edema) plus composite clinical assessments had similar clinical
and radiographic outcomes at two years compared with those guided by the clinical
assessments alone [52]. Treatment escalation was more frequent in the MRI-driven group
(73 versus 17 percent), with more of these patients receiving biologic agents (46 versus 2
percent). Serious adverse events occurred in 17 percent of the MRI group and 6 percent of
the conventional treat-to-target group. Similarly, in other studies, a lack of additional
benefit from using MSUS to guide therapy in patients with early RA has also been
described [53,54].

● Other considerations in the selection of treatment targets – Although the focus of

therapeutic decision-making is control of disease activity, additional factors, such as the
degree of joint injury or disability, may influence the choice of specific therapies in
individual patients [2,55]. Additionally, the efficacy of particular medications may be
affected by the presence or absence of comorbidities and other factors. (See
'Comorbidities and disease management' below and 'Prognosis' below.)

We consider the following factors, depending upon the specific treatment decision:

• Disability and function – General scales that measure disability may not identify
specific limitations of greater impact on an individual patient. As an example, specific
vocational requirements, family responsibilities, or recreational interests may affect a
patient's willingness to accept the risks of a given intervention that would help to
achieve a greater degree of disease control than low disease activity. We therefore
incorporate patient-specific needs in our assessment of the severity of disease-related
disability.

• Comorbidities – The presence of comorbidities, such as renal or hepatic disease, may

affect medication choices and may influence the degree of risk inherent in attempting
to reach a goal of remission or of low disease activity in a given patient. (See
'Comorbidities and disease management' below.)

• Joint damage – Good clinical control of disease activity may not result in complete
elimination of progressive joint injury in all patients. In patients with low disease
activity but with worsening joint injury on imaging studies, either changes in
medications or increased dosing may be of benefit. However, there is insufficient
evidence to determine whether treating to targets that are based upon imaging
findings of joint damage alone provides additional benefit for long-term outcomes,
compared with targets based upon measures of disease activity alone.

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NONPHARMACOLOGIC THERAPIES

A number of nonpharmacologic measures are important in the comprehensive management of

rheumatoid arthritis (RA) in all stages of disease. Briefly, these measures include:

● Patient education regarding RA and its management

● Psychosocial interventions
● Rest, exercise, and physical and occupational therapy
● Nutritional and dietary counseling

These therapies are discussed in detail separately. (See "Nonpharmacologic therapies for
patients with rheumatoid arthritis".)

PHARMACOLOGIC THERAPY

Pretreatment evaluation — Prior to starting, resuming, or a significant dose increase of

therapy with any nonbiologic, targeted synthetic (small molecule), or biologic disease-modifying
antirheumatic drug (DMARD), we do the following baseline studies [3,41]:

● General testing for all patients – Baseline complete blood count, serum creatinine,
aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). In
patients receiving interleukin 6 (IL-6) inhibitors and Janus kinase (JAK) inhibitors, lipids are
also monitored.

● Hepatitis virus screening – In all patients without a known history of hepatitis, we screen
for hepatitis B and C before initiating therapy with conventional DMARDs, including
methotrexate (MTX) and leflunomide (LEF); biologic DMARDs; and JAK inhibitors.

• Hepatitis B – We obtain testing for hepatitis B virus (HBV) surface antigen (HBsAg) and
HBV core antibody (HBc) prior to initiating these drugs and prior to treatment with
prednisone at doses of ≥20 mg daily. Some patients may require antiviral treatment
prior to initiating DMARD or immunosuppressive therapy, depending upon their level
of risk for HBV reactivation. (See "Hepatitis B virus reactivation associated with
immunosuppressive therapy".)

• Hepatitis C – Although we perform such testing in all patients without a known history
of hepatitis, some experts limit screening for hepatitis C to patients at increased risk of
hepatitis, such as those who have a history of intravenous drug abuse, have had
multiple sex partners in the previous six months, or who are health care workers [3,41].
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● Ophthalmologic screening for hydroxychloroquine use – A complete baseline

ophthalmologic examination should be performed within the first year of treatment with
hydroxychloroquine (HCQ), including examination of the retina through a dilated pupil and
automated visual field testing. Our approach to screening and subsequent monitoring for
ocular toxicity is described in detail separately. (See "Antimalarial drugs in the treatment of
rheumatic disease", section on 'Routine eye examinations'.)

● Testing for latent tuberculosis – We screen for latent tuberculosis (TB), consistent with
the Centers for Disease Control and Prevention (CDC) and 2015 American College of
Rheumatology (ACR) guidelines, with skin testing or an interferon-gamma release assay
prior to all biologic DMARDs and prior to use of a JAK inhibitor; such screening is based
upon evidence that these medications, including the tumor necrosis factor (TNF)
inhibitors, other biologics, and JAK inhibitors, may increase the risk of mycobacterial
infection [3,56,57].

Interferon-gamma release assays can be used in place of tuberculin skin testing in the
United States, according to CDC recommendations, and may be preferred in patients who
have previously received vaccination with Bacillus Calmette-Guerin (BCG). However, in
some countries, tuberculin skin testing is preferred. (See "Use of interferon-gamma
release assays for diagnosis of latent tuberculosis infection (tuberculosis screening) in
adults".)

We obtain a chest radiograph in patients with a history of other risk factors for latent TB,
even if screening tests are negative, given the risks of false-negative testing. Additionally,
screening should be repeated in patients with new TB exposures. Glucocorticoids and
other factors may cause false-negative results. Screening for latent TB is discussed in
detail separately. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial
infections" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to
diagnosis (screening)".)

Pretreatment interventions

● Interventions to reduce risks of cardiovascular disease – Strategies for cardiovascular

risk reduction (eg, smoking cessation and management of dyslipidemia) are described in
detail separately. (See "Overview of smoking cessation management in adults" and
"Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical
manifestations, and diagnostic implications" and "Coronary artery disease in rheumatoid
arthritis: Implications for prevention and management".)

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● Immunizations – Immunization with appropriate vaccines is indicated to decrease risk of

infectious complications of immunosuppressive therapies and disease-associated
immunosuppression and is described in detail separately. (See "Immunizations in
autoimmune inflammatory rheumatic disease in adults".)

Choice of therapy — Our specific drug choices for patients with rheumatoid arthritis (RA) and
the evidence supporting these choices are described in detail separately. (See "Initial treatment
of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of
rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to
initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid
arthritis in adults resistant to initial biologic DMARD therapy".)

● Factors affecting drug choices – Choices between treatment options are based upon
multiple factors, including:

• Level of disease activity (eg, mild versus moderate to severe)

• Presence of comorbid conditions
• Stage of therapy (eg, initial versus subsequent therapy in patients resistant to a given
intervention)
• Regulatory restrictions (eg, governmental or health insurance company coverage
limitations)
• Patient preferences (eg, route and frequency of drug administration, monitoring
requirements, personal cost, fertility planning)
• Presence of adverse prognostic signs

● DMARDs – Drugs classified as disease-modifying antirheumatic drugs (DMARDs), which all

have the potential to reduce or prevent joint damage and to preserve joint integrity and
function, include:

• Nonbiologic (traditional or conventional) DMARDs, including MTX, HCQ, sulfasalazine

(SSZ), and LEF. (See "Initial treatment of rheumatoid arthritis in adults" and
"Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in
adults".)

• Biologic DMARDs, which are produced by recombinant deoxyribonucleic acid (DNA)

technology and generally target cytokines or their receptors or are directed against
other cell surface molecules. These include anticytokine therapies, such as the TNF-
alpha inhibitors etanercept, infliximab, adalimumab, golimumab, and certolizumab
pegol; and the IL-6 receptor antagonists tocilizumab and sarilumab. They also include
other biologic response modifiers such as the T-cell costimulation blocker abatacept
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(CTLA4-Ig) and the anti-CD20 B-cell depleting monoclonal antibody rituximab. (See
"Overview of biologic agents in the rheumatic diseases" and "Treatment of rheumatoid
arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD
therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic
DMARD therapy".)

• Targeted synthetic DMARDs, including several JAK inhibitors, which are available for
use in RA and other disorders in the United States and several other countries. These
include tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib, which are orally
administered small molecule DMARDs that inhibit cytokine and growth factor signaling
through interference with JAKs. (See "Treatment of rheumatoid arthritis in adults
resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and
"Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD
therapy".)

● Approach to drug therapy – Briefly, we take the following approach:

• In patients with active RA, we initiate antiinflammatory therapy with either a

nonsteroidal antiinflammatory drug (NSAID) or glucocorticoid, depending upon the
degree of disease activity, and generally start DMARD therapy with MTX. NSAIDs and
systemic and intraarticular glucocorticoids can act rapidly to reduce disease activity,
while DMARDs, including MTX, may take weeks to months to achieve optimal effects.
(See "Initial treatment of rheumatoid arthritis in adults" and 'Adjunctive role of
antiinflammatory agents' below.)

