Diagnosis and differential diagnosis of rheumatoid arthritis

Author:
PJW Venables, MA, MB BChir, MD, FRCP
Section Editor:
James R O'Dell, MD
Deputy Editor:
Paul L Romain, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jun 2019. | This topic last updated: Aug 23, 2018.

INTRODUCTION

Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of

unknown etiology. It typically leads to deformity through the stretching of tendons and
ligaments and destruction of joints through the erosion of cartilage and bone. If it is
untreated or unresponsive to therapy, inflammation and joint destruction lead to loss
of physical function, inability to carry out daily tasks of living, and difficulties in
maintaining employment.

Early recognition and treatment with disease-modifying antirheumatic drugs (DMARDs)

is important in achieving control of disease and prevention of joint injury and disability.
However, in patients with early disease, the joint manifestations are often difficult to
distinguish from other forms of inflammatory polyarthritis. The more distinctive signs
of RA, such as joint erosions, rheumatoid nodules, and other extraarticular
manifestations, are seen primarily in patients with longstanding, poorly controlled
disease but are frequently absent on initial presentation.

This topic will review the approach to the diagnosis and differential diagnosis of RA.
The clinical features of this disorder, its extraarticular manifestations, and laboratory
markers that are clinically useful in the diagnosis of RA are discussed in detail
separately. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the
systemic and nonarticular manifestations of rheumatoid arthritis" and "Biologic
markers in the diagnosis and assessment of rheumatoid arthritis".)

EVALUATION FOR SUSPECTED RA

Rheumatoid arthritis (RA) should be suspected in the adult patient who presents with
inflammatory polyarthritis. The initial evaluation of such patients requires a careful
history and physical examination, along with selected laboratory testing to identify
features that are characteristic of RA or that suggest an alternative diagnosis.
(See "Clinical manifestations of rheumatoid arthritis" and 'Differential
diagnosis' below.)

We focus especially on the following for the purposes of diagnosis:

●We perform a thorough medical history, with particular attention to joint pain,
reported swelling, and the presence, location (peripheral joints rather than low
back), and duration (at least 30 minutes) of morning stiffness. The absence of
other conditions or symptoms suggesting an alternative diagnosis, such as
psoriasis, inflammatory bowel disease (IBD), or a systemic rheumatic disease such
as systemic lupus erythematosus (SLE), helps to exclude other disorders.
Symptoms of arthritis that have been present for a short time (for example, less
than six weeks) may well be due to an acute viral polyarthritis rather than to RA.
The longer symptoms persist, the more likely the diagnosis of RA becomes. Thus,
in patients presenting very early, close observation with frequent follow-up
appointments is required, with repeated serologic analysis for anti-cyclic
citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), and acute phase
reactants. In a minority of patients, several such visits are required before the
differential diagnosis between RA and viral arthritis becomes established.
(See "Clinical manifestations of rheumatoid arthritis", section on 'Typical 'classic'
RA' and 'Differential diagnosis'below.)
●A complete physical examination is indicated to assess for synovitis, including the
presence and distribution of swollen or tender joints and limited joint motion;
extraarticular disease manifestations, such as rheumatoid nodules; and signs of
diseases, such as SLE or psoriasis, included in the differential diagnosis.
(See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and
physical findings' and "Rheumatoid nodules" and 'Differential diagnosis' below.)
●We perform the following laboratory tests, which support the diagnosis if
positive and/or elevated:
•RF and anti-CCP antibodies – We perform both RF and anti-CCP antibody
testing when initially evaluating a patient with suspected RA. The results of
both tests are informative, since a positive result for either test increases
overall diagnostic sensitivity, while the specificity is increased when both
tests are positive. Despite this, both tests are negative on presentation in up
to 50 percent of patients and remain negative during follow-up in 20 percent
of patients with RA. (See "Biologic markers in the diagnosis and assessment
of rheumatoid arthritis", section on 'Rheumatoid factors' and "Biologic
markers in the diagnosis and assessment of rheumatoid arthritis", section on
'Anti-citrullinated peptide antibodies'.)
•Erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP)
levels – Both the ESR and CRP are typically elevated in RA. (See "Biologic
markers in the diagnosis and assessment of rheumatoid arthritis", section on
'Erythrocyte sedimentation rate' and "Biologic markers in the diagnosis and
assessment of rheumatoid arthritis", section on 'C-reactive protein'.)
●We perform the following testing in all patients, which may be helpful in the
differential diagnosis of RA and as baseline testing for monitoring of disease
activity or progression and medication safety:
•Antinuclear antibody (ANA) testing – A negative ANA helps exclude SLE and
other systemic rheumatic diseases; the ANA may be positive in up to one-third
of patients with RA. In patients with a positive ANA, anti-double stranded
DNA and anti-Smith antibody testing should also be performed; these
antibodies have high specificity for SLE. (See "Measurement and clinical
significance of antinuclear antibodies".)
•Complete blood count (CBC) with differential and platelet count, tests of
liver and kidney function, serum uric acid, and a urinalysis – The CBC is often
abnormal in RA, with anemia and thrombocytosis consistent with chronic
inflammation. Liver and kidney testing abnormalities indicate a disorder other
than RA; if caused by comorbid conditions, they may affect therapeutic
choices or drug dosing. Hyperuricemia may prompt additional efforts,
including arthrocentesis and crystal search, to exclude gout; polyarticular
gout can infrequently be mistaken for RA. (See "Hematologic manifestations
of rheumatoid arthritis", section on 'Anemia of chronic
disease' and "Hematologic manifestations of rheumatoid arthritis", section
on 'Platelet abnormalities' and 'Differential diagnosis' below.)
•Radiographs of the hands, wrists, and feet – We obtain radiographs during
the initial evaluation primarily as a baseline for monitoring disease
progression. However, characteristic joint erosions may be observed in
patients presenting with symptoms for the first time and, hence, aid in
diagnosis. Additionally, in patients with other disorders, such as psoriatic
arthritis, spondyloarthropathy, gout, or chondrocalcinosis, radiographic
changes more characteristic of these conditions may point to an alternative
diagnosis. (See '2010 ACR/EULAR criteria' below and 'Differential
diagnosis' below and "Clinical manifestations of rheumatoid arthritis", section
on 'Imaging'.)
●We perform the following studies in selected patients:
•Serologic studies for infection – In patients with a very short history (for
example, less than six weeks) particularly those who are seronegative for
anti-CCP and RF, we perform serologic testing for human parvovirus B19,
hepatitis B virus (HBV), and hepatitis C virus (HCV). In areas endemic for Lyme
disease, we perform serologic studies for Borrelia as well. In people who live
in or have traveled to parts of the world where mosquito (Aedes
aegypti and Aedes albopictus)-bite transmitted viral diseases are prevalent,
chikungunya virus infection should be suspected in patients with fever and
arthralgia, as this may be followed by a chronic polyarthritis; diagnosis is
confirmed by serologic tests. (See 'Viral polyarthritis' below and "Viruses that
cause arthritis" and "Diagnosis of Lyme disease", section on 'Indications for
serologic testing' and "Chikungunya fever: Epidemiology, clinical
manifestations, and diagnosis".)
 •Synovial fluid analysis – We perform arthrocentesis and synovial fluid
analysis for the diagnosis or exclusion of gout, pseudogout, or an infectious
arthritis if a joint effusion is present and if there is uncertainty regarding the
diagnosis, particularly in the setting a monoarthritis, oligoarthritis, or
asymmetric joint inflammation. Synovial fluid testing should include a cell
count and differential, crystal search, and Gram stain and culture. Synovial
fluid analysis should also be obtained to exclude infection or crystalline
arthropathy in patients who undergo glucocorticoid injections for
symptomatic relief. (See "Clinical manifestations of rheumatoid arthritis",
section on 'Laboratory findings' and "Synovial fluid analysis".)
•Magnetic resonance imaging (MRI) and ultrasound – MRI studies and
ultrasonography do not have an established role in the routine evaluation of
patients with polyarthritis. However, MRI and ultrasound are more sensitive
than radiography at detecting changes resulting from synovitis and may be
helpful in establishing the presence of synovitis in patients with normal
radiographs and uncertainty regarding either the diagnosis or the presence of
inflammatory changes, such as patients with obesity or subtle findings on
examination. (See "Clinical manifestations of rheumatoid arthritis", section on
'Imaging'.)

DIAGNOSIS

Our diagnostic criteria — The diagnosis of rheumatoid arthritis (RA) can be made
when the following clinical features are all present:
●Inflammatory arthritis involving three or more joints. (See "Clinical
manifestations of rheumatoid arthritis", section on 'Symptoms and physical
findings'.)
●Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody
(such as anti-cyclic citrullinated peptide [CCP])) testing. (See "Biologic markers in
the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-
citrullinated peptide antibodies'.)
●Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate
(ESR). (See "Biologic markers in the diagnosis and assessment of rheumatoid
arthritis", section on 'Erythrocyte sedimentation rate'.)
●Diseases with similar clinical features have been excluded, particularly psoriatic
arthritis, acute viral polyarthritis, polyarticular gout or calcium pyrophosphate
deposition disease, and systemic lupus erythematosus (SLE). (See 'Differential
diagnosis'below.)
●The duration of symptoms is more than six weeks.

These criteria are consistent with the 2010 American College of

Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification
criteria for RA. (See '2010 ACR/EULAR criteria' below.)
The diagnosis of RA may also be made in some patients who do not meet all of our
criteria. (See 'Patients not meeting above criteria' below.)

Inflammatory arthritis — Arthritis is typically present in the metacarpophalangeal

(MCP) and proximal interphalangeal (PIP) joints of the hands. The wrists are also
commonly involved, as are the metatarsophalangeal (MTP) joints in the feet, but any
upper or lower extremity joint may be affected. Symmetric polyarthritis, particularly of
the MCP, MTP, and/or PIP joints, strongly suggests RA. Although distal interphalangeal
(DIP) joint disease can occur in patients with RA, DIP involvement strongly suggests a
diagnosis of osteoarthritis or psoriatic arthritis. (See "Clinical manifestations of
rheumatoid arthritis", section on 'Symptoms and physical
findings' and 'Osteoarthritis' below and 'Psoriatic arthritis' below.)

Serology — RFs occur in 70 to 80 percent of patients with RA. Their diagnostic utility is
limited by their relatively poor specificity, since they are found in 5 to 10 percent of
healthy individuals, 20 to 30 percent of people with SLE, virtually all patients with
mixed cryoglobulinemia (usually caused by hepatitis C virus [HCV] infections), and in
those with many other inflammatory conditions. Higher titers of RF (at least three
times the upper limit of normal) have somewhat greater specificity for RA. The
prevalence of RF positivity in healthy individuals rises with age. (See "Origin and utility
of measurement of rheumatoid factors"and "Biologic markers in the diagnosis and
assessment of rheumatoid arthritis", section on 'Rheumatoid factors'.)

Antibodies to citrullinated peptides/proteins are usually measured by enzyme-linked

immunosorbent assays (ELISAs) using CCPs as antigen. Anti-CCP antibodies have a
similar sensitivity to RF for RA but have a much higher specificity (95 to 98 percent) [1-
4]. The specificity is greater in patients with higher titers of anti-CCP antibodies (at least
three times the upper limit of normal). Another test, anti-mutated citrullinated
vimentin, gives similar results to anti-CCP and is used as an alternative in some
laboratories [5]. (See "Biologic markers in the diagnosis and assessment of rheumatoid
arthritis", section on 'Anti-citrullinated peptide antibodies'.)

Acute phase reactants — Elevations of the ESR and/or CRP level are consistent with
the presence of an inflammatory state, such as RA. Normal acute phase reactants may
occur in untreated patients with RA, but such findings are very infrequent. The degree
of elevation of these acute phase reactants varies with the severity of inflammation. As
an example, an ESR of 50 to 80 is not uncommon in patients with severely active RA. By
comparison, an ESR of 20 to 30 can be observed with only a few mildly to moderately
active joints. Although increased levels of acute phase reactants are not specific for RA,
they are often useful for distinguishing inflammatory conditions from noninflammatory
disorders that present with musculoskeletal symptoms (eg, osteoarthritis or
fibromyalgia). (See "Acute phase reactants" and "Biologic markers in the diagnosis and
assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation
rate' and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis",
section on 'C-reactive protein'.)
Patients not meeting above criteria — The diagnosis of RA may also be made in
patients without all the criteria described in the previous section. Examples include the
following:
●Seronegative RA – Patients who lack both RF and anti-CCP antibodies may be
diagnosed with RA based upon findings otherwise characteristic of RA if
appropriate exclusions have been met. Such patients with seronegative RA differ
from anti-CCP-positive patients genetically and in their environmental risks,
disease severity, and clinical responsiveness to some medications [6]. Additional
research is needed to better characterize this population. (See "Biologic markers
in the diagnosis and assessment of rheumatoid arthritis".)
●Recent onset RA – Patients with disease for less than six weeks may be
diagnosed with RA based upon findings otherwise characteristic of RA, including
anti-CCP antibodies, if testing for viral serologies is negative and if other
appropriate exclusions have been met. (See 'Evaluation for suspected RA' above
and 'Viral polyarthritis' below.)
●Inactive RA – Patients without active arthritis or elevated acute phase reactants
(eg, due to treatment of recent onset disease or with longstanding disease) may
be diagnosed with RA based upon well-documented past findings characteristic of
RA, especially in the presence of positive testing for RF and anti-CCP, or typical
bone erosions on radiography, and in the absence of an alternative more likely
diagnosis.

Patients in the several categories above, and other patients who should be diagnosed
with RA but do not meet our standard criteria, will generally have findings that are
consistent with the 2010 ACR/EULAR classification criteria for RA [7,8]. These criteria
were developed for the classification of patients with RA for the purpose of
epidemiologic studies and clinical trials, not primarily for clinical diagnosis.
Nevertheless, the same features that are of value in classification tend to be useful for
the purpose of diagnosis in clinical practice. Further study is required to establish their
utility as diagnostic criteria in general practice. (See 'Classification criteria' below.)