Patients unable to take MTX may require an alternative agent, such as HCQ, SSZ, or LEF.
(See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in
adults".)

• In patients resistant to initial DMARD therapy (eg, MTX), we usually treat with a
combination of DMARDs (eg, MTX plus SSZ and HCQ, or MTX plus a TNF inhibitor), while
also treating the active inflammation with antiinflammatory drug therapy. The 2021
ACR recommendations conditionally recommend the addition of a biologic or targeted
synthetic DMARD in these patients, although they acknowledged that the safety issues
reported with JAK inhibitors may require a modification of this recommendation. (See
"Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic
(nonbiologic) DMARD therapy".)

• In patients resistant to initial or subsequent combination therapy or subsequent

treatment that includes a biologic or targeted synthetic DMARD (ie, a JAK inhibitor), we
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switch to an alternative biologic or targeted synthetic DMARD. Treatment with

antiinflammatories may also be required in such patients. (See "Treatment of
rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

Our approach to therapy is generally consistent with that of major professional

organizations, including the ACR and the European Alliance of Associations for
Rheumatology (EULAR) [1,4,6,11,41,44].

Assessment and monitoring

Overview of assessment and monitoring — Patients should be seen on a regular basis for
clinical and laboratory monitoring of disease and for screening for drug toxicities. The initial
evaluation and subsequent periodic monitoring should also include a quantitative composite
measure of disease activity. The use of periodic structured assessments of disease activity is
complementary to the ongoing regular monitoring of disease manifestations, including
extraarticular manifestations and complications of the disease; disease progression and joint
injury, including use of selected imaging studies; and functional status and disability. (See
'Clinical assessment of disease and related testing' below and 'Structured measures of disease
activity and functional status' below and 'Drug monitoring and prevention of drug toxicity'
below.)

Clinical assessment of disease and related testing — Patients should be seen at regular
intervals that vary with disease activity and severity. As an example, patients starting new
medications or with severely active disease may be seen at one- to two-month intervals, while
those with mildly active or well-controlled disease could be seen every three to six months, with
appropriate laboratory monitoring in the interim. Clinical assessment includes the following
major elements:

● Patient history – Patients should be questioned regarding the degree of joint pain, the
duration of morning stiffness, and the severity of fatigue [41,58]. In addition, evidence for
and changes in extraarticular manifestations of RA should be actively sought, including
systemic signs such as fever, anorexia, malaise, weight loss, and symptoms of ocular,
pulmonary, and cardiovascular disease. Because fever is not a common feature of RA in
adults, infection should be excluded before ascribing fever to RA. (See "Clinical
manifestations of rheumatoid arthritis".)

Patients should be queried regarding their functional capacity, including the performance
of activities of daily living; vocational activities; and avocational activities, such as hobbies
or participation in sports. Serial use of a self-report questionnaire that measures function
is helpful for this purpose (see 'Structured measures of disease activity and functional
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status' below). Functional assessment also helps to identify therapeutic needs for
additional interventions such as counseling, exercise, and occupational therapy. (See
"Nonpharmacologic therapies for patients with rheumatoid arthritis".)

● Physical examination – A detailed musculoskeletal exam and a general physical exam are
part of the periodic clinical assessment. Changes in previously affected joints or the
appearance of inflammation in previously uninvolved joints should be assessed. A 28-joint
examination is appropriate if the hands but not the feet are involved [59]. Examined joints
include the wrists, elbows, shoulders, and knees, as well as the metacarpophalangeal and
proximal interphalangeal joints of the hands. If the feet are involved, the
metatarsophalangeal joints and proximal interphalangeal joints of the feet should also be
assessed. The joints should be evaluated for the presence of swelling, tenderness, loss of
motion, and deformity.

In addition to the articular examination, a periodic general physical examination should be

performed, with particular attention to the skin for rheumatoid nodules or other dermal
manifestations of RA and to the lungs for signs of pleural or interstitial disease, to detect
evidence of systemic or extraarticular involvement. (See "Overview of the systemic and
nonarticular manifestations of rheumatoid arthritis".)

● Laboratory monitoring of disease activity – The acute phase reactants, such as CRP or
ESR, are useful for assessment of disease activity and are components of several of the
formal composite measures used for evaluating the level of disease activity (see
'Structured measures of disease activity and functional status' below). In addition to these
studies, we obtain other tests primarily for medication monitoring that may also reflect
changes or levels of disease activity (see 'Drug monitoring and prevention of drug toxicity'
below). Examples of the latter include serum hemoglobin, decreases in which may reflect
anemia of chronic inflammation, and serum albumin, which may also be reduced in
association with increased disease activity. Additionally, platelet counts may be mildly
elevated (typically up to 400,000 to 450,000/microL) in patients with ongoing
inflammation. (See "Hematologic complications of rheumatoid arthritis".)

● Imaging

• Plain radiography – Early in the course of RA, we obtain plain radiographs of the
hands and wrists (one film, posteroanterior [PA] view), as well as at least one
anteroposterior (AP) view of both forefeet to include the metatarsophalangeal joints.
These radiographs serve as a baseline for evaluating change in the joints during
treatment.

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Radiographs may be repeated when needed to guide clinical decisions but are not
advocated on a routine basis for asymptomatic patients. We view the therapy in use by
the patient as insufficient if radiologic evidence of disease progression, such as
periarticular osteopenia, joint space narrowing, or bone erosions, appears or worsens
from baseline and may intensify or modify the treatment regimen. Coexistent
osteoarthritis may also account, in part, for joint space narrowing near the joints
involved with RA in older patients [60].

• Ultrasonography and MRI – We prefer to use musculoskeletal ultrasound (MSUS) and

MRI to answer specific clinical questions in an individual patient but not in the routine
management of RA. MSUS and MRI are more sensitive for the detection of cartilage
and bone abnormalities and can reveal subclinical inflammation [61,62]. However, use
of these techniques for routine monitoring does not result in improved outcomes (see
'Tight control' above). Nonetheless, some clinicians routinely employ MSUS and MRI to
follow patients and to detect early changes.

Structured measures of disease activity and functional status — Effective implementation

of tight control strategies involves reassessment of disease activity on a regularly planned basis
with the use of quantitative composite measures to facilitate timely adjustment of treatment
regimens as part of a treat-to-target approach (see 'Tight control' above). Measurement of
functional status is also of particular value.

● Disease activity measures – Several disease activity measures have been identified by
the ACR as being preferred options to choose from for this purpose in clinical practice [63]:

• Disease Activity Score derivative for 28 joints (DAS28) with the ESR (calculator 1)
• DAS28 with the CRP (calculator 2)
• Simplified Disease Activity Index (SDAI) (calculator 3)
• Clinical Disease Activity Index (CDAI) (calculator 4)
• Routine Assessment of Patient Index Data 3 (RAPID3) [64]
• Patient Activity Scale (PAS) II [65]

The choice between these measures is based upon clinician preference. The RAPID3 and
PAS-II require only patient-reported data, and the CDAI includes patient and provider data.
All of the measures accurately reflect disease activity; are sensitive to change; discriminate
well between low, moderate, and high disease activity; have remission criteria; and are
feasible to perform in clinical settings [63,66]. These and other activity measures,
including instruments used in clinical research, are described in detail separately. (See
"Assessment of rheumatoid arthritis disease activity and physical function".)

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● Functional status assessment measures – As a complement to the medical history and

inferences drawn from clinical assessment, functional status can be quantitatively
assessed and followed by use of patient-reported functional status assessment measures.
A number of these are available and have been used in both clinical practice and for
research purposes. The ACR has identified three measures as those options most
appropriate to choose from for routine clinical use. These include [67]:

• Physical function 10-item short form (Patient-Reported Outcomes Measurement

Information System physical function 10-item short form [PROMIS PF10a])
• Health assessment questionnaire (HAQ) II
• Multidimensional HAQ

Functional assessment and measures used for this purpose are discussed in more detail
separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section
on 'Functional capacity' and "Assessment of rheumatoid arthritis disease activity and
physical function", section on 'Assessment of physical function'.)

Drug monitoring and prevention of drug toxicity — Because of the potential risks of serious
adverse effects and the frequency of common side effects of antirheumatic drugs, a careful
balance must be struck between the risks and potential benefits of these agents [68,69]. We
generally follow the recommendations of the ACR for drug monitoring in the treatment of RA
( table 1) [1,3,41,58,70], which are also consistent with the recommendations of other experts
[71]. Additional precautions, warnings, and the manufacturer's recommendations for clinical
and laboratory monitoring are provided in the individual UpToDate drug information topics for
each medication. (See appropriate topic reviews.)

Monitoring for adverse effects, such as osteoporosis, diabetes, and hypertension, should be
performed in patients on glucocorticoids, and appropriate preventive measures should be
undertaken. RA is considered an independent risk factor for osteoporotic fracture (see
"Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on
'Osteopenia'), and a fracture risk assessment should be performed to help guide treatment
decisions. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and
"Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk' and "Major
side effects of systemic glucocorticoids".)

Adjunctive therapies and flare management

Adjunctive role of antiinflammatory agents — We use antiinflammatory therapies,

including systemic and intraarticular glucocorticoids and NSAIDs, primarily as adjuncts for
temporary control of disease activity in patients starting or changing DMARDs and in patients
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who are experiencing disease flares (see 'Drug therapy for flares' below). Although these agents
act rapidly to control inflammation, they do not provide adequate benefit on their own for
longer-term control of disease or prevention of joint injury. We taper glucocorticoids as rapidly
as tolerated once disease control is achieved and can be maintained, with the ideal goal of
discontinuing systemic glucocorticoid therapy.

Glucocorticoids can retard radiographic progression in patients with RA in the short to medium
term (ie, up to two years of therapy), but we avoid long-term use, when possible, because
chronic use for inflammatory disease is often associated with adverse effects. However, some
patients with severe RA require sustained therapy with low doses of glucocorticoids (less than
10 mg/day) together with DMARD therapy; such doses in RA are generally well tolerated and
may also have some benefit in retarding disease progression. More detailed discussions of
NSAIDs and glucocorticoids in RA, including the evidence supporting their use, are presented
elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial
treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with
antiinflammatory drugs'.)

Intraarticular injections of long-acting glucocorticoids are used to reduce synovitis in particular

joints that are more inflamed than others. Occasional patients benefit from intramuscular
rather than oral administration. (See "Intraarticular and soft tissue injections: What agent(s) to
inject and how frequently?" and "Use of glucocorticoids in the treatment of rheumatoid
arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic
treatment with antiinflammatory drugs'.)

Drug therapy for flares — RA has natural exacerbations (also known as flares) and reductions
of continuing disease activity. It is important to distinguish a disease flare, characterized by
symptoms and by physical and laboratory findings of increased inflammatory synovitis, from
noninflammatory causes of local or generalized increased pain. Patients with recurrent flares
may require adjustment in the background DMARD therapy. (See "Clinical manifestations of
rheumatoid arthritis".)

The severity of the flare and background drug therapy influence the choice of therapies. The
following is a brief summary of glucocorticoid therapy, which is discussed in detail separately.
(See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

With respect to the severity of the flare:

● In patients with a single or few affected joints, intraarticular glucocorticoid injections may
be effective and avoid the need for additional or prolonged systemic therapy.

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● More widespread flares may be treated by initiating glucocorticoid therapy or by

increasing the dose of oral glucocorticoid, with the intention of reducing the dose once
the flare is under control. The magnitude of dose increase varies with the baseline dose
and severity of the flare. An alternative to an increase in the oral dose is the administration
of a single deep intramuscular injection of methylprednisolone acetate (120 mg in 3 mL)
or triamcinolone acetonide (60 mg in 1.5 mL).

● Pulse intravenous methylprednisolone therapy, usually consisting of three daily infusions

of up to 1000 mg, is generally limited to severe flares, particularly those associated with
systemic manifestations, such as rheumatoid vasculitis.

With respect to background drug therapy, an escalation in dose or a modification in drugs is

warranted if the patient is flaring frequently or severely. The strategy depends upon the
background DMARDs being used. As examples:

● Patients on MTX who will tolerate a slower resolution of their flare may respond to
optimization of the MTX dose by either an increase in the dose of MTX or switching from
oral to subcutaneous therapy [72]. (See "Use of methotrexate in the treatment of
rheumatoid arthritis", section on 'Dosing and administration'.)

● Patients initially controlled with a regimen that includes infliximab may benefit from a
decrease in the interval between infliximab doses or from higher doses [73,74]. However,
increasing the dose from 3 to 5 mg/kg was not beneficial in one well-designed trial [75,76].

● Increases in doses of etanercept (greater than 50 mg weekly) or adalimumab (weekly

rather than every two weeks), with or without MTX, do not appear to increase efficacy
[77,78].

Patients who require multiple treatment courses with glucocorticoids for recurrent disease
flares and whose medication doses have been increased to the maximally tolerated or
acceptable level should be treated as patients with sustained disease activity. (See "Treatment
of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD
therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD
therapy".)

Use of analgesics — Drugs that primarily or only provide analgesia, including topical
medications (eg, capsaicin) and oral agents, such as acetaminophen (paracetamol), tramadol,
and more potent opioids (eg, oxycodone, hydrocodone), have a limited role in most patients
with active disease but may be helpful in patients with end-stage disease and, occasionally, in
patients with more severe involvement or during disease flares for added temporary benefit.
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These medications should not be used as the sole or primary therapy in patients with active
inflammatory disease. An additional concern regarding opioid analgesics is an increased risk of
hospitalization for serious infection, which has been associated with their use by patients with
RA and may be due to impairment of certain immune functions by these agents [79].

Apparent need for additional analgesic medications when inflammatory disease is well
controlled (other than acetaminophen or occasional NSAIDs) should prompt a search for
alternative comorbid diagnoses, such as fibromyalgia, to explain the patient's symptoms. (See
"Clinical manifestations and diagnosis of fibromyalgia in adults" and "Overview of chronic
widespread (centralized) pain in the rheumatic diseases".)

Extraarticular disease — RA has many extraarticular manifestations. The treatment of these

specific features, such as vasculitis, interstitial lung disease (ILD), and others, is reviewed in
detail elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid
arthritis".)

Therapy of end-stage disease — Despite therapeutic intervention, some patients progress to

disabling, destructive joint disease. Symptoms in such patients may be present in the absence
of active inflammatory joint disease and may be due to the secondary degenerative changes
alone. The evaluation and management of patients with apparent end-stage RA are discussed
in detail separately. (See "Evaluation and medical management of end-stage rheumatoid
arthritis".)

The indications for surgical intervention in patients with RA include intractable pain or severe
functional disability due to joint destruction, as well as impending tendon rupture. The timing
of surgery and other important issues relating to joint replacement in RA are discussed
separately. (See "Total joint replacement for severe rheumatoid arthritis".)

COMORBIDITIES AND DISEASE MANAGEMENT

A number of medical conditions that often coexist with or result from rheumatoid arthritis (RA)
may influence the choice of medications; our approach is consistent with expert opinion,
including the American College of Rheumatology (ACR) treatment guidelines ( table 2)
[1,3,41,80].

Infection

● Serious infection – In patients with an active serious infection, conventional and biologic
disease-modifying antirheumatic drugs (DMARDs) and tofacitinib should be temporarily

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held until resolution of infection and completion of antimicrobial therapy. In patients with
a history of a serious infection, we recommend conventional DMARDs over biologic
agents. Medications administered more frequently are preferred in patients in whom
there is heightened concern regarding infection or with recurrent infections because of
the relative greater ease of discontinuing the therapy and its immunomodulatory effect if
needed.

● Hepatitis B – In patients with natural immunity to hepatitis B virus (HBV; HBV core
antibody [HBc] positive, normal liver chemistries, HBV surface antibody [HBs] positive, and
HBV surface antigen [HBsAg] negative), treatment for RA, other than with rituximab,
should be the same as for HBV-unexposed RA patients, but viral loads should be
monitored every 6 to 12 months to ensure there is no reactivation. For patients being
treated with rituximab, antiviral therapy is administered for at least 12 months following
rituximab therapy, consistent with guidance from the ACR and the American Association
for the Study of Liver Diseases (AASLD) [45,81]. For patients with active untreated
hepatitis, referral for antiviral therapy should be obtained before immunosuppressive
therapy, and patients should be treated in collaboration with their hepatologist. In the
absence of additional harms, RA treatment may proceed for patients with active HBV on
concomitant antiviral treatment. (See "Hepatitis B virus: Screening and diagnosis" and
"Hepatitis B virus: Overview of management".)

● Hepatitis C – Patients with hepatitis C virus (HCV) infection should be managed in

collaboration with their hepatologist. If underlying liver disease is present, non-
hepatotoxic DMARDs (sulfasalazine [SSZ] or hydroxychloroquine [HCQ]) are preferred
initially. Patients with previously treated HCV infection and normal liver function may
tolerate usual RA treatment as in patients without HCV. (See "Overview of the
management of chronic hepatitis C virus infection".)