CLASSIFICATION CRITERIA

The 2010 American College of Rheumatology (ACR)/European League Against

Rheumatism (EULAR) classification criteria focus on features that would identify
patients at an earlier stage of disease than would the previously used criteria that had
been last revised in 1987 [7-10]. The 1987 ACR criteria were formulated to distinguish
patients with established rheumatoid arthritis (RA) from patients with other defined
rheumatic diseases; the 2010 ACR/EULAR criteria for RA focused on identifying the
factors, among patients newly presenting with undifferentiated inflammatory synovitis,
which could allow for the identification of patients for whom the risk of symptom
persistence or structural damage is sufficient to be considered for intervention with
disease-modifying antirheumatic drugs (DMARDs) [7,8]. (See below.)
2010 ACR/EULAR criteria — Using the 2010 ACR/EULAR classification criteria for RA,
classification as definite RA is based upon the presence of synovitis in at least one joint,
the absence of an alternative diagnosis that better explains the synovitis, and the
achievement of a total score of at least 6 (of a possible 10) from the individual scores in
four domains [7,8,11]. The highest score achieved in a given domain is used for this
calculation. These domains and their values are:
●Number and site of involved joints
•2 to 10 large joints (from among shoulders, elbows, hips, knees, and ankles)
= 1 point
•1 to 3 small joints (from among the metacarpophalangeal joints, proximal
interphalangeal joints, second through fifth metatarsophalangeal joints,
thumb interphalangeal joints, and wrists) = 2 points
•4 to 10 small joints = 3 points
•Greater than 10 joints (including at least 1 small joint) = 5 points
●Serological abnormality (rheumatoid factor or anti-
citrullinated peptide/protein antibody)
•Low positive (above the upper limit of normal [ULN]) = 2 points
•High positive (greater than three times the ULN) = 3 points
●Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-
reactive protein [CRP]) above the ULN = 1 point
●Symptom duration at least six weeks = 1 point

In addition to those with the criteria above, which are best suited to patients with
newly presenting disease, the following patients are classified as having RA:

●Patients with erosive disease typical of RA with a history compatible with prior
fulfillment of the criteria above
●Patients with longstanding disease, including those whose disease is inactive
(with or without treatment) who have previously fulfilled the criteria above based
upon retrospectively available data

1987 ACR criteria — It is important to recognize that RA has been defined in virtually all
clinical trials of drugs for RA initiated from 1987 through 2010 based upon the criteria
developed and validated by the ACR (previously the American Rheumatism
Association) in 1987 (table 1) [9,10]. A patient was classified as having RA if at least four
of these seven criteria were satisfied; four of the criteria must have been present for at
least six weeks: morning stiffness, arthritis of three or more joint areas, arthritis of the
hands, and symmetric arthritis. Rheumatoid factor (RF) was included as a criterion, but
anti-cyclic citrullinated peptide (CCP) antibody testing was not available at that time.
The other two criteria were rheumatoid nodules and radiographic erosive changes
typical of RA, but these are generally not present in the early stages of disease.

Thus, while these criteria were very good at separating inflammatory from
noninflammatory arthritis, the major drawback of the 1987 criteria has been their
insensitivity in identifying some patients with early disease who subsequently develop
typical established RA [10]. On the other hand, the criteria did not require any
exclusions, and patients could initially fulfill the diagnostic criteria but occasionally
evolve into other diagnoses, particularly systemic lupus erythematosus (SLE), Sjögren's
syndrome, scleroderma, mixed connective tissue disease, psoriatic arthritis, and
crystalline arthritis.

TABLE 1
DIFFERENTIAL DIAGNOSIS

A variety of conditions must be considered in the differential diagnosis of rheumatoid

arthritis (RA). Features of some disorders that are included in the differential diagnosis
of RA are shown in the table (table 2). (See "Evaluation of the adult with polyarticular
pain".)

TABLE 2
Viral polyarthritis — A number of viral infections may cause an acute viral polyarthritis.
●Viral infections such as rubella [12], parvovirus B19 [13], and hepatitis B virus
(HBV) can cause an acute polyarthritis syndrome that may be mistaken for the
inflammatory polyarthritis of RA. However, the syndrome is usually short-lived,
lasting only from a few days to several weeks, and rarely beyond six weeks.
Hepatitis C virus (HCV) can cause a polyarthritis or oligoarthritis in a minority of
patients, but is more commonly associated with arthralgias.
 Serologic testing can help identify patients with HBV, HCV, or human parvovirus
B19 in some individuals with early disease, but a viral etiology cannot always be
excluded until after symptoms are present for at least six to eight weeks in the
absence of diagnostic serologic testing for a specific virus (see "Viruses that cause
arthritis") Unlike rheumatoid factor (RF) (which may occur in patients with a
variety of infections, including HCV infection), anti-cyclic citrullinated peptide
(CCP) antibodies are usually negative in patients with HCV infection who do not
have RA. (See "Biologic markers in the diagnosis and assessment of rheumatoid
arthritis", section on 'Anti-citrullinated peptide antibodies'.)
●Increasingly reported in travelers, alphaviruses are globally distributed mosquito-
borne RNA viruses that cause epidemics of polyarthritis/arthralgia [14,15]. Among
all of the viruses that can cause arthritis, the alphaviruses are unusual because
nearly all symptomatic infections in adults result in joint symptoms. The incubation
period lasts from several days to three weeks; infection is typically associated with
triad of fever, arthritis, and rash [14]. However, all aspects of the triad may not be
present, thereby making the diagnosis difficult.
One such alphavirus, Chikungunya, has become a global disease with increasing
world travel and has caused large outbreaks in Italy, India, Indian Ocean islands,
and in the Caribbean region and surrounding countries [16,17]. Patients with more
persistent disease can mimic seronegative RA clinically to a sufficient degree to
satisfy the 2010 classification criteria for RA if the initial symptoms of fever and
rash and history of travel to an endemic region are not appreciated [18]. Serologic
studies can help to document exposure to the Chikungunya virus.
(See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis",
section on 'Clinical manifestations'.)
Alphavirus infections generally resolve over three to six months. The diagnosis of
alphavirus infection can be made by appropriate serologic testing in travelers from
endemic areas with persistent arthritic symptoms. (See "Viruses that cause
arthritis", section on 'Alphaviruses' and "Chikungunya fever: Epidemiology, clinical
manifestations, and diagnosis".)
●A large joint arthritis has been reported in association with human T
lymphotropic virus type 1 (HTLV-I) [19]. These infections are sometimes associated
with the presence of RFs (usually in low titer), antinuclear antibodies (ANA), and
elevated acute phase reactants. HTLV-I infections can generally be distinguished
from RA by the finding of specific antiviral antibodies and the typically self-limited
nature of arthritis associated with HTLV-I.

Systemic rheumatic diseases — Early RA may be difficult to distinguish from the

arthritis of systemic lupus erythematosus (SLE), Sjögren's syndrome, dermatomyositis
(DM), or overlap syndromes such as mixed connective tissue disease. In contrast with
RA, these disorders are generally characterized by the presence of other systemic
features, such as rashes, dry mouth and dry eyes, myositis, or nephritis, and by various
autoantibodies not seen in RA. Additionally, the relative responses of the erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP) can be less well-correlated with
each other in other diseases, particularly SLE, than in RA. Whereas both are commonly
raised in RA, the CRP is often normal or only minimally elevated in patients with active
SLE even when the ESR is elevated.

Taken together, the pattern of longstanding disease, morning stiffness, symmetric

arthritis, subcutaneous nodules, and the deformities characteristic of RA does not
develop in these other disorders. There are several exceptions to this observation:

●Morning stiffness is common in all inflammatory arthritides. Symmetric arthritis is

seen in patients with SLE and can be present in other disorders. Infrequently,
nodules similar to those seen in RA may occur in patients with SLE, and other
nodular lesions may mimic rheumatoid nodules. (See "Rheumatoid nodules",
section on 'Subcutaneous nodules' and "Rheumatoid nodules", section on
'Differential diagnosis'.)
●An erosive arthritis has been described in some overlap syndromes, particularly
those associated with anti-tRNA synthetases and anti-U1 RNP antibodies [20].
(See "Clinical manifestations of mixed connective tissue disease".)
●Jaccoud's arthropathy occurs in up to 5 to 10 percent of patients with Sjögren's
syndrome or SLE and can also occur in sarcoidosis [21]. (See "Musculoskeletal
manifestations of systemic lupus erythematosus" and "Sarcoid arthropathy".)
The joint deformities of Jaccoud's arthropathy are not caused by destruction of
joints but by loosening and lengthening of periarticular structures and tendons.
The ulnar drift or swan neck deformities caused by this disorder resemble RA
superficially but can be distinguished by the fact that they are "correctable" on
physical examination: fingers with these deformities can be moved manually back
into normal alignment. In addition, radiographs in Jaccoud's arthropathy rarely
reveal the cartilage loss, erosions, or cysts that are typical of longstanding RA.

Palindromic rheumatism — Palindromic rheumatism is characterized by episodes of

joint inflammation sequentially affecting one to several joint areas for hours to days,
with symptom-free periods that may last from days to months. Some patients
presenting with this syndrome eventually develop a well-defined rheumatic disease,
the most common being RA (ranging from 28 to 67 percent); some of the remaining
patients develop SLE and other systemic disorders [22,23]. Patients with anti-CCP
antibodies appear more likely to progress to definite RA [24,25]. Close follow-up and
specific serologic evaluation can help distinguish among these disorders. (See "Clinical
manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism'.)

Hypermobility syndrome and fibromyalgia — Pain, rather than stiffness or swelling, is

the dominant symptom of the two common disorders, hypermobility syndrome and
fibromyalgia [26,27]. Although the hypermobility syndrome and fibromyalgia can both
bear superficial resemblances to RA due to the presence of polyarthralgia, there are
important distinguishing features:
●The hypermobility syndrome is associated with hyperextensible joints, and
patients lack signs of synovitis. (See "Joint hypermobility syndrome".)
 ●Fibromyalgia is associated with tender points at nonarticular sites and chronic
widespread pain. However, there is no evidence of synovitis, such as swelling,
warmth, or diminished joint range of motion, although patients may exhibit joint
line tenderness on exam. (See "Clinical manifestations and diagnosis of
fibromyalgia in adults".)
●Neither the hypermobility syndrome nor fibromyalgia is associated with
significant titers of RF or anti-CCP antibodies or with elevated levels of acute phase
reactants.

Although RA is normally not difficult to distinguish from fibromyalgia, a significant

minority of patients with RA also develop fibromyalgia. The source of complaints in
such patients needs to be carefully assessed to distinguish heightened pain sensitivity
from pain related to inflammatory joint disease.

Reactive arthritis and arthritis of IBD — Reactive arthritis often presents as a

monoarthritis or oligoarthritis in large joints, such as the knees, and RA may
occasionally present in this fashion as well [28]. The physical signs of both reactive
arthritis and RA can be identical in the knees. (See "Reactive arthritis".)

The following findings on history, physical examination, or other assessments are more
consistent with reactive arthritis than RA:

●History of recent urethritis or enteric infection

●Asymmetric pattern of joint involvement
●Symptoms or signs of enthesopathy (inflammation at the site where a tendon
inserts into a bone, eg, the insertion point of the Achilles tendon into the heel)
●Keratoderma blenorrhagica or circinate balanitis (see "Reactive
arthritis" and "Reactive arthritis", section on 'Extraarticular signs and symptoms')
●Radiologic evidence of sacroiliitis and/or spondylitis
●The presence of human leukocyte antigen (HLA)-B27

Involvement of the hands in reactive arthritis does not pose as great a diagnostic
dilemma as that of the knees. Hand arthritis is more commonly asymmetric than in RA.
Furthermore, reactive arthritis will often involve not only the joint but also the
tenosynovium, entheses, and surrounding tissues of the digit, giving rise to a
characteristic "sausage" swelling of the fingers (or toes if the feet are involved)
(picture 1).

PICTURE 1 Sausage toe in reactive arthritis

 ausage toe (with diffuse swelling)
of the second digit and mild
keratoderma blenorrhagica on the
dorsum of the foot in a man with
reactive arthritis (formerly
Reiter's syndrome).

The arthritis associated with inflammatory bowel disease (IBD) or other

gastrointestinal (GI) disorders is also part of the differential diagnosis. Patients with IBD
may develop a peripheral polyarthritis with prominent involvement of the
metacarpophalangeal (MCP) joints that can be mistaken for RA; other presentations
include predominantly large joint oligoarticular involvement or a spondyloarthropathy
with sacroiliitis. This disorder may be missed if abdominal symptoms or symptoms of
diarrhea and/or blood or mucus in the stool are not prominent or are not specifically
sought in the history. (See "Clinical manifestations and diagnosis of arthritis associated
with inflammatory bowel disease and other gastrointestinal diseases".)

Lyme arthritis — Lyme arthritis, a late manifestation of Lyme disease, occurs primarily
in individuals who live in or travel to Lyme disease-endemic areas. Lyme arthritis is
characterized by intermittent or persistent inflammatory arthritis in a few large joints,
especially the knee. The most commonly involved joints, after the knee, are the
shoulder, ankle, elbow, temporomandibular joint, and wrist. Migratory arthralgias
without frank arthritis may occur during early localized or early disseminated Lyme
disease. (See "Musculoskeletal manifestations of Lyme disease".)

The diagnosis of Lyme arthritis can usually be made by serologic testing, which should
be performed in patients presenting with undiagnosed inflammatory arthritis in
endemic areas. In addition, several clinical features help distinguish Lyme arthritis from
RA. Unlike RA, for example, involvement of the small joints of the hands and feet is
uncommon in patients with Lyme arthritis. Furthermore, many, but not all, patients
with Lyme arthritis will describe an antecedent history of erythema migrans or other
early disease manifestations. (See "Musculoskeletal manifestations of Lyme disease",
section on 'Laboratory testing'.)

Psoriatic arthritis — Psoriatic arthritis can be difficult to distinguish from RA because a

symmetric polyarthritis can be observed in both disorders [29]. We generally make the
diagnosis of psoriatic arthritis in such patients who also have psoriasis and are
seronegative for RF and anti-CCP. However, we diagnose RA in those with a symmetric
polyarthritis who are seropositive for at least one of these antibodies, since skin
psoriasis is so common. However, serologic testing and skin findings may not be
informative, since patients with RA may not have RF or CCP antibodies (eg,
seronegative RA) and the joint symptoms of psoriatic arthritis may precede the onset
of skin disease by many years. Such patients should be evaluated and monitored for
other signs more characteristic of psoriatic arthritis, such as nail changes or enthesitis;
occasional patients exhibit overlapping features of both disorders.

In some patients with a symmetric inflammatory polyarthritis, the only clue to the
diagnosis of psoriatic arthritis is a family history of psoriasis. However, in the majority,
the findings of skin psoriasis, nail changes (onychodystrophy), sausage toes or fingers,
oligoarticular asymmetric large joint or spinal involvement, and/or arthritis mutilans
help distinguish the two entities. (See "Clinical manifestations and diagnosis of
psoriatic arthritis".)

Polymyalgia rheumatica — Polymyalgia rheumatica (PMR) can sometimes be mistaken

for RA in patients presenting with more limited arthritis over the age of 50 who are
seronegative or only have a low RF titer. Unlike RA, PMR is usually associated with
marked myalgias in the shoulders and hips, and joint involvement tends to be milder,
more limited, and more often asymmetric.

Stiffness is thus more axial in PMR and more likely to be described as difficulty getting
out of bed, while stiffness in the small joints of the hands and other involved joints
predominates in RA, in which difficulty buttoning clothing is more likely to be reported.
However, similar complaints to RA may be present in patients with PMR with synovitis
affecting the small joints in the hands.

The arthritis in PMR tends to respond strikingly to modest doses of glucocorticoids

used to control other symptoms [30]. In patients initially diagnosed with PMR,
persistent or recurrent small joint arthritis with tapering of glucocorticoids and the
absence of other findings suggestive of PMR may lead to a change in the diagnosis to
RA after several months or even years of treatment. (See "Clinical manifestations and
diagnosis of polymyalgia rheumatica".)

Crystalline arthritis — Crystalline arthritis (gout and pseudogout) can become chronic
and even assume a polyarticular distribution. The diagnosis is established by the finding
of urate or calcium pyrophosphate crystals, respectively, in synovial fluids. The
presence of tophi on physical examination, the detection of serological markers of RA,
and the characteristic appearance of gouty erosions are also useful in distinguishing RA
from polyarticular gout. (See "Clinical manifestations and diagnosis of
gout"and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal
deposition (CPPD) disease".)
Infectious arthritis — Infectious arthritis is usually monoarticular, but polyarthritis can
occur. The diagnosis is established by culturing the pathogen from the synovial fluid or
from the blood. Patients with septic arthritis may or may not appear toxic on
examination, depending upon the stage of their infection, the presence of medications
that can mask infection (eg, glucocorticoids), and other clinical variables. Peripheral
blood leukocytosis with a left shift is common but not invariably present.
A low threshold for suspecting infection is required, particularly in compromised hosts.
Patients with RA are at increased risk for joint infections because a damaged joint can
serve as a nidus of infection. Synovial fluid changes, including marked granulocytosis
and low glucose levels, are similar to those seen in RA. (See "Septic arthritis in adults".)

Osteoarthritis — Osteoarthritis (OA) can be confused with RA in the middle aged or

older patient when the small joints of the hands are involved. However, different
patterns of clinical involvement usually permit the correct diagnosis (table 3). The
following are examples (see "Clinical manifestations and diagnosis of osteoarthritis"):
●OA of the fingers typically affects the distal interphalangeal joints and is
frequently associated with Heberden's nodes in this area. In contrast, RA typically
affects the MCP and proximal interphalangeal (PIP) joints and is not associated
with Heberden's nodes.
●The carpometacarpal joint of the thumb is typically involved in OA.
●Swelling of the joints is hard and bony in OA. In contrast, soft, warm, boggy, and
tender joints are typical of RA.
●Stiffness of the joint is a very common feature of RA but is relatively uncommon
in OA. Furthermore, the stiffness of RA is characteristically worse after resting the
joint (eg, morning stiffness), while the stiffness of OA, if present, is typically worse
after any effort and is often described as evening stiffness. Morning stiffness in
OA, when present, is usually transient or lasts no more than a few minutes, unlike
the more sustained stiffness typical of RA.
●Radiographs also help distinguish RA from OA. OA is characterized by narrowing
of the joint space due to cartilage loss and osteophytes due to bone remodeling,
but not erosions or cysts.
●OA is classically associated with the absence of RFs and normal levels of acute
phase reactants. However, RFs may be present, usually in low titer, consistent
with the patient's (older) age.

Paraneoplastic disease — Joint pain or frank polyarthritis can occur in association with
cancer. The following are some examples:
●Hypertrophic osteoarthropathy – Patients with hypertrophic osteoarthropathy,
sometimes termed hypertrophic pulmonary osteoarthropathy, typically
demonstrate clubbing of the digits, joint pain, and periosteal new bone formation.
Additionally, they give a characteristic history suggestive of bone pain and often
describe the pain as deep and achy; nocturnal pain is common. Joint effusions may
occur. This is an important diagnosis because lung cancer is the commonest
underlying cause. (See "Malignancy and rheumatic disorders", section on
'Hypertrophic osteoarthropathy'.)
●Myelodysplasia – Patients with myelodysplastic syndrome sometimes develop an
inflammatory polyarthritis that mimics RA [31]. The majority of patients are
seronegative for RF and few are positive for anti-citrullinated peptide antibody or
exhibit erosive changes on joint radiography. The arthritis may precede the
diagnosis of myelodysplasia in at least half of the patients. In a cohort study of 87
 patients with myelodysplastic syndrome, five (6 percent) had inflammatory
arthritis that resembled RA [32]. Persistence of anemia, other cytopenias, or
elevated acute phase reactants despite control of the arthritis should heighten
suspicion of myelodysplasia [31]. (See "Clinical manifestations and diagnosis of the
myelodysplastic syndromes".)

Multicentric reticulohistiocytosis — Multicentric reticulohistiocytosis is a rare but

highly destructive form of arthritis. The rapid joint destruction of multicentric
reticulohistiocytosis resembles the arthritis mutilans occasionally observed in RA.
Multiple smooth, shiny, erythematous nodules located in the periungual region suggest
multicentric reticulohistiocytosis. Binucleated or multinucleated foreign body type
giant cells are present on skin or synovial biopsies in multicentric reticulohistiocytosis
[33,34]. In a minority of patients, an underlying malignancy may be present.
(See "Cutaneous manifestations of internal malignancy", section on 'Summary'.)

Multicentric reticulohistiocytosis is relatively resistant to glucocorticoids and to

disease-modifying antirheumatic drugs (DMARDs) such
as methotrexate and hydroxychloroquine. However, there are case reports of response
to tumor necrosis factor (TNF)-alpha inhibition [35,36] and to parenteral administration
of an aminobisphosphonate [37,38].

Sarcoid arthropathy — Chronic arthritis in sarcoidosis may be oligoarticular or

polyarticular and can appear similar to RA in some patients. It most frequently affects
the ankles, knees, hands, wrist, and MCP and PIP joints, and it is frequently associated
with parenchymal pulmonary disease.

This disorder is distinguished from RA by the following findings:

●Elevated serum concentrations of angiotensin-converting enzyme (ACE) are

found in up to 50 percent of patients.
●A chest radiograph may reveal characteristic findings of sarcoidosis.
●The pattern of acute arthritis with Lofgren’s syndrome in patients with
sarcoidosis is not observed in those with RA.

(See "Sarcoid arthropathy".)

Fibroblastic rheumatism — Fibroblastic rheumatism, a rare disease of unknown

etiology, shares the features of arthralgia, arthritis, and nodules with RA [39-41].
Flexion contractures of the fingers occur in most patients, while thickened palmar
fascia is noted in about one-half of reported cases. Biopsy of a nodule or thickened skin
typically reveals increased thickness of collagen fibers and fibroblastic proliferation.
Decreased elastic fibers and the presence of myofibroblasts are noted in approximately
50 percent. Radiographic findings are variable, but periarticular osteopenia and
erosions may be noted.
Due to the rarity of fibroblastic rheumatism, there is no well-established treatment.
Progressive disease may lead to sclerodactyly and ankylosis of affected joints.

SOCIETY GUIDEKINE 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.)

●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)")

●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:
Complementary and alternative therapies for rheumatoid arthritis (Beyond the
Basics)")

SUMMARY AND RECOMMENDATIONS

●Rheumatoid arthritis (RA) should be suspected in the adult patient who presents
with inflammatory polyarthritis. The initial evaluation of such patients requires a
careful history and physical examination, along with selected laboratory testing to
identify features that are characteristic of RA or that suggest an alternative
diagnosis. (See 'Evaluation for suspected RA'above and 'Differential
diagnosis' above.)
●The following components of the medical evaluation are helpful in making a
clinical diagnosis of RA, both for the identification of characteristic findings and for
the exclusion of other diagnoses (see 'Evaluation for suspected RA' above):
 •A thorough medical history, with particular attention to joint pain, stiffness,
and associated functional difficulties
•A complete physical examination to assess for synovitis, limited joint
motion, extraarticular disease manifestations, and signs of diseases included
in differential diagnosis
•Basic and selected laboratory testing, including assays for acute phase
reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein
[CRP]), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP)
antibodies, and antinuclear antibodies (ANA)
•Selected imaging studies, including bilateral radiographs of the hands,
wrists, and feet
•Arthrocentesis, if there is diagnostic uncertainty
●The diagnosis of RA can be made in a patient with inflammatory arthritis
involving three or more joints, positive RF and/oranti-
citrullinated peptide/protein antibody, disease duration of more than six weeks,
and elevated CRP or ESR, but without evidence of diseases with similar clinical
features. (See 'Our diagnostic criteria' above.)
●RA may also be diagnosed in patients without all of the classic findings of
disease. This includes patients with seronegative RA, those with clinically
quiescent disease, and those with recent onset RA. Such patients
have findings/clinical features that are generally consistent with those described
as meeting the American College of Rheumatology (ACR)/European League
Against Rheumatism (EULAR) classification criteria for RA. (See 'Patients not
meeting above criteria' above.)
●The 2010 classification criteria for RA were developed primarily for the
identification for research purposes of patients with RA who are at high risk of
persistent symptoms and joint injury unless treated with disease-modifying
antirheumatic drugs (DMARDs). These criteria have replaced the 1987 criteria,
which were based only upon patients with established disease. (See 'Classification
criteria' above.)
●The differential diagnosis of RA includes multiple disorders that can generally be
distinguished clinically or by limited laboratory testing, based upon a combination
of the following features (see 'Differential diagnosis' above):
•Limited duration (eg, in viral arthropathy)
•The presence of other diseases (eg, in psoriatic arthritis or arthritis of
inflammatory bowel disease [IBD])
•The pattern of joint involvement and other symptoms (eg, in psoriatic
arthritis, spondyloarthropathy, or polymyalgia rheumatica [PMR])
•The presence of systemic features (eg, in systemic lupus erythematosus
[SLE] or dermatomyositis [DM])
•Diagnostic laboratory tests associated with other conditions (eg, specific
autoantibodies in SLE, synovial fluid crystals in gout or calcium
pyrophosphate disease)
•Relatively high specificity of anti-CCP antibodies for RA
 Clinical manifestations of rheumatoid arthritis

Author:
PJW Venables, MA, MB BChir, MD, FRCP
Section Editor:
James R O'Dell, MD
Deputy Editor:
Paul L Romain, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jun 2019. | This topic last updated: Oct 12, 2017.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown

etiology that primarily involves synovial joints. The arthritis is typically symmetrical, and
usually leads, if uncontrolled, to destruction of joints due to erosion of cartilage and
bone, causing joint deformities. The disease usually progresses from the periphery to
more proximal joints and results in significant locomotor disability within 10 to 20 years
in patients who do not fully respond to treatment.

The major clinical features of RA, including the articular manifestations, are reviewed
here. The systemic and nonarticular features and the diagnosis and differential
diagnosis of RA are discussed in detail separately. (See "Overview of the systemic and
nonarticular manifestations of rheumatoid arthritis" and "Diagnosis and differential
diagnosis of rheumatoid arthritis".)

INITIAL CLINICAL PRESENTATION

Rheumatoid arthritis (RA) most typically presents as polyarticular disease and with a
gradual onset, but some patients can present with acute onset with intermittent or
migratory joint involvement or with monoarticular disease. (See 'Typical 'classic'
RA'below and 'Palindromic rheumatism' below and 'Monoarthritis' below.)

The symptoms of arthritis can affect the patient's capacity to perform the activities of
daily living (eg, walking, stairs, dressing, use of a toilet, getting up from a chair, opening
jars, doors, typing) and their ability to do their job.

Systemic symptoms may also be present in these patients; in up to one-third of

patients, the acute onset of polyarthritis is associated with prominent myalgia, fatigue,
low-grade fever, weight loss, and depression. Less often, extraarticular manifestations
such as nodules or episcleritis may also be present. (See 'Extraarticular
involvement' below.)

Articular disease

Typical 'classic' RA — The disease onset in RA is usually insidious, with the predominant
symptoms being pain, stiffness (especially morning stiffness), and swelling of many
joints [1]. Typically, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP)
joints of the fingers, the interphalangeal joints of the thumbs, the wrists, and the
metatarsophalangeal (MTP) joints of the toes are sites of arthritis early in the disease.
Other synovial joints of the upper and lower limbs, such as the elbows, shoulders,
ankles, and knees, are also commonly affected [2,3].