● Tuberculosis – Prior to initiation of immunomodulatory therapy, all patients who will be

receiving a biologic DMARD, a targeted synthetic DMARD (ie, a Janus kinase [JAK]
inhibitor), and any other patients with risk factors for tuberculosis (TB) should be screened
for latent TB and treated if indicated (see 'Pretreatment evaluation' above). In patients in
whom latent TB is diagnosed, at least one month of treatment should be completed prior
to the initiation of immunosuppressive agents.

In patients with latent TB who are unable to complete anti-TB therapy, we prefer to use
conventional synthetic DMARDs as monotherapy or in combinations. In patients with
persistent disease activity despite such intervention, it may be necessary to use a biologic
DMARD, in which case we prefer agents other than tumor necrosis factor (TNF) inhibitors.
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We also review the risks of such intervention in detail with the patient when deciding upon
therapy and consult with a specialist in infectious disease for additional assistance in
management. (See "Treatment of tuberculosis infection (latent tuberculosis) in
nonpregnant adults without HIV infection".)

Malignancy — Management of RA in patients with malignancy or a history of malignancy is

based upon findings from observational studies involving relatively small numbers of patients
with typically imprecise results, together with expert opinion [3,82-86].

● Nonmelanoma skin cancer (basal cell and squamous cell carcinoma) – In patients with
a history of nonmelanoma skin cancer, we use conventional DMARDs over biologic
DMARDs or JAK inhibitors. There is no contraindication to escalation of therapy to include
biologics, but routine skin cancer surveillance is indicated. (See "Epidemiology,
pathogenesis, clinical features, and diagnosis of basal cell carcinoma" and "Cutaneous
squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

● Melanoma skin cancer – In patients with a history of melanoma, we use conventional

DMARDs over biologic DMARDs or JAK inhibitors. Approaches including monoclonal
antibody treatments that activate T cells have shown benefit in treating melanoma (see
"Systemic treatment of metastatic melanoma lacking a BRAF mutation"); therefore, some
clinicians avoid the use of abatacept in patients with a prior history of melanoma [87].
Routine skin cancer surveillance is indicated. (See "Screening for melanoma in adults and
adolescents".)

● History of lymphoproliferative disorder – In patients with a history of a

lymphoproliferative disorder, we prefer conventional DMARDs, and if a biologic agent is
needed, the first choice would be rituximab, given its use in the treatment of
lymphoproliferative disorders and a lack of evidence for increased cancer risk with its use.

● Solid organ malignancy – In patients with a treated solid organ malignancy within the
past five years, we use conventional DMARDs over biologic DMARDs. If a biologic agent is
needed, the first choice would be rituximab, given the lack of evidence for increased
cancer risk with its use.

In patients who are more than five years out from a treated solid organ malignancy,
excluding melanoma, RA treatment is no different than from those without malignancy.

Lung disease — Comorbid interstitial lung disease (RA-ILD) and chronic obstructive pulmonary
disease (COPD) are common in patients with RA. Pneumonitis may also be a complication of
many different RA therapeutic agents [80]. The limited available data for drug toxicity are often
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prone to confounding and selection bias. Drugs with the potential for causing adverse
pulmonary effects include methotrexate (MTX), leflunomide (LEF), TNF inhibitors, SSZ,
parenteral gold, abatacept, and rituximab [88]. In general, we avoid the use of MTX in patients
with clinically significant or progressive RA-ILD. Although abatacept has had a safety concern
for exacerbation of COPD when compared with placebo, subsequent data have not shown it to
be increased when compared with other biologic DMARDs. These agents should be used
cautiously in patients with severe COPD [89,90]. (See "Overview of pleuropulmonary diseases
associated with rheumatoid arthritis".)

Cardiovascular disease — Comorbid cardiovascular disease can occur in patients with RA and
may also be a complication of therapy [80]. Both glucocorticoids and nonsteroidal
antiinflammatory drugs (NSAIDs) may increase cardiovascular risk. Active RA is associated with
an increased risk of cardiovascular disease, but good control of disease activity has been
associated with reduced cardiovascular complications. (See "Coronary artery disease in
rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic
implications" and "Coronary artery disease in rheumatoid arthritis: Implications for prevention
and management" and "Major side effects of systemic glucocorticoids", section on
'Cardiovascular effects' and "Nonselective NSAIDs: Overview of adverse effects", section on
'Cardiovascular effects'.)

TNF inhibitors should be avoided in patients with moderate or severe heart failure (HF), as they
can worsen HF. Such patients should be treated instead with traditional nonbiologic DMARDs,
non-TNF inhibitor biologics, or a JAK inhibitor. (See "Tumor necrosis factor-alpha inhibitors: An
overview of adverse effects", section on 'Heart failure' and "Heart failure in rheumatoid
arthritis".)

Neurologic manifestations — Neurologic manifestations of RA and the presence of coexistent

neurologic disease are generally uncommon, other than the occurrence of impingement
neuropathies such as carpal tunnel syndrome. However, TNF inhibitors should be avoided in
those with a history of or an ongoing demyelinating disorder because of case reports of such
disorders in patients being treated for RA and because of increased risk of disease worsening in
trials of TNF blockade in patients with multiple sclerosis (MS). Some RA experts are also cautious
about using TNF-alpha inhibitors in patients with family histories of MS [80]. (See "Neurologic
manifestations of rheumatoid arthritis" and "Tumor necrosis factor-alpha inhibitors: An
overview of adverse effects", section on 'Demyelinating disease'.)

Diabetes — The risk of diabetes mellitus is not increased in patients with RA. However, in
patients with both diabetes and RA, glucocorticoids should be used with particular caution
because they may worsen control of the diabetes [80]. By contrast, patients being treated with
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HCQ or TNF inhibitors for RA have a lower risk of diabetes [91], and SSZ may have glucose-
lowering effects [92]. (See "Major side effects of systemic glucocorticoids", section on 'Metabolic
and endocrine effects' and "Antimalarial drugs in the treatment of rheumatic disease", section
on 'Noninfectious indications for antimalarials'.)

Renal disease — RA infrequently affects the kidney, but, if renal disease coexists, it increases
mortality risk [80]. In addition to NSAIDs, the use of some medications occasionally or only
historically used in the treatment of patients with RA may adversely affect renal function,
including gold, penicillamine, and cyclosporine. Some nonbiologic DMARDs, particularly MTX
and cyclosporine, should be avoided or used with particular caution in patients with
significantly decreased renal function. (See "NSAIDs: Acute kidney injury" and "Membranous
nephropathy: Pathogenesis and etiology", section on 'Drugs' and "Cyclosporine and tacrolimus
nephrotoxicity".)

Diverticulitis and gastrointestinal perforation — RA does not cause direct effects on the
bowels, but upper and lower gastrointestinal (GI) perforation can be seen and is driven by use
of drugs, especially glucocorticoids and NSAIDs, and particularly when used in combination and
in older patients [93,94]. For patients with a history of diverticulitis, but not diverticulosis, lower
GI perforation is significantly higher with interleukin 6 (IL-6) inhibitors, and likely with targeted
synthetic DMARDs (eg, JAK inhibitors) when compared with TNF inhibitors. Although data are
limited, the risk does not appear to be increased with the use of abatacept or rituximab. (See
"NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and
"Major side effects of systemic glucocorticoids", section on 'Gastrointestinal effects' and
"Interleukin 6 inhibitors: Biology, principles of use, and adverse effects".)

Multimorbidity — Patients with RA often have multimorbidity (defined as the coexistence of at

least two long-term conditions). In a study of 154,391 patients with RA, the adjusted odds of
multimorbidity for patients with RA versus controls was 2.19 (95% CI 2.16-2.23) [95].

Multimorbidity is associated with increased mortality and decreased functional status and
quality of life [96]. In a study of 1558 patients with RA who had initiated therapy with a new
DMARD, patients with the highest burden of multimorbidity had the lowest odds of achieving
low disease activity or remission, as measured by the Routine Assessment of Patient Index Data
3 (RAPID3; odds ratio [OR] 0.54, 95% CI 0.34, 0.85) [97]. Patients with RA with multimorbidity
have longer and more frequent hospitalizations when compared with patients without RA or
patients with RA without multimorbidity [98].

PREGNANCY
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Rheumatoid arthritis (RA) often improves or remits completely during pregnancy. Issues related
to the pregnant woman with RA, including the use of immunosuppressive drugs, are discussed
separately. (See "Rheumatoid arthritis and pregnancy" and "Safety of rheumatic disease
medication use during pregnancy and lactation".)

PROGNOSIS

Clinical outcomes have improved significantly since the 1980s with changes in drug therapy and
in the approach to treatment [10,99,100]. Rheumatoid arthritis (RA) was historically associated
with a high degree of economic loss, morbidity, and early mortality; these have all improved
with the widespread use of methotrexate (MTX) that began in the 1980s, more aggressive
treatment of early disease, and the availability of targeted biologic agents since the later part of
the 1990s [101,102]. More severe RA was associated with higher mortality rates prior to these
developments due to higher rates of myocardial infarction, infection, and certain malignancies
than at present; mortality had been comparable to that for three-vessel coronary artery disease
or with stage IV Hodgkin lymphoma [103]. (See "Disease outcome and functional capacity in
rheumatoid arthritis".)