Morning stiffness is a common feature of those with active RA; it can be defined as
"slowness or difficulty moving the joints when getting out of bed or after staying in one
position too long, which involves both sides of the body and gets better with
movement" [4]. Morning stiffness lasting more than one hour reflects a severity of
joint inflammation that rarely occurs in diseases other than RA, although morning
stiffness, or stiffness after any prolonged period of inactivity, is also seen in virtually all
inflammatory arthropathies [5].

Occasionally, features suggesting polymyalgia rheumatica (PMR) may be present in

addition to features of polyarticular RA, and some patients who subsequently develop
RA may present with typical PMR. When this occurs in the absence of clinically
detectable synovitis, the distinctive clinical features of RA may not develop until
months or even years later. (See "Clinical manifestations and diagnosis of polymyalgia
rheumatica", section on 'History' and "Clinical manifestations and diagnosis of
polymyalgia rheumatica", section on 'Differential diagnosis'.)

Palindromic rheumatism — The onset of RA is episodic in a few patients, with one to

several joint areas being affected sequentially for hours to days, alternating with
symptom-free periods that may last from days to months; this episodic pattern is
referred to as "palindromic rheumatism." Patients with palindromic rheumatism have
similar predisposing genetic risk factors to patients with a more typical persistent
presentation of RA and exhibit a similar dose effect of carriage of certain human
leukocyte antigen (HLA) alleles [6]. (See "Epidemiology of, risk factors for, and possible
causes of rheumatoid arthritis", section on 'Genetic susceptibility' and "Diagnosis and
differential diagnosis of rheumatoid arthritis", section on 'Palindromic rheumatism'.)

The proportion of patients presenting with palindromic rheumatism who progress to

develop RA or another well-defined disease varies between studies. In one study of 60
patients with palindromic rheumatism followed over 20 years, 40 (67 percent)
developed RA [7]. In another study, among 147 such patients seen in a tertiary referral
center, 41 were eventually diagnosed with RA (28 percent) and four with other
disorders (three with systemic lupus erythematosus and one with Behçet syndrome)
[6].

The presence of anti-citrullinated peptide/protein antibodies (ACPA), a serologic finding

that is common in RA, might predict progression of palindromic rheumatism to RA, but
evidence evaluating this possibility has been mixed [8]. In one study, involving 61
patients followed for a mean of five-and-a-half years, ACPA testing was performed
within a year of symptom onset and antibodies were present in 83 percent of patients
who progressed to definite RA, but only 19 percent of those whose disease did not [9].
However, in another study, a majority of those with palindromic rheumatism also had
ACPA, but there was no significant difference in the frequency of ACPA between
patients with persistent palindromic rheumatism and those who subsequently
developed RA [10]. (See "Biologic markers in the diagnosis and assessment of
rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)

A response by patients with palindromic rheumatism to hydroxychloroquine, which are

also used for the treatment of RA, further supports the possibility that palindromic
rheumatism can be a presenting feature of RA. The use of hydroxychloroquine in such
patients may also reduce the risk of progression to RA. One retrospective study of 113
patients with palindromic rheumatism found that those who received
hydroxychloroquine were 20 percent less likely to develop a chronic rheumatic disease
[11].

Monoarthritis — Persistent single joint arthritis (monoarthritis), frequently of a large

joint such as the wrist, knee, shoulder, hip, or ankle, may be the sole manifestation of
RA or may herald the onset of polyarticular disease. There may be a history of joint
trauma as an apparent initiating event. The interval between monoarthritis and
polyarthritis may extend from days to several weeks in patients whose disease
progresses. Until polyarthritis develops, the approach to such patients is that for any
patient with monoarticular arthritis. (See "Overview of monoarthritis in adults".)

Extraarticular involvement — A proportion of patients complain of a constellation of

persistent nonarticular symptoms, which may antedate the onset of polyarthritis by
many months; these include generalized aching, stiffness, symptoms of bilateral carpal
tunnel syndrome, loss of weight, depression, and fatigue (the last simulating chronic
fatigue syndrome [CFS], also known as myalgic encephalomyelitis/chronic fatigue
syndrome [ME/CFS]). In addition, patients may rarely present with extraarticular
disease in the absence of clinical arthritis. (See 'Symptoms and physical findings' below
and "Overview of the systemic and nonarticular manifestations of rheumatoid
arthritis".)

SYMPTOMS AND PHYSICAL FINDINGS

Joint pain and swelling, especially of the small joints of the hands, wrist, and forefoot
are common, along with morning stiffness and decreased grip strength, although all
peripheral joints and, to a lesser degree, the more proximal joints of the extremities
can be affected. The axial skeleton is usually spared, other than the cervical spine,
where severe disease may cause serious neurologic compromise, generally in patients
with longstanding disease. Patients with poorly controlled disease typically experience
progressive joint damage, which may result in significant joint deformities and
functional impairment (see 'Physical findings of joint inflammation' below
and 'Distribution of involved joints' below and 'Upper extremity' below and 'Lower
extremity'below and 'Axial skeleton' below and 'Cricoarytenoid joint' below). Disease
outcome and functional impairment in rheumatoid arthritis (RA) are reviewed in detail
separately. (See "Disease outcome and functional capacity in rheumatoid arthritis".)

Symptoms and findings of systemic and nonarticular manifestations may include

generalized aching, stiffness, weight loss, depression, and fatigue. Most patients with
extraarticular features of RA have longstanding and severe disease; these features,
which are discussed in more detail separately, include anemia, fatigue, subcutaneous
("rheumatoid") nodules, pleuropericarditis, neuropathy, episcleritis, scleritis,
splenomegaly, Sjögren's syndrome, vasculitis, and others. (See "Overview of the
systemic and nonarticular manifestations of rheumatoid arthritis".)

Physical findings of joint inflammation — The key features of early rheumatoid

inflammation are pain and swelling of the affected joints. Painful inflammation is
demonstrated either by local tenderness from pressure applied on the joint or by pain
on moving the joint. Swelling may be due to synovial hypertrophy or effusion. Synovial
thickening is detected by a "boggy" feel to a swollen joint, and effusion by
demonstrating fluctuance. Heat and redness are not prominent features of RA,
although an involved joint is often perceptibly warmer on careful examination.
Synovitis of the wrist may present as carpal tunnel syndrome even in very early disease,
when swelling may not be particularly evident. The characteristic joint deformities are
late manifestations of disease that result from the physical stresses and damage to the
local anatomy of involved joints.

Distribution of involved joints — RA eventually affects the peripheral joints in almost

all patients. Involvement of axial and central joints is less common, occurring in 20 to
50 percent of patients; such joints include the interfacetal and atlantoaxial joints of the
neck; the acromioclavicular [12], sternoclavicular, temporomandibular, and
cricoarytenoid joints; and the shoulders and hips. Lumbar spine facet joint synovitis
may occur, but the frequency of such involvement is rare.

Symmetrical involvement of joints is a characteristic feature, although this may be less

apparent early in the disease. The severity of joint disease and consequent deformity is
sometimes notably asymmetrical, an observation that may be attributed to increased
structural damage to joints related to unilateral overuse of a dominant limb, or joint
protection of a limb resulting from neurologic disease. Squeeze tenderness at the
metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints and palpable
synovial thickening at these joints are characteristic of RA.

Upper extremity

Hands — The main signs of disease can often be found in the hands early in the course
of RA [13]. Symmetrical effusions and soft tissue swelling around the MCP and proximal
interphalangeal (PIP) joints typically occur. These joints are tender to the touch and
exhibit a restricted range of movement. Reduced grip strength is a sensitive but
nonspecific feature of disease activity affecting the hands and wrists. Palmar erythema
may be present (as with any peripheral arthritis).

Occasionally, thickening of the flexor tendons can be detected by palpation of the

palm; this finding is due to synovitis of the tendon sheaths ("tenosynovitis"). Nodules
may form along the palmar tendon sheaths, resulting in the tendon sheath catching (or
triggering) and in an inability to fully extend the finger. The nodules may cause tendon
rupture, especially of the extensor pollicis longus (extensor of the distal
interphalangeal [DIP] joint of the thumb).

Other physical signs include:

●Reduced grip strength, which is common, can be a surprisingly sensitive indicator

of early disease, as well as a useful parameter in the evaluation of disease activity
and progression. However, the multiplicity of factors (joint pain, tendon
involvement, nerve compression, and muscle wasting) that contribute to a weak
grip makes this assessment rather nonspecific.
●The whole hand may be swollen in very acute RA, with pitting edema over the
dorsum giving rise to the "boxing glove" appearance. The range of movement of
involved joints is restricted, and loss of active flexion may be so severe that the
patient is unable to oppose the finger tips to the palm.
●Between 1 and 5 percent of patients present with carpal tunnel syndrome.
Affected patients develop dysesthesia and muscle weakness of the first three
fingers and the radial side of the fourth finger. A positive Tinel's or Phalen's sign is
usually present. (See "Carpal tunnel syndrome: Clinical manifestations and
diagnosis".)

The characteristic joint deformities appear in more established chronic RA. These
findings include ulnar deviation or "ulnar drift", swan neck and Boutonniere
deformities of the fingers (picture 1A-C), and the "bow string" sign (prominence of the
tendons in the extensor compartment of the hand). Occasional patients present with
extensor tendon rupture, most commonly affecting the thumb or little or ring fingers
of either hand. The nails and fingertips may show evidence of digital infarcts in patients
with rheumatoid vasculitis. (See "Clinical manifestations and diagnosis of rheumatoid
vasculitis", section on 'Cutaneous vasculitis'.)
PICTURE 1 Synovial thickening of the metacarpophalangeal joint

Bilateral swelling of the MCP

joints is evident in this
patient with rheumatoid
arthritis. Note also the mild
swan neck deformities
present in several fingers,
particularly the left middle
and fifth fingers.

Swelling of the metacarpophalangeal joints of the right hand in rheumatoid arthritis

Swelling of the MCP joints,

moderate MCP flexion, and swan
neck deformities are evident in
this patient with rheumatoid
arthritis.

Rheumatoid arthritis hand deformities: Boutonniere deformity and Z-deformity of the

thumb
 A woman with longstanding rheumatoid
arthritis has soft tissue swelling and
subluxation of the metacarpophalangeal
joints. The right thumb shows
hyperextension of the interphalangeal joint
(a Z deformity). Both ring fingers have
boutonniere deformities with flexion of the
proximal and hyperextension of the distal
interphalangeal joints.

Wrists, elbows, and shoulders — All of the upper extremity joints may be involved in
RA, including the wrists, usually early in the disease course, as well as the elbows and
shoulders:

●Wrists – The wrist is probably the most common upper extremity joint to be
involved other than the small joints in the hand. Early in the disease there is a loss
of extension. Late changes due to erosive damage lead to volar subluxation and
radial drift of the carpus, resulting in increasing prominence of the ulnar styloid
and lateral deviation [14]. Tendon rupture can also occur at the wrist.
●Elbows – The elbow is frequently affected, with loss of extension (fixed flexion)
both in early and late disease (image 1). An effusion or synovitis may be detected
as a bulge between the head of the radius and the olecranon. A compressive
neuropathy of the ulnar nerve, with dysesthesias of the fourth and fifth fingers,
can result from elbow synovitis. Olecranon bursitis is also common. Destruction of
the joint may occur due to erosion of cartilage and bone.

IMAGE 1 Rheumatoid arthritis of the elbow

Lateral view of the elbow in a patient

with rheumatoid arthritis (RA) reveals
soft tissue swelling and osteopenia with
destruction of the elbow joint (arrows).
There are also secondary proliferative
bony changes, which have arisen due to
joint space destruction.
 The elbow is the most common site for subcutaneous rheumatoid nodules (picture
2). These should always be looked and felt for in view of their diagnostic and
prognostic importance. (See "Rheumatoid nodules".)

PICTURE 2 Rheumatoid nodules

Rheumatoid nodules are firm,

nontender lesions that typically
occur in areas of trauma in
individuals with rheumatoid
arthritis. Nodules are present near
the elbows in this patient

●Shoulders – The shoulder, being more proximal, tends to be involved later in the
disease. A prospective study performed prior to the widespread availability of
biologic agents assessed shoulder involvement over time in 74 patients with RA
[15]. At 15 years, 55 percent had developed radiographic evidence of erosive
glenohumeral joint disease [15]. The most common site for erosions was the
superolateral aspect of the humerus.
Disease in the glenohumeral joint leads to painful restriction of movement
resembling a capsulitis, and can result in the development of a "frozen" shoulder.
This will typically cause pain at night, when the patient lies on the affected
shoulder. Rotator cuff injury is common. Effusions are relatively rare, but when
they occur they may be detected in the anterior glenohumeral joint as a filling of
the depression under the clavicle anterior to the head of the humerus.

Lower extremity — Lower extremity joints are often involved in RA, particularly in the
forefoot and ankles; the knees and hips may also be affected, but hip involvement
tends to occur in more severe or longstanding disease. Synovitis in the knee may
predispose to the development of popliteal (Baker's) cysts.
 ●Feet and ankles – Foot involvement, especially of the MTP joints, is common in
early disease, with a pattern which mirrors that occurring in the hand.
•Tenderness of the MTP joints may be marked, resulting in the tendency to
bear weight on the heels and hyperextend the toes.
•Erosive damage results in lateral drift of the toes and plantar subluxation of
the metatarsal heads (picture 3), resulting in "cock-up" deformities. The latter
may be palpable as bony lumps on the sole with associated callosities.
•Involvement of the tarsus and the associated tendon sheaths is also
common, leading to pain on inversion or eversion of the foot and diffuse
edema and erythema over the dorsum of the foot.
•Heel pain may be associated with retrocalcaneal bursitis or tarsal tunnel
syndrome, caused by impingement of the posterior tibial nerve. Tarsal tunnel
syndrome is also associated with paresthesiae of the toes and is important
because it can be diagnosed by ultrasound and treated by local injection or
surgical release. (See "Overview of lower extremity peripheral nerve
syndromes", section on 'Tarsal tunnel syndrome'.)