These improvements have decreased the need for joint surgery and reduced disability in
patients with RA. As an example, the number of total hip and knee joint arthroplasties in
patients with RA decreased from 1995 to 2010, despite substantial increases in these
procedures among the general population [104]. In another study, patients able to achieve
remission with combination therapy had significantly less work disability over five years of
follow-up compared with patients with incomplete responses to treatment [105].

A number of factors have been associated with poorer outcomes in patients with RA. The
following four markers of adverse prognosis can be used to identify patients who may require
more aggressive pharmacotherapy, especially in early stages of disease [41]:

● Functional limitation
● Extraarticular disease
● Rheumatoid factor positivity or presence of anticyclic citrullinated peptide (CCP) antibodies
● Bony erosions documented radiographically

Other factors associated with a worse prognosis include concurrent medical disorders, cigarette
smoking, lack of formal education, and lower socioeconomic status (SES), older age, female sex,
and the presence of the shared epitope. We do not suggest routine testing for the shared
epitope due to cost, limited availability, and lack of data supporting its clinical use [41,106,107].

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The individual factors associated with a poor prognosis are discussed in detail separately. (See
"Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Disease
outcome and functional capacity in rheumatoid arthritis" and "HLA and other susceptibility
genes in rheumatoid arthritis".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and
diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment
(Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs
(DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Principles and goals of therapy – In patients with rheumatoid arthritis (RA), affected
areas may be irreversibly damaged or destroyed if inflammation persists. Thus, prompt
diagnosis, early recognition of active disease, and measures to quickly achieve and
maintain control of inflammation and the underlying disease process, with the goal of
remission or low disease activity, are central to modifying disease outcome. The
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application of these principles in the management of patients with RA, together with the
development and use of newer and more potent drugs, has resulted in significant
improvement in the outcomes of treatment. (See 'General principles' above and 'Early
recognition and diagnosis' above.)

● Care by a rheumatologist – An expert in the care of rheumatic disease, such as a

rheumatologist, should participate in the care of patients suspected of having RA and in
the ongoing care of patients diagnosed with this condition. The treatment of patients with
RA by a rheumatologist is associated with better disease outcomes compared with care
rendered primarily by other clinicians. (See 'Care by a rheumatologist' above.)

● Nonpharmacologic measures – Nonpharmacologic measures, such as patient education,

psychosocial interventions, and physical and occupational therapy, should be used in
addition to drug therapy. Other medical interventions that are important in the
comprehensive management of RA in all stages of disease include cardiovascular risk
reduction and immunizations to decrease the risk of complications of drug therapies. (See
'Nonpharmacologic therapies' above and 'Pretreatment interventions' above.)

● Initiation of DMARD therapy soon after RA diagnosis – We suggest that all patients
diagnosed with RA be started on disease-modifying antirheumatic drug (DMARD) therapy
as soon as possible following diagnosis, rather than using antiinflammatory drugs alone,
such as nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids (Grade 2C).
Better outcomes are achieved by early compared with delayed intervention with DMARDs.
(See 'Early use of DMARDs' above.)

● Tight control of disease activity – Tight control treatment strategies to "treat to target"
are associated with improved radiographic and functional outcomes compared with less
aggressive approaches. Such strategies involve reassessment of disease activity on a
regularly planned basis with the use of quantitative composite measures and adjustment
of treatment regimens to quickly achieve and maintain control of disease activity if
targeted treatment goals (remission or low disease activity) have not been achieved. (See
'Tight control' above and 'Assessment and monitoring' above.)

● Pretreatment evaluation – Laboratory testing prior to therapy should include a complete

blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP),
aminotransferases, blood urea nitrogen, and creatinine. Patients receiving
hydroxychloroquine (HCQ) should have a baseline ophthalmologic examination, and most
patients who will receive a biologic agent or Janus kinase (JAK) inhibitor should be tested
for latent tuberculosis (TB) infection. Screening for hepatitis B and C should be performed

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in all patients. Some patients may require antiviral treatment prior to initiating DMARD or
immunosuppressive therapy, depending upon their level of risk for hepatitis B virus (HBV)
reactivation. (See 'Pretreatment evaluation' above.)

● Adjunctive use of antiinflammatory agents – We use antiinflammatory drugs, including

NSAIDs and glucocorticoids, as bridging therapies to rapidly achieve control of
inflammation until DMARDs are sufficiently effective. Some patients may benefit from
longer-term therapy with low doses of glucocorticoids. (See 'Adjunctive role of
antiinflammatory agents' above.)

● Drug therapy for flares – RA has natural exacerbations (also known as flares) and
reductions of continuing disease activity. The severity of the flare and background drug
therapy influence the choice of therapies. Patients who require multiple treatment courses
with glucocorticoids for recurrent disease flares and whose medication doses have been
increased to the maximally tolerated or acceptable level should be treated as patients with
sustained disease activity. Such patients require modifications of their baseline drug
therapies. (See 'Drug therapy for flares' above.)

● Monitoring – The monitoring that we perform on a regular basis includes testing that is
specific to evaluation of the safety of the drugs being used ( table 1); periodic
assessments of disease activity with composite measures; monitoring for extraarticular
manifestations of RA, other disease complications, and joint injury; and functional
assessment. (See 'Assessment and monitoring' above.)

● Other factors affecting target and choice of therapy – Other factors in RA management
that may influence the target or choice of therapy include the disabilities or functional
limitations important to a given patient, progressive joint injury, comorbidities ( table 2),
and the presence of adverse prognostic factors. (See 'Tight control' above and
'Comorbidities and disease management' above and 'Prognosis' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier
version of this topic review.

Use of UpToDate is subject to the Terms of Use.

REFERENCES

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1. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of
Rheumatology recommendations for the use of disease-modifying antirheumatic drugs
and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken)
2012; 64:625.
2. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target:
recommendations of an international task force. Ann Rheum Dis 2010; 69:631.
3. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline
for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2016; 68:1.
4. Knevel R, Schoels M, Huizinga TW, et al. Current evidence for a strategic approach to the
management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a
systematic literature review informing the EULAR recommendations for the management
of rheumatoid arthritis. Ann Rheum Dis 2010; 69:987.
5. Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target:
results of a systematic literature search. Ann Rheum Dis 2010; 69:638.
6. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management
of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic
drugs: 2019 update. Ann Rheum Dis 2020; 79:685.

7. Hazlewood GS, Pardo JP, Barnabe C, et al. Canadian Rheumatology Association Living
Guidelines for the Pharmacological Management of Rheumatoid Arthritis With Disease-
Modifying Antirheumatic Drugs. J Rheumatol 2022; 49:1092.

8. Sokka T, Pincus T. Rheumatoid arthritis: strategy more important than agent. Lancet 2009;
374:430.
9. Lard LR, Visser H, Speyer I, et al. Early versus delayed treatment in patients with recent-
onset rheumatoid arthritis: comparison of two cohorts who received different treatment
strategies. Am J Med 2001; 111:446.
10. Pincus T, Sokka T, Kautiainen H. Patients seen for standard rheumatoid arthritis care have
significantly better articular, radiographic, laboratory, and functional status in 2000 than in
1985. Arthritis Rheum 2005; 52:1009.
11. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management
of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic
drugs. Ann Rheum Dis 2010; 69:964.
12. Huizinga TW, Pincus T. In the clinic. Rheumatoid arthritis. Ann Intern Med 2010; 153:ITC1.

13. Ward MM, Leigh JP, Fries JF. Progression of functional disability in patients with rheumatoid
arthritis. Associations with rheumatology subspecialty care. Arch Intern Med 1993;

https://www.uptodate.com/contents/7516/print 26/42
3/30/23, 1:45 AM 7516

153:2229.
14. Solomon DH, Bates DW, Panush RS, Katz JN. Costs, outcomes, and patient satisfaction by
provider type for patients with rheumatic and musculoskeletal conditions: a critical review
of the literature and proposed methodologic standards. Ann Intern Med 1997; 127:52.
15. Criswell LA, Such CL, Yelin EH. Differences in the use of second-line agents and prednisone
for treatment of rheumatoid arthritis by rheumatologists and non-rheumatologists. J
Rheumatol 1997; 24:2283.

16. Rat AC, Henegariu V, Boissier MC. Do primary care physicians have a place in the
management of rheumatoid arthritis? Joint Bone Spine 2004; 71:190.
17. Lacaille D, Anis AH, Guh DP, Esdaile JM. Gaps in care for rheumatoid arthritis: a population
study. Arthritis Rheum 2005; 53:241.
18. van der Linden MP, le Cessie S, Raza K, et al. Long-term impact of delay in assessment of
patients with early arthritis. Arthritis Rheum 2010; 62:3537.
19. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in
rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000; 43:22.

20. van der Heide A, Jacobs JW, Bijlsma JW, et al. The effectiveness of early treatment with
"second-line" antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 1996;
124:699.
21. Nell VP, Machold KP, Eberl G, et al. Benefit of very early referral and very early therapy with
disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.
Rheumatology (Oxford) 2004; 43:906.

22. Sokka T, Mäkinen H. Drug management of early rheumatoid arthritis - 2008. Best Pract Res
Clin Rheumatol 2009; 23:93.
23. Emery P, Kvien TK, Combe B, et al. Combination etanercept and methotrexate provides
better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4
months and <2 years): post hoc analyses from the COMET study. Ann Rheum Dis 2012;
71:989.

24. Molina E, Del Rincon I, Restrepo JF, et al. Association of socioeconomic status with
treatment delays, disease activity, joint damage, and disability in rheumatoid arthritis.
Arthritis Care Res (Hoboken) 2015; 67:940.
25. van Nies JA, Tsonaka R, Gaujoux-Viala C, et al. Evaluating relationships between symptom
duration and persistence of rheumatoid arthritis: does a window of opportunity exist?
Results on the Leiden early arthritis clinic and ESPOIR cohorts. Ann Rheum Dis 2015;
74:806.

https://www.uptodate.com/contents/7516/print 27/42
3/30/23, 1:45 AM 7516

26. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments
of hands and feet in a three-year prospective followup of patients with early rheumatoid
arthritis. Arthritis Rheum 1992; 35:26.
27. Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in
rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989; 16:585.
28. Wakefield RJ, Gibbon WW, Conaghan PG, et al. The value of sonography in the detection of
bone erosions in patients with rheumatoid arthritis: a comparison with conventional
radiography. Arthritis Rheum 2000; 43:2762.
29. Weidekamm C, Köller M, Weber M, Kainberger F. Diagnostic value of high-resolution B-
mode and doppler sonography for imaging of hand and finger joints in rheumatoid
arthritis. Arthritis Rheum 2003; 48:325.
30. McQueen FM. The use of MRI in early RA. Rheumatology (Oxford) 2008; 47:1597.
31. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic
outcomes of four different treatment strategies in patients with early rheumatoid arthritis
(the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52:3381.
32. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment
strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007; 146:406.
33. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, et al. Progression of joint
damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and
anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis
Rheum 2008; 58:1293.

34. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with

single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.
Lancet 1999; 353:1568.
35. Puolakka K, Kautiainen H, Möttönen T, et al. Impact of initial aggressive drug treatment
with a combination of disease-modifying antirheumatic drugs on the development of work
disability in early rheumatoid arthritis: a five-year randomized followup trial. Arthritis
Rheum 2004; 50:55.
36. Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a
combination of traditional disease-modifying antirheumatic drugs is sustained over time:
the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.
Arthritis Rheum 2009; 60:1222.

37. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for
rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet

https://www.uptodate.com/contents/7516/print 28/42
3/30/23, 1:45 AM 7516

2004; 364:263.

38. van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Drug-free remission,
functioning and radiographic damage after 4 years of response-driven treatment in
patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 2009; 68:914.
39. Finckh A, Bansback N, Marra CA, et al. Treatment of very early rheumatoid arthritis with
symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-
effectiveness analysis. Ann Intern Med 2009; 151:612.

40. Stoffer MA, Schoels MM, Smolen JS, et al. Evidence for treating rheumatoid arthritis to
target: results of a systematic literature search update. Ann Rheum Dis 2016; 75:16.
41. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic
drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59:762.
42. Bathon JM, Cohen SB. The 2008 American College of Rheumatology recommendations for
the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid
arthritis: where the rubber meets the road. Arthritis Rheum 2008; 59:757.
43. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014
update of the recommendations of an international task force. Ann Rheum Dis 2016; 75:3.
44. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline
for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68:1.
45. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology
Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2021; 73:1108.
46. Pincus T, Castrejón I. Evidence that the strategy is more important than the agent to treat
rheumatoid arthritis. Data from clinical trials of combinations of non-biologic DMARDs,
with protocol-driven intensification of therapy for tight control or treat-to-target. Bull Hosp
Jt Dis (2013) 2013; 71 Suppl 1:S33.
47. Rantalaiho V, Korpela M, Laasonen L, et al. Early combination disease-modifying
antirheumatic drug therapy and tight disease control improve long-term radiologic
outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish
Rheumatoid Arthritis Combination Therapy trial. Arthritis Res Ther 2010; 12:R122.
48. Leirisalo-Repo M, Kautiainen H, Laasonen L, et al. Infliximab for 6 months added on
combination therapy in early rheumatoid arthritis: 2-year results from an investigator-
initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study). Ann
Rheum Dis 2013; 72:851.

https://www.uptodate.com/contents/7516/print 29/42
3/30/23, 1:45 AM 7516

49. Moreland LW, O'Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of
oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid
arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum
2012; 64:2824.
50. Schipper LG, van Hulst LT, Grol R, et al. Meta-analysis of tight control strategies in
rheumatoid arthritis: protocolized treatment has additional value with respect to the
clinical outcome. Rheumatology (Oxford) 2010; 49:2154.

51. Silvagni E, Zandonella Callegher S, Mauric E, et al. Musculoskeletal ultrasound for treating
rheumatoid arthritis to target-a systematic literature review. Rheumatology (Oxford) 2022;
61:4590.
52. Møller-Bisgaard S, Hørslev-Petersen K, Ejbjerg B, et al. Effect of Magnetic Resonance
Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and
Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical
Trial. JAMA 2019; 321:461.
53. Dale J, Stirling A, Zhang R, et al. Targeting ultrasound remission in early rheumatoid
arthritis: the results of the TaSER study, a randomised clinical trial. Ann Rheum Dis 2016;
75:1043.
54. Haavardsholm EA, Aga AB, Olsen IC, et al. Ultrasound in management of rheumatoid
arthritis: ARCTIC randomised controlled strategy trial. BMJ 2016; 354:i4205.

55. McInnes IB, O'Dell JR. State-of-the-art: rheumatoid arthritis. Ann Rheum Dis 2010; 69:1898.

56. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in

rheumatoid arthritis. N Engl J Med 2012; 367:495.

57. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus
placebo in rheumatoid arthritis. N Engl J Med 2012; 367:508.
58. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines.
Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum
2002; 46:328.
59. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid
arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42:244.
60. Khanna D, Ranganath VK, Fitzgerald J, et al. Increased radiographic damage scores at the
onset of seropositive rheumatoid arthritis in older patients are associated with
osteoarthritis of the hands, but not with more rapid progression of damage. Arthritis
Rheum 2005; 52:2284.

https://www.uptodate.com/contents/7516/print 30/42
3/30/23, 1:45 AM 7516

61. Gandjbakhch F, Haavardsholm EA, Conaghan PG, et al. Determining a magnetic resonance
imaging inflammatory activity acceptable state without subsequent radiographic
progression in rheumatoid arthritis: results from a followup MRI study of 254 patients in
clinical remission or low disease activity. J Rheumatol 2014; 41:398.
62. Brown AK, Conaghan PG, Karim Z, et al. An explanation for the apparent dissociation
between clinical remission and continued structural deterioration in rheumatoid arthritis.
Arthritis Rheum 2008; 58:2958.

63. England BR, Tiong BK, Bergman MJ, et al. 2019 Update of the American College of
Rheumatology Recommended Rheumatoid Arthritis Disease Activity Measures. Arthritis
Care Res (Hoboken) 2019; 71:1540.
64. Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (Routine Assessment of Patient Index
Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with
DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories,
scored in five versus more than ninety seconds. Arthritis Care Res (Hoboken) 2010; 62:181.
65. Wolfe F, Michaud K, Pincus T. A composite disease activity scale for clinical practice,
observational studies, and clinical trials: the patient activity scale (PAS/PAS-II). J Rheumatol
2005; 32:2410.
66. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures:
American College of Rheumatology recommendations for use in clinical practice. Arthritis
Care Res (Hoboken) 2012; 64:640.