Picture 3 Rheumatoid arthritis in the feet: Metatarsal head subluxation

Chronic inflammation at the metatarsophalangeal

(MTP) joints causes damage resulting in
subluxation of the toes upwards. With the MTP
joints displaced, weightbearing is not shared
through the toes, but falls directly on the
prominent metatarsal heads. This painful
condition results in pain on weightbearing and
difficulty in walking, and can cause the
metatarsal to erode through the skin on the sole
of the foot. Treatment in the early stages
includes appropriate shoes and fitting of an
orthotic that will support weight away from the
painful metatarsal heads. Late-stage treatment
may involve surgical excision of the prominent
metatarsal heads.

•Arthritis of the ankle can lead to a diffuse swelling around the tibiotalar
joints, which may be red and edematous. These findings may be wrongly
attributed to fluid retention or an infective cellulitis of the skin.
●Knees – The knee manifests many changes in RA. Synovial thickening is easily
detected at the knee, often extending around the patella. Effusion is a common
feature of knee involvement and can be elicited by patellar tap. Restriction of
movement, particularly flexion, is also a common physical finding. In addition,
ligamentous laxity leading to deformities and quadriceps atrophy is frequently
observed. Erosion of the femoral condyles and tibial plateau can result in either
genu varus or genu valgus.
Patients with RA may develop popliteal (Baker's) cysts, which can be detected by
palpation of the popliteal fossa [16]. Ruptured Baker's cysts extending down the
calf are of clinical importance because they can resemble a deep vein thrombosis
or acute thrombophlebitis [17]. A history of arthritis, morning stiffness, lack of a
palpable occluded venous cord, and edema below the posterior of the knee all
suggest a Baker's cyst. Ultrasonography is generally used for the detection of
intact or ruptured Baker's cysts (image 2A-B), and they can be readily imaged by
magnetic resonance imaging (MRI), although historically a ruptured Baker's cyst
was usually demonstrated using arthrography [18]. (See "Popliteal (Baker's)
cyst".)

IMAGE 2 A Y B Small popliteal cyst on ultrasound imaging

US in transverse projection
shows a popliteal cyst (arrow)
that measures 1.1 cm by .75
cm.

Ruptured popliteal cyst on ultrasound

 US through the popliteal fossa (A) in transverse projection shows a decompressed popliteal
cyst (arrow). Image B is a longitudinal view inferior to the popliteal fossa and shows fluid
dissecting through the muscle planes (arrow).

●Hips – Involvement of the hips typically occurs only in well-established disease.

Hip disease is most frequently manifested as pain in the groin, thigh, or low back,
or referred to the knee on standing or movement. Restriction of movement,
detected by "log rolling the leg" or rotation of the hip, also may be seen. Pain in
the lateral thigh suggests trochanteric bursitis. (See "Greater trochanteric pain
syndrome (formerly trochanteric bursitis)".)

Axial skeleton — Cervical spine involvement is relatively common in RA, especially in

longstanding disease, compared with the very infrequent involvement that occurs in
the thoracolumbar spine or sacroiliac joints. Symptoms of pain and stiffness in the neck
are the most typical manifestation, but disease affecting the joints of the cervical spine
can be of critical clinical importance, as longstanding disease may lead to instability and
cause symptoms related to subluxation such as neck pain, stiffness, and radicular pain.
If the subluxation is causing spinal cord compression, there may be signs of long tract
involvement such as hyperreflexia or up going toes on Babinski testing. The clinical
manifestations of cervical spine subluxation and the approach to diagnosis and
management are discussed in detail separately. (See "Cervical subluxation in
rheumatoid arthritis".)

Involvement of the facet joints of the lumbar spine and occasionally discitis has been
reported to occur in RA, both from radiographic and post-mortem studies [19].
However, in clinical practice, it is important to exclude common and serious causes of
back pain, such as vertebral compression fractures associated with low bone mass,
before attributing back pain to rheumatoid involvement of the lumbar spine.

Cricoarytenoid joint — Nearly 30 percent of patients with RA have involvement of the

cricoarytenoid joint; symptoms may include hoarseness and an inspiratory stridor.

LABORATORY FINDINGS

A number of abnormalities are present in the blood and synovial fluid of patients with
rheumatoid arthritis (RA) that reflect the presence of systemic and intraarticular
inflammation and the autoimmune features of the disorder; these include
inflammatory joint fluid, anemia of chronic inflammation, the presence of rheumatoid
factors (RF) and anti-citrullinated peptide/proteinantibodies (ACPA), and evidence of
an acute phase response that tends to correlate with the degree of disease activity.
●Synovial fluid – Synovial fluid examination in affected joints usually reveals an
inflammatory effusion, with a leukocyte count typically between 1500
and 25,000/cubic mm characterized by a predominance of polymorphonuclear
cells [20]. Cell counts in excess of 25,000 may occur in very active disease, but
levels over 25,000 should alert the clinician to the increased possibility of
coexisting infection [21,22]. Additional findings in RA synovial fluid are low glucose,
low C3 and C4 complement levels, and protein levels approaching those in serum,
but these tests are generally not obtained in clinical practice as they are rarely
helpful. (See "Synovial fluid analysis" and "Diagnosis and differential diagnosis of
rheumatoid arthritis", section on 'Evaluation for suspected RA'.)
●Hematologic – Common hematologic abnormalities associated with active
disease include anemia of chronic inflammation, thrombocytosis, and sometimes a
mild leukocytosis. There is an increased risk of lymphoproliferative disease,
including non-Hodgkin lymphoma. Felty's syndrome, with neutropenia and
splenomegaly is very infrequent. The hematologic features of RA are described in
detail separately. (See "Hematologic manifestations of rheumatoid
arthritis" and "Clinical manifestations and diagnosis of Felty syndrome" and "Large
granular lymphocyte leukemia in rheumatoid arthritis".)
●Autoantibodies – About 75 to 80 percent of patients with RA test positive for RF,
ACPA, or both; patients with RA and such antibodies are defined as having
"seropositive RA" and the presence of the antibodies has diagnostic, therapeutic,
and prognostic implications. About a quarter to a third of patients have
antinuclear antibodies as well. These serologic features of RA are reviewed in
detail separately. (See "Biologic markers in the diagnosis and assessment of
rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid
arthritis", section on 'Serology' and "Diagnosis and differential diagnosis of
rheumatoid arthritis", section on 'Evaluation for suspected RA'.)
●Acute phase response – Measures of the acute phase response, including the
erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP), are
usually elevated in patients with active disease, and the degree of elevation in a
 given patient tends to correlate with disease activity; however, mild disease
activity is sometimes present without such abnormalities. ESR and CRP in RA and
the acute phase response are discussed in more detail separately. (See "Biologic
markers in the diagnosis and assessment of rheumatoid arthritis", section on
'Erythrocyte sedimentation rate' and "Biologic markers in the diagnosis and
assessment of rheumatoid arthritis", section on 'C-reactive protein' and "Acute
phase reactants".)

IMAGING

Patients with rheumatoid arthritis (RA) develop joint space narrowing and bony
erosions, which are best observed in plain radiographs of the hands and feet (see 'Plain
film radiography' below). These may already be present when first seen by a clinician
but more usually become evident over time with ongoing synovitis beyond the first few
months of disease. Erosions of cartilage and bone are among the cardinal features of
RA. However, they can also occur in some other forms of inflammatory and gouty
arthropathy and are therefore not diagnostic of RA in and of themselves.
(See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on
'Differential diagnosis'.)

Magnetic resonance imaging (MRI) studies and ultrasonography are more sensitive
than radiography for the detection of changes resulting from synovitis, but additional
research is ongoing to determine the prognostic importance of changes observed with
these studies that are not evident radiographically. (See 'MRI' below
and 'Ultrasonography' below.)

Plain film radiography — Progressive radiographic changes occur in the affected joints
of patients with active disease, including periarticular osteopenia, joint space
narrowing, and bone erosions. Deformities, including joint subluxation, and secondary
degenerative changes may occur with an active disease course.

Plain radiographs are often normal early in disease, and the early changes evident on
plain films may include only soft tissue swelling and periarticular osteopenia (image 3A-
C). To be detected by plain radiography, erosions must have eroded through the cortex
of the bone around the margins of the joint. Erosions in the metacarpophalangeal
(MCP) (image 4A-B) and proximal interphalangeal (PIP) joints (image 5A-B) can be
identified by plain radiography in 15 to 30 percent of patients in the first year of the
disease. By the end of the second year of disease in patients who do not respond to
therapy, the cumulative incidence of erosions is 90 percent [23,24]. In some patients,
erosions occur first in the ulnar styloid (image 6A-B) or metatarsophalangeal (MTP)
joints (image 7A-B). Joint space narrowing may also be present. Radiographic evidence
of joint injury in patients with early RA is often greater in the dominant than the non-
dominant hand [25]. Similar asymmetry in joint damage has long been observed in
patients with hemiplegia [26].
With extreme destruction, the severity of erosions may reach a level beyond which
further progression cannot be assessed radiographically, despite the presence of
ongoing joint damage [27].

IMAGE 3 A-B Soft tissue swelling and periarticular osteopenia of proximal

interphalangeal joints in rheumatoid arthritis

The plain radiographs of the

hand are magnified at the
proximal interphalangeal joints
of the third and fourth fingers
showing soft tissue swelling
(arrows) and periarticular
osteopenia (arrowheads).

Plain radiograph of osteopenia of metacarpophalangeal joints in rheumatoid arthritis

The plain radiograph of the left hand in the AP projection shows a normal patient (A) and a patient with
radiologically mild rheumatoid arthritis (B). The patient with rheumatoid arthritis demonstrates osteopenia
around the metacarpophalangeal joints (arrows) and mild soft tissue swelling (arrowheads).

Plain radiograph of osteopenia of the wrist in rheumatoid arthritis

The normal radiograph of the left wrist in the AP projection (A) is compared with the left wrist of a patient with
rheumatoid arthritis (B). The subtle diffuse osteopenia of the carpal bones is typified by an overall decrease in the
density of the bones and by a relative paucity of trabecular markings. Less subtle is the prominent soft tissue
nodule overlying the styloid process (arrow).

IMAGE 4 A-B Plain radiograph of mild metacarpophalangeal joint erosion rheumatoid

arthritis

The plain x-ray of the left hand is from a patient with radiologically mild rheumatoid
arthritis. The magnified view of the second metacarpophalangeal joint in (A) is shown
with arrows in (B). Subtle erosive changes are noted at the second metacarpophalangeal
joint (arrow), while soft tissue changes are more obvious (arrowheads).

Plain radiograph of normal left hand (AP, lateral, and oblique)

 The
radiographs of
the left hand
in the AP (A),
lateral (B),
and oblique
(C)
projections
are normal.

IMAGE 5 A-B Plain radiograph of rheumatoid arthritis proximal interphalangeal joint

erosions

The plain x-ray of the right hand magnified at the proximal interphalangeal joints shows
soft tissue swelling (arrows) and mild erosive changes (arrowheads).

Plain radiograph of a normal right

hand (AP, lateral, and oblique)
 The radiographs of the right hand
in the AP (A), lateral (B), and
oblique (C) projections are
normal.

IMAGE 6 A B Plain radiograph of ulnar styloid erosion in rheumatoid arthritis

The radiograph of the right wrist in

the AP projection reveals a
deformed and eroded ulnar styloid
process (arrow) in this patient who
has rheumatoid arthritis. No other
remarkable changes are present.

Plain radiograph of a normal wrist

 The radiograph
of the normal
right wrist is
displayed in the
AP (A), oblique
(B), and lateral
(C) projections.

IMAGE 7 A B Plain radiograph of metatarsophalangeal joint space narrowing and

erosions in rheumatoid arthritis

The radiograph of the

left foot in the AP
projection
demonstrates an
erosion in the
periarticular, marginal
"bare" area of the joint
of the 5th MTP joint and
more subtle erosions at
the 1st, 2nd, 3rd, and
4th MTPs (arrows), characteristic of rheumatoid arthritis. Also present is joint space
narrowing of the 1st and 2nd MTP joints (arrowheads).
Plain radiograph of normal left foot

The normal radiograph of the left foot

is from a 53-year-old female. The foot
is shown in the AP (A), oblique (B),
and lateral projections (C).
AP: anterior-posterior.

MRI — MRI is a more sensitive technique than plain radiography for identifying bone
erosions; however, the clinical significance of erosions only detected by MRI awaits
elucidation [28]. When radiography and MRI were compared in a group of 55 patients
with early arthritis, MRI identified seven times as many erosions in the MCP and PIP
joints than plain radiography [29].

MRI also may detect bone erosions earlier in the course of the disease than is possible
with plain films [30]. As an example, approximately 45 percent of patients with
symptoms for only four months were found to have erosions detected by this method
[31]. Decreased signal from the bone marrow on T1-weighted images and enhancement
of the marrow with gadolinium administration is interpreted as bone marrow edema.
The presence of marrow edema on MRI is predictive of later development of erosive
disease [32]. A similarly increased sensitivity of MRI has also been noted for early RA of
the forefoot [33].