67. Barber CEH, Zell J, Yazdany J, et al. 2019 American College of Rheumatology Recommended
Patient-Reported Functional Status Assessment Measures in Rheumatoid Arthritis. Arthritis
Care Res (Hoboken) 2019; 71:1531.
68. O'Dell JR. Combination DMARD therapy for rheumatoid arthritis: a step closer to the goal.
Ann Rheum Dis 1996; 55:781.
69. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select
second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials.
Arthritis Rheum 1992; 35:1117.
70. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of
Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.
71. Rigby WFC, Lampl K, Low JM, Furst DE. Review of Routine Laboratory Monitoring for
Patients with Rheumatoid Arthritis Receiving Biologic or Nonbiologic DMARDs. Int J
Rheumatol 2017; 2017:9614241.

https://www.uptodate.com/contents/7516/print 31/42
3/30/23, 1:45 AM 7516

72. Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for

the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis:
integrating systematic literature research and expert opinion of a broad international
panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009; 68:1086.
73. Ariza-Ariza R, Navarro-Sarabia F, Hernández-Cruz B, et al. Dose escalation of the anti-TNF-
alpha agents in patients with rheumatoid arthritis. A systematic review. Rheumatology
(Oxford) 2007; 46:529.

74. Rahman MU, Strusberg I, Geusens P, et al. Double-blinded infliximab dose escalation in
patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:1233.
75. Pavelka K, Jarosová K, Suchý D, et al. Increasing the infliximab dose in rheumatoid arthritis
patients: a randomised, double blind study failed to confirm its efficacy. Ann Rheum Dis
2009; 68:1285.
76. van Vollenhoven RF. How to dose infliximab in rheumatoid arthritis: new data on a serious
issue. Ann Rheum Dis 2009; 68:1237.
77. Johnsen AK, Schiff MH, Mease PJ, et al. Comparison of 2 doses of etanercept (50 vs 100 mg)
in active rheumatoid arthritis: a randomized double blind study. J Rheumatol 2006; 33:659.
78. Weinblatt ME, Schiff MH, Ruderman EM, et al. Efficacy and safety of etanercept 50 mg twice
a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept
50 mg once a week: results of a multicenter, randomized, double-blind, active drug-
controlled study. Arthritis Rheum 2008; 58:1921.

79. Wiese AD, Griffin MR, Stein CM, et al. Opioid Analgesics and the Risk of Serious Infections
Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study. Arthritis
Rheumatol 2016; 68:323.

80. Makol A, Wright K, Matteson EL. Safe use of antirheumatic agents in patients with
comorbidities. Rheum Dis Clin North Am 2012; 38:771.
81. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of
chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67:1560.
82. Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour necrosis factor
therapy, and risk of malignant melanoma: nationwide population based prospective cohort
study from Sweden. BMJ 2013; 346:f1939.
83. Dixon WG, Watson KD, Lunt M, et al. Influence of anti-tumor necrosis factor therapy on
cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy:
results from the British Society for Rheumatology Biologics Register. Arthritis Care Res
(Hoboken) 2010; 62:755.

https://www.uptodate.com/contents/7516/print 32/42
3/30/23, 1:45 AM 7516

84. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis
factor inhibitors. J Rheumatol 2005; 32:2130.
85. Kameda T, Dobashi H, Miyatake N, et al. Association of higher methotrexate dose with
lymphoproliferative disease onset in rheumatoid arthritis patients. Arthritis Care Res
(Hoboken) 2014; 66:1302.

86. Raaschou P, Frisell T, Askling J, ARTIS Study Group. TNF inhibitor therapy and risk of breast
cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann
Rheum Dis 2015; 74:2137.
87. de Germay S, Bagheri H, Despas F, et al. Abatacept in rheumatoid arthritis and the risk of
cancer: a world observational post-marketing study. Rheumatology (Oxford) 2020; 59:2360.
88. England BR, Hershberger D. Management issues in rheumatoid arthritis-associated
interstitial lung disease. Curr Opin Rheumatol 2020; 32:255.
89. Suissa S, Hudson M, Dell'Aniello S, et al. Comparative safety of abatacept in rheumatoid
arthritis with COPD: A real-world population-based observational study. Semin Arthritis
Rheum 2019; 49:366.
90. Kang EH, Jin Y, Desai RJ, et al. Risk of exacerbation of pulmonary comorbidities in patients
with rheumatoid arthritis after initiation of abatacept versus TNF inhibitors: A cohort study.
Semin Arthritis Rheum 2020; 50:401.
91. Solomon DH, Massarotti E, Garg R, et al. Association between disease-modifying
antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis.
JAMA 2011; 305:2525.
92. Haas RM, Li P, Chu JW. Glucose-lowering effects of sulfasalazine in type 2 diabetes. Diabetes
Care 2005; 28:2238.
93. Curtis JR, Lanas A, John A, et al. Factors associated with gastrointestinal perforation in a
cohort of patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012; 64:1819.
94. Jagpal A, Curtis JR. Gastrointestinal Perforations with Biologics in Patients with Rheumatoid
Arthritis: Implications for Clinicians. Drug Saf 2018; 41:545.
95. Kronzer VL, Dykhoff HJ, Stevens MA, et al. Racial Differences in Multimorbidity and
Comorbidities in Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2023; 75:76.
96. Canning J, Siebert S, Jani BD, et al. Examining the Relationship Between Rheumatoid
Arthritis, Multimorbidity, and Adverse Health-Related Outcomes: A Systematic Review.
Arthritis Care Res (Hoboken) 2022; 74:1500.

97. England BR, Yun H, Chen L, et al. Influence of Multimorbidity on New Treatment Initiation
and Achieving Target Disease Activity Thresholds in Active Rheumatoid Arthritis: A Cohort

https://www.uptodate.com/contents/7516/print 33/42
3/30/23, 1:45 AM 7516

Study Using the Rheumatology Informatics System for Effectiveness Registry. Arthritis Care
Res (Hoboken) 2023; 75:231.
98. Morton FR, Jani BD, Mair FS, et al. Association between risk, duration and cause of
hospitalisations in people with rheumatoid arthritis and multimorbidity in the UK Biobank
and Scottish Early Rheumatoid Arthritis (SERA) cohorts: Longitudinal observational study.
Semin Arthritis Rheum 2023; 58:152130.
99. Ajeganova S, van Steenbergen HW, van Nies JA, et al. Disease-modifying antirheumatic
drug-free sustained remission in rheumatoid arthritis: an increasingly achievable outcome
with subsidence of disease symptoms. Ann Rheum Dis 2016; 75:867.
100. Krishnan E, Fries JF. Reduction in long-term functional disability in rheumatoid arthritis
from 1977 to 1998:a longitudinal study of 3035 patients. Am J Med 2003; 115:371.

101. Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid
arthritis: results after 20 years. Lancet 1987; 1:1108.
102. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum
1994; 37:481.
103. Pincus T, Callahan LF. What is the natural history of rheumatoid arthritis? Rheum Dis Clin
North Am 1993; 19:123.
104. Harty L, O'Toole G, FitzGerald O. Profound reduction in hospital admissions and
musculoskeletal surgical procedures for rheumatoid arthritis with concurrent changes in
clinical practice (1995-2010). Rheumatology (Oxford) 2015; 54:666.

105. Puolakka K, Kautiainen H, Möttönen T, et al. Early suppression of disease activity is

essential for maintenance of work capacity in patients with recent-onset rheumatoid
arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum 2005; 52:36.
106. Busby AD, Wason J, Pratt AG, et al. The role of comorbidities alongside patient and disease
characteristics in long-term disease activity in RA using UK inception cohort data.
Rheumatology (Oxford) 2022; 61:4297.

107. Symmons DP. Environmental factors and the outcome of rheumatoid arthritis. Best Pract
Res Clin Rheumatol 2003; 17:717.
Topic 7516 Version 49.0

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GRAPHICS

Monitoring strategies for drug treatment of rheumatoid arthritis

Ongoing monitoring via Ongoing laboratory

Drugs system review and physical monitoring and other
¶Δ
examination* testing

Salicylates, NSAIDs Dyspepsia, nausea/vomiting, CBC and complete metabolic panel

abdominal pain, edema, blood (electrolytes, creatinine, albumin,
pressure transaminases) every 6 months.

Glucocorticoids Mood, weight gain, visual changes, Diabetes screening, lipids, bone
weakness, polyuria, polydipsia, mineral density testing.
edema, infection, blood pressure

Hydroxychloroquine Visual change, skin color change, Ophthalmologic evaluation for retinal
paresthesia ◊ toxicity. ◊

Sulfasalazine Headache, nausea, diarrhea, CBC, aminotransferases and

photosensitivity, symptoms of creatinine every 2 to 4 weeks for the
myelosuppression, hepatotoxicity, first 3 months or after increasing the
rash dose, every 8 to 12 weeks for months
3 to 6, then every 12 weeks.