It is also possible to identify and estimate the quantity of hypertrophic synovial tissue
using MRI. The presence of MRI-detected synovial proliferation correlates with the
later development of bone erosions [34]. Use of this imaging technique outside of
research settings may be hastened by the development of MRI scanners that are
designed specifically for imaging the extremities, but clinical indications for the use of
such techniques remain uncertain [35,36].
Ultrasonography — Ultrasonography is another sensitive alternative imaging
technique for estimating the degree of inflammation and the volume of inflamed
tissue. Direct comparison of color Doppler ultrasonography and contrast-enhanced
MRI in one study of 29 patients demonstrated agreement regarding the presence or
absence of inflammation between the two techniques in 75 percent of the joints of the
hands and wrists [37]. Both imaging modalities found features of inflammation in joints
that were neither tender nor swollen on physical examination. The clinical importance
of these findings remains to be determined. Ultrasonography can also be used to
assess the MTP joints, which may become affected early in the course of disease [38].
Ultrasound evaluation for bone erosions and synovitis is described in further detail
separately. (See "Musculoskeletal ultrasonography: Clinical applications", section on
'Joints'.)

CLINICAL COURSE

Rheumatoid arthritis (RA) shows a marked variation of clinical expression in individual

patients (table 1). These differences may be apparent in the number of involved joints
and pattern of joint involvement, fluctuations in disease activity and ability to achieve
remission, and the rate of progression and extent of structural damage. Some patients
may have mainly small joints or large joints affected. A given patient may also have only
a few or almost all joints involved. In addition, extraarticular disease may be prominent
in a subset of patients. (See "Overview of the systemic and nonarticular manifestations
of rheumatoid arthritis".)

TABLE 1
Patterns of progression — Variation is seen in the course of disease activity and the
rapidity of structural damage to joints [39].
●Most patients show fluctuation of disease activity over periods lasting weeks to
months. This corresponds to an increase or decrease in symptoms of arthritis, a
pattern which may recur throughout the course of the disease.
●Remission has been reported in a small proportion of patients with a well-
established diagnosis of RA, but is very rare, in our experience, without treatment
using disease-modifying antirheumatic drugs (DMARDs) [40,41].
(See 'Remission' below.)

Disease activity versus structural damage — The concept of disease activity is based
upon the state of the underlying inflammatory response and may be distinguished from
the destructive process that leads to irreversible damage of the joint (table 2):
●Disease activity can (and does) vary. This variation in part reflects the
endogenous rhythms of the disease process but is mainly the result of therapeutic
interventions. Thus, periods of spontaneous exacerbations and quiescence,
characterized by an increase (a "flare") or decrease in symptoms, are modulated
by both the beneficial effects of drug therapy and withdrawal of therapy due to
loss of efficacy or side effects. The assessment of disease activity in patients with
RA is described in detail separately. (See "Assessment of rheumatoid arthritis
activity in clinical trials and clinical practice".)
●By contrast, structural damage is cumulative and irreversible. The degree of
damage is closely linked to inflammation and hence to disease activity, but is also
associated with degeneration and repair [42]. As structural damage progresses,
the detection of variation in disease activity by clinical examination becomes
increasingly difficult. At these later stages, symptoms and signs of inflammation,
such as pain, stiffness, tenderness, swelling, and joint effusions, may be caused
either by continuing rheumatoid disease or as a secondary result of mechanical
and degenerative change.

Remission — Disease remission occurs when there is little or no evidence of clinical

disease activity (see below for criteria). However, achieving remission does not entirely
preclude the development of further erosive changes. This was illustrated in a
retrospective study of 187 patients who were in remission for six months and whose
clinical course and radiographic findings were subsequently followed [43]. A majority
(52 percent) remained in remission during two years of follow-up. However, despite
inapparent clinically active disease, one new erosion in a previously unaffected joint
appeared in 14 percent of these patients.

In our experience, reaching remission is very rare without DMARDs. As an example,

among 191 patients treated with such drugs beginning within a year of disease onset,
48 (25 percent) met criteria for remission after three years of treatment, and 38 (20
percent) after five years of DMARD therapy [44]. The likelihood of achieving a
remission with DMARD treatment within the first year of disease was greater in
patients with less initial disease activity, less disability, lower levels of acute phase
reactants, absence of rheumatoid factor (RF) and anti-
citrullinated protein/peptide antibodies (ACPA), and less radiographic joint damage.

TABLE 2
Attempts to define clinical remission for clinical practice and in clinical trials, in order to
understand better the natural history of RA and the effects of therapy, have resulted in
provisional definitions of remission by a joint effort of the American College of
Rheumatology (ACR) and the European League Against Rheumatism (EULAR) [45,46].
These definitions take into account that a complete lack of joint pain, swelling, and
tenderness may be impossible to achieve in patients who have developed structural
damage of the joints, despite actual remission in the rheumatoid disease process, and
the absence of all such symptoms and findings is not required by
the ACR/EULAR criteria. (See "Assessment of rheumatoid arthritis activity in clinical
trials and clinical practice", section on 'Remission'.)

The ACR/EULAR definitions of remission include use of either the Clinical Disease
Activity Index (in clinical practice) or the Simplified Disease Activity Index (for clinical
trials). Alternatively, the definition of remission for clinical practice can be met in
patients with scores on the tender joint count, swollen joint count, and patient global
assessment (0-10 scale) all ≤1. The C-reactive protein (CRP) (in mg/dL) is also included in
the definition for use in clinical trials.

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.)

●Basics topics (see "Patient education: Rheumatoid arthritis (The

Basics)" and "Patient education: Hand pain (The Basics)")
●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:
Complementary and alternative therapies for rheumatoid arthritis (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS

●The onset of rheumatoid arthritis (RA) is usually insidious, with the predominant
symptoms being pain, stiffness, and swelling of many joints. Typically, the
metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the
fingers, the interphalangeal joints of the thumbs, the wrists, and the
metatarsophalangeal (MTP) joints of the toes are sites of arthritis early in the
disease. Other joints of the upper and lower limbs are also commonly affected.
Onset may occasionally be intermittent or with migratory joint involvement, or
may be monoarticular. RA may adversely affect a patient's capacity to perform the
activities of daily living. (See 'Initial clinical presentation' above and 'Typical
'classic' RA' above and 'Palindromic rheumatism' above
and 'Monoarthritis' above.)
●The key features of early rheumatoid inflammation are pain and swelling of the
affected joints. Painful inflammation is demonstrated either by local tenderness
from pressure applied on the joint or by pain on moving the joint. Swelling may be
due to synovial hypertrophy or effusion. Synovial thickening is detected by a
"boggy" feel to a swollen joint, and effusion by demonstrating fluctuation.
(See 'Symptoms and physical findings' above and 'Hands' above and 'Lower
extremity' above and 'Axial skeleton' above and 'Cricoarytenoid joint' above.)
●RA eventually affects the peripheral joints in almost all patients. Involvement of
axial and central joints is less common, occurring in 20 to 50 percent of patients.
Symmetrical joint involvement is characteristic, although this may be less apparent
early in the disease. The pattern of joint involvement may also be diagnostically
useful. Squeeze tenderness at the MCP and metatarsophalangeal MTP joints and
palpable synovial thickening at these joints are characteristic of RA.
(See 'Distribution of involved joints' above.)
●Extraarticular features of RA, including anemia, fatigue, subcutaneous
("rheumatoid") nodules, pleuropericarditis, neuropathy, episcleritis, scleritis,
splenomegaly, Sjögren's syndrome, vasculitis, and renal disease, may occur during
the course of the disease. (See 'Extraarticular involvement' above and "Overview
of the systemic and nonarticular manifestations of rheumatoid arthritis".)
●A number of abnormalities are present in the blood and synovial fluid of patients
with RA. These include changes reflecting systemic and intraarticular
inflammation, and the autoimmune features of the disorder, including the
presence of rheumatoid factors (RF) and anti-
citrullinated protein/peptide antibodies (ACPA). (See 'Laboratory findings' above.)
●Patients with RA develop joint space narrowing and bony erosions, which are
best observed in plain radiographs of the hands and feet. These may already be
present when first seen by a clinician but more usually become evident over time
with ongoing synovitis beyond the first few months of disease.
(See 'Imaging' above.)
 ●RA shows a marked variation of clinical expression in individual patients (table 1).
This difference may be apparent in the number and pattern of joint involvement
and whether extraarticular disease is prominent. Variation is also seen in the
course of disease activity and the rapidity of structural damage to joints.
(See 'Clinical course' above and 'Patterns of progression'above.)
●The concept of disease activity is based upon the state of the underlying
inflammatory response, and may be distinguished from the destructive process
that leads to irreversible damage of the joint (table 2). Rarely, disease activity is
absent; in this circumstance, the disease is said to be in remission. (See 'Disease
activity versus structural damage' above and 'Remission'above.)

General principles 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:
Paul L Romain, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jun 2019. | This topic last updated: Apr 17, 2019.
What's New
Lack of role for MRI in treat-to-target strategies for rheumatoid arthritis (March 2019)
Magnetic resonance imaging (MRI) can detect subclinical synovitis and early erosive
changes in rheumatoid arthritis (RA), but its clinical value is uncertain. In an open-label
randomized trial involving 200 patients with RA in clinical remission on conventional
disease-modifying antirheumatic drugs (DMARDs), adding protocol-driven treatment
adjustments guided by MRI imaging to composite clinical assessments did not improve
clinical and radiographic outcomes after two years [1]. Treatment escalation and use of
biologic DMARDs was more common in the MRI group, as were serious adverse events.
While we find MRI useful to answer specific clinical questions in an individual patient,
these findings do not support broader use of MRI in the routine management of
RA. (See "General principles of management of rheumatoid arthritis in adults", section
on 'Tight control benefits and rationale'.)
 Read more

INTRODUCTION

The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis
and the prevention of joint injury. The choice of therapies depends upon several
factors, including the severity of disease activity when therapy is initiated and the
response of the patient to prior therapeutic interventions.

Common principles that guide management strategies and the choice of agents have
been derived from an increased understanding of the disease and evidence from
clinical trials and other studies. These strategies include approaches directed at
achieving remission or low disease activity by more rapid and sustained control of
inflammation by the institution of disease-modifying antirheumatic drug (DMARD)
therapy early in the disease course.

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 DMARDs are discussed in greater detail elsewhere.
(See "Nonpharmacologic therapies and preventive measures for patients with
rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of
rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in
adults" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic
DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial
biologic DMARD therapy".)

GENERAL PRINCIPLES

Our overall approach to the treatment of patients with rheumatoid arthritis (RA)
depends upon the timely and judicious use of several types of therapeutic
interventions. The appropriate use of these therapies is based upon an understanding
of a group of general principles that have been widely accepted by major working
groups and by professional organizations of rheumatologists [1-5].
(See 'Recommendations by major groups' below.)

These principles 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 RA (see 'Early use of DMARDs' below)
●Importance of 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 therapy (see 'Adjunctive role of
antiinflammatory agents' below)

The application of these principles has resulted in significant improvement in the

outcomes of treatment, although the etiology and pathogenesis of RA are complex
and are not fully understood [6-8]. Such improvements may owe even more to the
therapeutic strategies that have been adopted than to the development and use of
newer and more potent drugs [9].

RA is characterized by acute and chronic inflammation in the synovium, which is

associated with a proliferative and destructive process in joint tissues [8,10,11]. Many
elements of innate and adaptive immunity are involved in this process, and persistent
inflammation may lead to significant and irreversible joint injury as early as the first two
years of disease. Therefore, measures aimed at identifying early active disease and at
markedly reducing inflammation are essential for modifying disease outcome
[7,9,12,13]. (See "Pathogenesis of rheumatoid arthritis" and 'Tight control' below.)

Early recognition and diagnosis — Achieving the benefits of early intervention with
DMARDs depends upon making the diagnosis of RA as early as possible. The
recognition of RA early in the course of inflammatory arthritis, before irreversible injury
has occurred, is thus an important element of effective management. (See 'Early use of
DMARDs' below.)

In 2010, international collaborative efforts led to the development of new classification

criteria for RA, which have identified factors that support the early diagnosis of RA
among patients presenting with inflammatory arthritis [14]. These criteria are directed
at the recognition of patients with early arthritis who are most likely to develop
progressive and erosive disease. The diagnosis and differential diagnosis of RA are
reviewed in detail elsewhere. (See "Diagnosis and differential diagnosis of rheumatoid
arthritis" and "Clinical manifestations of rheumatoid arthritis".)

Care by a rheumatologist — An expert in the treatment of rheumatic diseases, such as

a rheumatologist, should participate in the care of patients with inflammatory arthritis
who are suspected of having RA and in the ongoing care of patients diagnosed with
this condition [3,15]. The early and ongoing care of patients with RA by a
rheumatologist is associated with better disease outcomes, such as reduced joint injury
and less functional disability, compared with care rendered primarily by other clinicians
[16-21].

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
and risks associated with the therapy, and the preferences of the patient and primary
care clinician.

NONPHARMACOLOGIC AND PREVENTIVE THERAPIES

A number of nonpharmacologic measures and other medical interventions are

important in the comprehensive management of rheumatoid arthritis (RA) in all stages
of disease, in addition to antirheumatic drug therapies. Patient education that
addresses issues related to the disease and its management is indicated for all patients
with RA. Attention to health promotion and specific strategies aimed at minimizing the
adverse effects of RA and of agents used to treat it are also appropriate. These
therapies are discussed in detail elsewhere. (See "Nonpharmacologic therapies and
preventive measures for patients with rheumatoid arthritis".)

Briefly, these measures include:

●Patient education
●Psychosocial interventions
●Rest, exercise, and physical and occupational therapy
●Nutritional and dietary counseling
●Interventions to reduce risks of cardiovascular disease, including smoking
cessation and lipid control
●Screening for and treatment of osteoporosis
●Immunizations to decrease risk of infectious complications of
immunosuppressive therapies

PHARMACOLOGIC THERAPY

Pretreatment evaluation — Prior to starting, resuming, or significantly increasing

therapy with nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs),
we do the following baseline studies [22]:
●General testing for all patients – We obtain a baseline complete blood count,
serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-
reactive protein (CRP) in all patients.
●Hepatitis B and C – 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 tofacitinib. Patients should be screened for hepatitis B with testing for
hepatitis B virus (HBV) surface antigen and HBV core antibody prior to initiating
these drugs and prior to treatment with prednisone at doses of ≥20 mg daily.
 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 healthcare workers.
[5,22]. 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".)
●Ophthalmologic screening for hydroxychloroquine use – A complete baseline
ophthalmologic examination should be performed within the first year of
treatment, including examination of the retina through a dilated pupil and
automated visual field testing. Our approach to screening and monitoring for
ocular toxicity is described in detail separately. (See "Antimalarial drugs in the
treatment of rheumatic disease", section on 'Monitoring for toxicity'.)
●Testing for latent tuberculosis – We screen for latent tuberculosis (TB),
consistent with the US Centers for Disease Control (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 the Janus
kinase inhibitor, tofacitinib; such screening is based upon evidence that these
medications, including the tumor necrosis factor (TNF) inhibitors, other biologics,
and tofacitinib, may increase the risk of mycobacterial infection [5,23,24].
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, skin testing 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 "Approach to diagnosis
of latent tuberculosis infection (tuberculosis screening) in adults".)

Choice of therapy — 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)
 ●Presence of adverse prognostic signs

A combination of the following types of therapies may be used:

●Rapidly acting antiinflammatory medications, including nonsteroidal

antiinflammatory drugs (NSAIDs) and systemic and intraarticular glucocorticoids.
(See 'Adjunctive role of antiinflammatory agents' below.)
●DMARDs, including nonbiologic (traditional small molecule or synthetic) and
biologic DMARDs, and an orally administered small molecule kinase inhibitor,
which all have the potential to reduce or prevent joint damage and to preserve
joint integrity and function. (See "Overview of immunosuppressive and
conventional (non-biologic) disease-modifying drugs in the rheumatic diseases".)
The nonbiologic (or conventional synthetic) DMARDs most frequently used
include hydroxychloroquine (HCQ), sulfasalazine(SSZ), MTX, and LEF.
(See "Overview of immunosuppressive and conventional (non-biologic) disease-
modifying drugs in the rheumatic diseases", section on 'Disease-modifying
antirheumatic drugs' and "Antimalarial drugs in the treatment of rheumatic
disease" and "Sulfasalazine: Pharmacology, administration, and adverse effects in
the treatment of rheumatoid arthritis" and "Use of methotrexate in the treatment
of rheumatoid arthritis" and "Pharmacology, dosing, and adverse effects of
leflunomide in the treatment of rheumatoid arthritis".)
Biologic DMARDs, produced by recombinant DNA technology, 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; the interleukin (IL)-1 receptor antagonist anakinra; and the IL-6 receptor
antagonist tocilizumab. They also include other biologic response modifiers such
as the T-cell costimulation blocker abatacept (CTLA4-Ig) and the anti-CD20 B-cell
depleting monoclonal antibody rituximab. (See "Overview of biologic agents and
kinase inhibitors in the rheumatic diseases" and "T-cell targeted therapies for
rheumatoid arthritis", section on 'Abatacept' and "Randomized clinical trials in
rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section
on 'Tocilizumab' and "Rituximab: Principles of use and adverse effects in
rheumatoid arthritis".)
Targeted synthetic DMARDs, including several kinase inhibitors, are in
development for use in rheumatoid arthritis (RA); one of these, tofacitinib, is
available for such clinical use in the United States and several other countries.
Tofacitinib is an orally administered small molecule DMARD that inhibits cytokine
and growth factor signalling through interference with Janus kinases.
(See "Investigational therapies for rheumatoid arthritis", section on 'Janus kinase
inhibitors'.)

Early use of DMARDs — We recommend that all patients diagnosed with RA be started
on DMARD therapy as soon as possible. Our choice of drug therapies in patients with
RA and the evidence supporting these choices is described in detail separately. Briefly,
we take the following approach (see 'Assessment of disease activity' below):
●In patients with active RA, we initiate antiinflammatory therapy with either a
NSAID or glucocorticoid, depending upon the degree of disease activity, and
generally start DMARD therapy with MTX. (See "Initial treatment of rheumatoid
arthritis in adults".)
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 treat with a
combination of DMARDs (eg, MTX plus either SSZ and HCQ or a TNF inhibitor),
while also treating the active inflammation with antiinflammatory drug therapy.
(See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic
DMARD therapy".)

Much of the joint damage that ultimately results in disability begins early in the course
of the disease [25,26]. As an example, 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 [26]. 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, although the prognostic implications of such findings are unknown [27-
29].

Better outcomes are achieved by early compared with delayed intervention with
DMARDs in patients with RA [12,30-35]. As an example, one study in Texas found that
low socioeconomic status was associated with a significant delay in starting DMARD
therapy; both factors were independently associated with greater disease activity, joint
damage, and physical disability [35]. Some evidence suggests that the effect upon
outcomes is not linear with time, but that there may be an early "window of
opportunity" for optimal DMARD treatment benefit [36]. As examples:

●The effect of symptom duration prior to DMARD therapy on the likelihood of

DMARD-free sustained remission was examined during five years of follow-up in
patients with RA from two cohorts, the Leiden Early Arthritis Clinic (EAC; n = 738)
and Étudeet Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR; n = 533) [36].
Remission was maintained in 11.5 and 5.4 percent of patients from the two
cohorts, respectively. The symptom durations that optimally discriminated
between greater and lesser likelihood of remission were between 11.4 and 19.1
weeks, depending upon the cohort and whether or not patients were anti-
citrullinated peptide antibody (ACPA)-positive, suggesting there is a limited period
of several months following symptom onset during which RA is most susceptible
to intervention with DMARDs.
●An observational study of 1435 patients involved in 14 trials, primarily of MTX or
other nonbiologic DMARDs, found a progressive decrease over time in the
 likelihood of a significant response to DMARD therapy. 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) [30].

ASSESSMENT AND MONITORING

Patients should be seen on a regular basis for clinical evaluation and monitoring of
clinical and laboratory assessment of disease activity and for screening for drug
toxicities. The initial evaluation and subsequent monitoring should also include periodic
assessment of disease activity using a quantitative composite measure of disease
activity. (See 'Assessment of disease activity'below.)

Additionally, the ongoing evaluation and monitoring of patients with rheumatoid

arthritis (RA) following the initiation of therapy also involves:

●Patient and clinician assessment of symptoms and functional status

(see 'Symptoms and functional status' below)
●Evaluation of joint involvement and extraarticular manifestations (see 'Physical
examination' below)
●Laboratory markers (see 'Laboratory monitoring of disease activity' below
and 'Monitoring and prevention of drug toxicity'below)
●Imaging (see 'Imaging' below)

Assessment of disease activity — Disease activity should be evaluated initially and at all
subsequent visits. We recommend that a structured assessment of disease activity
using a composite measure, such as those described here, should be performed
initially, and most patients should be seen at least every three months to monitor the
response to therapy using the same measure. Adjustments to treatment regimens
should be made to quickly achieve and maintain control of disease activity if targeted
treatment goals (remission or low disease activity), rather than an undefined degree of
improvement, have not been achieved. (See "Assessment of rheumatoid arthritis
activity in clinical trials and clinical practice", section on 'Composite indices for disease
activity assessment' and 'Tight control' below.)

The initial assessment, made once the diagnosis is established, helps to distinguish the
smaller group of patients who present with mild disease from the majority of patients
who present with moderately to severely active disease and who are usually treated
initially with methotrexate (MTX). (See "Alternatives to methotrexate for the initial
treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid
arthritis in adults".)
The use of periodic structured assessments of disease activity is complementary to
ongoing regular monitoring of disease manifestations, disease progression, joint injury,
disability, and complications of the disease and to monitoring for adverse effects of
medications. (See 'Assessment and monitoring' above.)

Multiple composite measures employing different combinations and weighting of

these variables have been developed for use in clinical research and practice. Among
the more than 60 activity measures available for evaluation of patients with RA, the six
measures noted below have been identified by the American College of Rheumatology
(ACR) as having the greatest utility in clinical practice because they 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 [37]. The choice of measure is based upon clinician preference; some measures
require both patient and clinician input, while others are based only upon patient-
reported data. (See "Assessment of rheumatoid arthritis activity in clinical trials and
clinical practice", section on 'Composite indices for disease activity assessment'.)

Measures that require both patient and clinician input, as well as calculators for these
measures, include the following:

●Disease Activity Score derivative for 28 joints (DAS28) (calculator 1)

●Simplified Disease Activity Index (SDAI) (calculator 2)

●Clinical Disease Activity Index (CDAI) (calculator 3)

The patient-reported outcome measures include:

●Routine Assessment of Patient Index Data 3 (RAPID3) [38]

●Patient Activity Scale (PAS) [39]
●PAS-II [39]

The RAPID3 correlates well with the results obtained by use of the DAS28 or CDAI [ 38].
(See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice",
section on 'RAPID3 score'.)

Symptoms and functional status — The clinical assessment of disease activity should
include questions concerning the degree of joint pain, the duration of morning
stiffness, and the severity of fatigue [22,40]. 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 cardiovascular disease.
(See "Clinical manifestations of rheumatoid arthritis".)

Fever is not a common feature of RA in adults. Infection must be excluded before

ascribing fever to RA.

Patients should be queried regarding their functional capacity, including the

performance of activities of daily living, of vocational activities, and of avocational
activities, such as hobbies or participation in sports. A self-report questionnaire that
measures function can also be often helpful for this purpose. The Stanford Health
Assessment Questionnaire (HAQ) is one of the best known and tested of these
questionnaires [41,42]; others include the Functional Independence Measure [43], the
Arthritis Impact Measurement Scale (AIMS), the Short Form 36 (SF36), and the
Modified Health Assessment Questionnaire (MHAQ) [44]. (See "Disease outcome and
functional capacity in rheumatoid arthritis", section on 'Functional capacity'.)

We use the evaluation of functional capacity to identify which of a variety of

interventions may be required in addition to pharmacologic therapy, especially in
patients with diminished functional capacity, such as counseling, exercise, and
occupational therapy. (See "Nonpharmacologic therapies and preventive measures for
patients with rheumatoid arthritis".)

Physical examination — A physical examination should be performed at regular

intervals that vary with disease activity and severity. As an example, patients 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. At these visits, an examination should
be performed to assess changes in previously affected joints or the appearance of
inflammation in previously uninvolved joints.

A 28-joint examination is appropriate if the hands but not the feet are involved [45].
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 C-

reactive protein (CRP) or erythrocyte sedimentation rate (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. In addition to these studies,
we obtain other tests primarily for medication monitoring that may also reflect
changes or levels of disease activity. 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 'Pretreatment evaluation' above
and "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice",
section on 'Acute phase reactants' and "Acute phase reactants" and "Biologic markers
in the diagnosis and assessment of rheumatoid arthritis" and "Anemia of chronic
disease/inflammation" and "Hematologic manifestations of rheumatoid arthritis".)

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 [46,47]. We generally follow the recommendations of the ACR for drug
monitoring in the treatment of RA (table 1) [1,5,22,40,48]. 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, 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" and "Antimalarial
drugs in the treatment of rheumatic disease", section on 'Monitoring for
toxicity' and "Pharmacology, dosing, and adverse effects of leflunomide in the
treatment of rheumatoid arthritis", section on 'Adverse effects'.)
TABLE 1
Imaging — Early in the course of RA, it is appropriate to 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. Radiographs should be repeated every two years in patients in remission or
with low disease activity. 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 during this interval, despite good
control of disease activity by other measures. In such patients, based upon our clinical
experience, we may intensify or modify the treatment regimen. The clinician must be
aware that, in hand radiographs of older patients, coexistent osteoarthritis may
account, in part, for joint space narrowing noted near the joints involved with RA [49].

Musculoskeletal ultrasonography (MSUS) and magnetic resonance imaging (MRI) are

more sensitive for the detection of cartilage and bone abnormalities and can reveal
subclinical inflammation [50,51]. MSUS is increasingly utilized at the point of care by
rheumatologists for diagnosis and monitoring disease progression and therapeutic
response [27,52]. Likewise, MRI has become increasingly employed to demonstrate
subclinical synovitis, early erosive changes, and therapeutic response [27,53,54]. Some
clinicians routinely employ these modalities to follow patients over time. The authors
prefer to use MSUS and MRI to answer specific clinical questions in an individual
patient, but not in the routine management of RA. This approach is supported by
evidence suggesting that use of these techniques for routine monitoring does not
result in improved outcomes. (See 'Tight control benefits and rationale' below.)

TIGH CONTROL

We recommend the use of tight control treatment strategies to quickly minimize

inflammation and disease progression; our therapeutic target is remission or a state of
minimal disease activity, without compromising safety. In patients resistant to initial
disease-modifying antirheumatic drug (DMARD) therapy, we either add additional
DMARDs to the ongoing regimen or switch the patient to a different DMARD, while
also treating the active inflammation with antiinflammatory drug therapy. 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 'Drug therapy for flares' below and "Treatment of rheumatoid arthritis
in adults resistant to initial nonbiologic DMARD 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.)

Tight control benefits and rationale — The use of strategies for tight control involves
frequent periodic reassessment of disease activity, 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 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 [7,55-64].

The periodic reevaluation of disease activity using a quantitative composite measure

and the use of antiinflammatory drugs, including NSAIDs and glucocorticoids, as
bridging therapies are both important elements in the strategy of tight control.
Glucocorticoids can rapidly achieve control of inflammation until DMARDs are
sufficiently effective. (See 'Assessment of disease activity' above and "Assessment of
rheumatoid arthritis activity in clinical trials and clinical practice" and 'Adjunctive role of
antiinflammatory agents' below.)