Methotrexate § Stomatitis, alopecia, diarrhea, CBC, aminotransferases, and

nausea/vomiting, flu-like symptoms, creatinine every 2 to 4 weeks for the
shortness of breath, symptoms of first 3 months or after increasing the
myelosuppression, hepatotoxicity, dose, every 8 to 12 weeks for months
infection, lymph node swelling, 3 to 6, then every 12 weeks.
pregnancy

Leflunomide § Nausea/vomiting, diarrhea, shortness CBC, aminotransferases, and

of breath, paresthesia, hepatotoxicity, creatinine every 2 to 4 weeks for the
weight loss, blood pressure, first 3 months or after increasing the
pregnancy dose, every 8 to 12 weeks for months
3 to 6, then every 12 weeks.

Minocycline Hyperpigmentation, dizziness, falls None after baseline.

Azathioprine Diarrhea, nausea/vomiting, CBC and platelet count every 1 to 2

symptoms of myelosuppression, weeks with changes in dose, every 1
infection to 3 months thereafter.

TNF inhibitors Infection, malignancy, demyelination, No routine laboratory monitoring

(eg, etanercept, congestive heart failure, autoimmune (unless also receiving a concurrent
infliximab, phenomenon conventional DMARD).
adalimumab,

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certolizumab pegol,
and golimumab)

IL-6 inhibitors Infection, symptoms of CBC with differential (neutrophils) and

(eg, tocilizumab and myelosuppression (PMNs and LFTs every 4 to 8 weeks until stable,
sarilumab) platelets), demyelination, then every 3 months. Lipids 4 to 8
hepatotoxicity, gastrointestinal weeks after starting therapy, then
perforations every 6 months.

Rituximab Infection, PML, symptoms of CBC every 2 to 4 months.

neutropenia

Abatacept Infection, COPD exacerbation, No routine laboratory monitoring

malignancy (unless also receiving a concurrent
conventional DMARD).

JAK inhibitors Infection, zoster, symptoms of CBC with differential, creatinine, LFTs
(eg, tofacitinib, myelosuppression, hepatotoxicity, (transaminases, albumin, bilirubin)
baricitinib, and malignancy, gastrointestinal every month for 3 months, then every
upadacitinib) perforation 3 months; lipids 6 to 8 weeks after
drug start.

These are general guidelines. Patients should be assessed on an individual basis to determine if they
require additions or other modifications to the monitoring noted in this table.

NSAIDs: nonsteroidal antiinflammatory drugs; CBC: complete blood cell count (hematocrit,
hemoglobin, white blood cell count, including differential white blood cell count and platelet
counts); TB: tuberculosis; TNF: tumor necrosis factor; DMARD: disease-modifying antirheumatic
drug; IL-6: interleukin 6; PMNs: polymorphonuclear leukocytes; LFTs: liver function tests; PML:
progressive multifocal leukoencephalopathy; COPD: chronic obstructive pulmonary disease; JAK:
Janus kinase.

* Confirm that immunizations are up to date in all patients.

¶ Screening for latent TB prior to all biologic DMARDs and prior to use of a JAK inhibitor, and repeat
TB testing in patients at increased risk of or with known exposure to TB and patients treated for
latent TB with potential ongoing exposure.

Δ Patients receiving a biologic DMARD or JAK inhibitor should also continue appropriate monitoring
for concurrent conventional DMARD therapies.

◊ Refer to the UpToDate topic review on antimalarial drugs in the treatment of rheumatic disease
for a detailed discussion of appropriate screening procedures for hydroxychloroquine-related
ophthalmologic toxicity.

§ In patients receiving methotrexate and leflunomide in combination: CBC, creatinine, albumin, and
transaminases every 2 to 4 weeks for the first 3 months or following dose increase, every 4 weeks
for the next 3 months, then every 3 months.

Adapted from:

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1. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc
Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.
2. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the
Management of Rheumatoid Arthritis: 2002 Update. Arthritis Rheum 2002; 46:328.
3. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of
nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;
59:762.
4. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of
Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68:1.

Graphic 78846 Version 7.0

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Comorbidities that affect management of rheumatoid arthritis in adults

Comorbid Pretreatment Relevant

Notes
conditions testing drugs/monitoring

Infections

Serious infections Hold Risk/benefit should

immunosuppressive be based on clinical
medications judgment

Hepatitis B past HBcAb positive No change in Monitor HBV viral

infection with HBsAb positive recommended load every 6 to 12
natural immunity treatment, except months
HBsAg negative
for rituximab Prophylactic
LFTs
antiviral therapy
recommended with
the use of rituximab

Hepatitis B HBcAb positive Consult with

current/chronic HBsAb negative hepatologist prior
infection to treatment
HBsAg positive
HBeAg positive
LFTs

Hepatitis C infection HCV Ab or RNA Attempt to use non- Manage in

LFTs hepatotoxic collaboration with
DMARDs initially hepatologist

Tuberculosis PPD or interferon All patients prior to If positive, treat for

gamma release a bDMARD or latent tuberculosis,
assay tsDMARD (eg, JAK starting at least 1
inhibitors), and month prior to
those at risk prior starting
to cDMARD therapy immunomodulatory
therapy

Malignancy

Nonmelanoma skin Skin check All Routine skin cancer

cancer immunomodulatory surveillance
agents

Melanoma skin Skin check cDMARDs preferred Dermatology

cancer over bDMARDs or suggested follow-
tsDMARDs; up surveillance per
generally avoid

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abatacept and TNF melanoma stage

inhibitors; prefer protocols
rituximab if
bDMARD needed

Lymphoproliferative cDMARDs preferred Manage in

disorder over bDMARDs or consultation with
tsDMARD; prefer hematology and
rituximab if oncology
bDMARD needed

Solid organ If <5 years out, Manage in

malignancy prefer cDMARDs consultation with
over bDMARDs or oncologist
tsDMARD; if >5
years out, no
change in
treatment

Cardiovascular disease

Congestive heart Recent Caution with

failure echocardiogram NSAIDs, GCs
TNF inhibitors may
worsen moderate
to severe
congestive heart
failure and should
be avoided

Hypertension BP monitoring LEF may raise BP Regular BP

monitoring

Hyperlipidemia Lipid panel IL-6 inhibitors and Lipid panel

tsDMARDs may IL-6: every 6
increase lipids months
tsDMARD: 6 to 8
weeks after drug
start

Other

Lung disease Chest radiograph Caution with agents Avoid MTX in

and PFTs that may patients with
exacerbate lung significant or
issues: MTX, LEF, progressive ILD,
abatacept, bDMARDs may
exacerbate COPD

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rituximab, gold,
SSZ, TNF inhibitor

Demyelinating Avoid TNF inhibitors

disorders

Diabetes Blood glucose GCs may worsen Caution patients on

Hemoglobin A1C HCQ and SSZ may oral glucose-
lower blood glucose lowering agents to
watch for
hypoglycemia

Renal disease sCr, GFR Dose medications Serial sCr and GFR
for GFR
For severe renal
disease, avoid MTX,
CSA

Gastrointestinal History of Avoid IL-6 inhibitors Higher risk with

disease diverticulitis and tsDMARDs, concomitant
which may increase NSAIDs or GCs
risk of diverticular
and other
gastrointestinal
perforation

Pregnancy Avoid MTX, LEF RA frequently

remits during
pregnancy
Manage in
consultation with
OB-GYN

These are general guidelines. Patients should be assessed on an individual basis to determine if they
require additions or other modifications to the monitoring and other guidance noted in this table.
Refer to the UpToDate topic review on the general principles and overview of management of
rheumatoid arthritis in adults.

HBcAb: hepatitis B core antibody; HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B surface
antigen; LFTs: liver function tests; HBV: hepatitis B virus; HBeAg: hepatitis B e-antigen; HCV Ab:
hepatitis C virus antibody; DMARDs: disease-modifying antirheumatic drugs; PPD: purified protein
derivative; bDMARD: biologic DMARD; tsDMARD: targeted synthetic DMARD; JAK: Janus kinase;
cDMARD: conventional DMARD; TNF: tumor necrosis factor; NSAIDs: nonsteroidal antiinflammatory
drugs; GCs: glucocorticoids; BP: blood pressure; LEF: leflunomide; IL-6: interleukin 6; PFTs:
pulmonary function tests; MTX: methotrexate; SSZ: sulfasalazine; ILD: interstitial lung disease; COPD:

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chronic obstructive pulmonary disease; HCQ: hydroxychloroquine; sCr: serum creatinine; GFR:
glomerular filtration rate; CSA: cyclosporin A; RA: rheumatoid arthritis.

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Contributor Disclosures
Larry W Moreland, MD Other Financial Interest: Boehringer Ingelheim [Rheumatoid arthritis – Data and
safety monitoring board member]. All of the relevant financial relationships listed have been
mitigated. Amy Cannella, MD, MS, RhMSUS No relevant financial relationship(s) with ineligible
companies to disclose. James R O'Dell, MD No relevant financial relationship(s) with ineligible companies
to disclose. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible companies to
disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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