The use of either magnetic resonance imaging (MRI) or musculoskeletal ultrasound

(MSUS) to assess disease activity in addition to standard composite clinical outcome
measures does not appear to provide greater clinical benefit when used to determine
need for treatment escalation and may be associated with increased adverse effects
and potentially with greater cost [65-67]. In an open-label trial involving 200 patients
with established rheumatoid arthritis (RA) in clinical remission on conventional
DMARDs, patients were randomly assigned to receive protocol-driven treatment
adjustments guided by either MRI imaging plus composite clinical assessments or the
composite clinical assessments alone every four months; those in the MRI-guided
group had similar clinical and radiographic outcomes at two years to the patients in the
conventional assessment group [65]. Treatment escalation was performed more often
in the MRI-driven group (73 versus 17 percent), and at the two-year follow-up, a larger
proportion of the MRI-guided group had received 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 [66,67].

Taken together, studies that have compared tight control with less aggressive
approaches support the following observations:

●Most patients should receive a DMARD as soon as possible after diagnosis.

Achieving and maintaining low disease activity using a DMARD or DMARD
combinations as quickly as possible improve long-term outcomes and are cost-
effective compared with older, more gradual approaches to initiating DMARD
therapy. (See 'Early use of DMARDs' above.)
●Excellent treatment responses can be 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, as
described below.
●Escalation in the treatment regimen is needed for patients resistant to initial
treatment; both intraarticular glucocorticoids and oral or intramuscular
glucocorticoids help minimize disease activity until DMARDs are sufficient.
(See 'Adjunctive role of antiinflammatory agents' below.)
●Regular assessment with composite measures of disease activity is critical to
optimize clinical decision-making. (See 'Assessment of disease activity' above.)

These observations are reflected in the 2008, 2012, and 2015 American College of
Rheumatology (ACR) and 2010 European League Against Rheumatism (EULAR)
treatment recommendations and in the recommendations of an international task
force that were presented in 2010 and updated in 2014 [1-3,7,22,64,68-70].

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 [71].
Significantly 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 statistically
significantly 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 studies 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 that were statistically
significant 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 activity in clinical trials and clinical practice",
section on 'Health Assessment Questionnaire (HAQ)'.)

A number of randomized trials and related studies illustrate the range of medications
and approaches that provide evidence favoring a treat-to target approach [55-61,72-
74]. Especially notable examples include the Behandel-Strategieën voor Reumatoide
Artritis (Dutch for "treatment strategies for rheumatoid arthritis" or BeSt) trial [55,56];
the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial [58-60,72]; the
NEO-RACo trial [73]; the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR)
trial [74]; and the Tight Control of Rheumatoid Arthritis (TICORA) trial [61]. Taken
together, these reports provide strong support for the view that it is the treat-to-target
strategy, more than the specific agents used, that results in better outcomes for
patients with RA [75].

As an example, in the TICORA trial, 111 patients were randomly assigned to intensive or
routine management [61]. Intensively managed patients in this trial had monthly visits,
with calculation of disease activity scores (a validated composite score based upon the
erythrocyte sedimentation rate [ESR], Ritchie articular index, joint swelling count, and
patients' global assessment of disease activity defining high, moderate, and low
disease activity levels of ≥3.6, of ≥2.4 to <3.6, and of ≥1.6 to <2.4, respectively);
glucocorticoid injections of swollen joints; and, every three months, adjustment of their
treatment regimen by a predefined protocol if moderate or highly active disease was
present. Routinely managed patients were seen every three months, with no formal
measurement of disease activity performed, and glucocorticoid injections and other
treatment adjustments were made at the discretion of the rheumatologist. After 18
months, the patients receiving intensive management demonstrated a significantly
greater decrease in their disease activity scores compared with the routine
management group (-3.5 versus -1.9), and a higher proportion achieved a good
response by EULAR criteria (82 versus 44 percent). Additionally, physical function
assessed by the HAQ was improved to a statistically and clinically significantly greater
degree in the patients receiving intensive management (change in HAQ of -0.97 versus
-0.47).

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 in whom treatment is being started
with DMARDs, in patients in whom the DMARD regimen requires modification, or in
patients who are experiencing disease flares. Although NSAIDs act rapidly to control
inflammation, they do not provide adequate benefit on their own for longer-term
control of disease or for prevention of joint injury.

There is strong evidence that glucocorticoids retard radiographic progression in

patients with RA in the short to medium term (ie, up to two years of therapy) [76-78].
However, these agents should not be used alone for an extended period. We avoid
long-term use, if possible, because chronic use for inflammatory disease is often
associated with adverse effects [79]. However, patients with severe RA sometimes
require sustained therapy with low doses of glucocorticoids (less than 10 mg/day); such
doses in RA are generally well-tolerated and may have some benefit in retarding
disease progression [78,80] (see "Use of glucocorticoids in the treatment of
rheumatoid arthritis", section on 'Efficacy of chronic use'). More detailed discussions of
NSAID and glucocorticoids in RA 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'.)

In patients who receive glucocorticoids, we taper the medication as rapidly as tolerated

once disease control is achieved and can be maintained, with the ideal goal of
discontinuing systemic glucocorticoid therapy.

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?".)
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" and 'Assessment of
disease activity' above.)

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.
●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 with the 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 methotrexate (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 [81]. (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
[82,83]. However, increasing the dose from 3 to 5 mg/kg was not beneficial in one
well-designed trial [84,85].
●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 [86,87].
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 nonbiologic
DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial
biologic DMARD therapy".)

OTHER CONSIDERATIONS IN RA MANAGEMENT

The focus of therapeutic decision-making is control of disease activity, as described

above, but additional factors, such as the degree of joint injury or disability, may
influence the choice of specific therapies in individual patients [2,8]. Additionally, the
efficacy of particular medications may be affected by the presence or absence of some
of these factors, which are associated with an adverse prognosis.
(See 'Prognosis' below.)

The relative importance of these factors depends upon the individual treatment choice;
these are discussed in more detail in the appropriate individual treatment topics. 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.
●Joint injury – Good 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 findings 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 provides additional benefit for long-term outcomes, compared with
targets based upon measures of disease activity alone.
●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.

Comorbidities — 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 [1,5,22,88].
Infection

●Serious infection – In patients with an active serious infection, conventional and

biologic disease-modifying antirheumatic drugs (DMARDs) and tofacitinib should
be temporarily 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
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
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 active hepatitis C virus (HCV) and normal liver function
should not be treated differently than RA patients without HCV. If underlying liver
disease is present, non-hepatotoxic DMARDs (sulfasalazine [SSZ]
or hydroxychloroquine [HCQ]) are preferred initially. Patients with HCV infection
should be managed in collaboration with their hepatologist. (See "Overview of the
management of chronic hepatitis C virus infection".)
●Tuberculosis – Prior to initiation of immunomodulatory therapy, 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.

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[5,89-
93].

●Non-melanoma skin cancer (basal cell and squamous cell carcinoma) – In

patients with a history of non-melanoma skin cancer, we use conventional
DMARDs over biologic DMARDs or tofacitinib. There is no contraindication to
escalation of therapy to include biologics, but routine skin cancer surveillance is
indicated. (See "Epidemiology, pathogenesis, and clinical features of basal cell
 carcinoma" and "Clinical features and diagnosis of cutaneous squamous cell
carcinoma (SCC)".)
●Melanoma skin cancer – In patients with a history of melanoma, we use
conventional DMARDs over biologic DMARDs or tofacitinib. Approaches including
monoclonal antibody treatments that activate T cells have shown benefit in
treating melanoma (see "Immunotherapy of advanced melanoma with immune
checkpoint inhibition"); therefore, some clinicians avoid the use of abatacept in
patients with a prior history of melanoma. Routine skin cancer surveillance is
indicated. (See "Screening and early detection of 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.

Pregnancy — 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".)

Lung disease — Comorbid pulmonary disease is common in patients with RA and may
also be a complication of therapy or of the disease [88]. Therapeutic agents with
potential for causing adverse pulmonary effects
include methotrexate (MTX), leflunomide (LEF), tumor necrosis factor (TNF) inhibitors,
SSZ, parenteral gold, abatacept, and rituximab. (See "Overview of lung disease
associated with rheumatoid arthritis".)

Cardiovascular disease — Comorbid cardiovascular disease can occur in patients with

RA and may also be a complication of therapy [88]. 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 tofacitinib. (See "Tumor necrosis
factor-alpha inhibitors: An overview of adverse effects", section on 'Heart failure'.)

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 [88]. (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 [88]. By contrast, patients
being treated with HCQ or with TNF inhibitors for RA have a lower risk of diabetes [94],
and SSZ may have glucose-lowering effects [95]. (See "Major side effects of systemic
glucocorticoids", section on 'Metabolic and endocrine effects' and "Antimalarial drugs
in the treatment of rheumatic disease", section on 'Reduction of diabetes risk'.)

Renal disease — RA infrequently affects the kidney, but, if renal disease coexists, it
increases mortality risk [88]. 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 (acute renal failure)" and "Membranous
nephropathy: Epidemiology, pathogenesis, and etiology", section on
'Drugs' and "Cyclosporine and tacrolimus nephrotoxicity".)

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

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

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. 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 [96].

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".)

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 accurate evaluation of such patients is essential, since deterioration
associated with mechanical problems of the muscle or joint is treated much differently
from ongoing inflammation or systemic manifestations of rheumatoid arthritis (RA).
Disease exacerbations and their systemic effects are usually easily recognized by the
presence of many inflamed joints, fever, anemia, an elevated erythrocyte
sedimentation rate (ESR), or an elevated serum C-reactive protein (CRP) concentration.

The goals of therapy in the patient with end-stage disease are:

●Pain relief
●Protection of remaining articular structures
●Maintenance of function
●Relief from fatigue and weakness

In the absence of inflammation, which requires antiinflammatory medications and

disease-modifying antirheumatic drugs (DMARDs), treatments other than medications
may be particularly important in management. These include nonpharmacologic
interventions, such as physical and occupational therapy and the use of adaptive
devices, and surgery. (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 is often critical. If one waits too long, there may be so
much muscle atrophy from disuse that postoperative rehabilitation is unsuccessful. On
the other hand, a decision about joint replacement should take into account the
average life of the artificial joint. (See "Total joint replacement for severe rheumatoid
arthritis".)

RECOMMENDATIONS BY MAJOR GROUPS

Recommendations for the management of patients with rheumatoid arthritis (RA)

have been developed by major professional organizations, including the American
College of Rheumatology (ACR) and the European League Against Rheumatism
(EULAR) [1,3,4,22,70]. In addition, an international task force has developed
recommendations for treating RA to targeted goals [2,7,64,69]. Our approach to
treatment is generally consistent with these recommendations. The 2015 ACR
recommendationsand supporting documents can be accessed online.

The EULAR recommendations for the management of RA represent a European

consensus on the management of RA with disease-modifying antirheumatic drugs
(DMARDs) and glucocorticoids and on the strategies to reach optimal outcomes, based
upon evidence and expert opinion [3,4]. The evidence used was detailed in a series of
systematic literature reviews, and the recommendations were updated in 2013 [4,6,97-
100]. The 2013 recommendations include three overarching principles for the care of
patients with RA and a set of 14 recommendations covering major issues in disease
management. The 2013 EULAR recommendations can be accessed online.

PROGNOSIS

Rheumatoid arthritis (RA) was associated with a high degree of economic loss,
morbidity, and early mortality prior to 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. As an example, almost 20
percent of patients in one center were severely disabled after 20 years of follow-up
(from 1967 to 1987); an additional one-third had died [101]. Patients with RA that
required hospital care had at least a twofold increased mortality when compared with
those without disease [102], and more severe RA was associated with higher mortality
rates due to higher rates of myocardial infarction, infection, and certain malignancies,
comparable to three-vessel coronary artery disease or to stage IV Hodgkin lymphoma
[103].

Clinical outcomes have improved significantly with changes in drug therapy and in the
approach to treatment. These improvements have decreased the need for joint surgery
and reduced disability in patients with RA. As an example, in a study involving data
from 57 hospitals in Ireland, 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].

An analysis of 1007 patients with RA diagnosed between 1993 and 2011 in the Leiden
Early Arthritis Clinic found that more intensive treatment strategies adopted over the
years of study increased the chances for DMARD-free sustained remissions [105].
Moreover, those patients achieving DMARD-free remission had normal functional
status when compared with the general population. The average level of disability in
RA was found in a longitudinal study of over 3000 patients to have declined by about
40 percent from 1977 to 1998, even prior to the introduction of the biologic DMARDs
[106]. Similarly, patients with RA seen in a single university clinic from 1984 through
1986 had significantly more disability and greater radiographic evidence of joint injury
compared with a cohort from the same clinic seen from 1999 through 2001 (modified
Health Assessment Questionnaire [HAQ] disability score on a 0 to 3 scale of 1 versus
0.4, respectively, and Larsen radiographic score on a 0 to 100 scale of 20 versus 3,
respectively) [13]. 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 [107]. (See "Disease outcome and functional
capacity in rheumatoid arthritis".)

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
[22]:

●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 [108].
Older age, female sex, and the presence of the shared epitope have also been
associated with a poorer prognosis [22]. Some studies have derived models to estimate
prognosis, such as persistent erosive disease [109]. However, these models have not
been validated in other cohorts. 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 "Biologic markers in the diagnosis and assessment of
rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of
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) (Beyond the
Basics)" and "Patient education: Complementary and alternative therapies for
rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●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
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.)
●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, 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 and preventive therapies' above.)
●We recommend 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 1B). Better outcomes
are achieved by early compared with delayed intervention with DMARDs.
(See 'Early use of DMARDs' above.)
●We recommend the use of tight control treatment strategies to guide
adjustments in the treatment regimen, rather than less aggressive approaches
(Grade 1B). Tight control involves 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), rather than an
undefined degree of improvement, have not been achieved. Such tight control
treatment strategies are associated with improved radiographic and functional
outcomes compared with less aggressive approaches. (See 'Tight control' above
and 'Assessment of disease activity' above.)
●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 should be tested
for latent tuberculosis (TB) infection. Screening for hepatitis B and C should be
performed 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.)
●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.)
●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.)
●The monitoring that we perform on a regular basis includes testing that is
specific to evaluation of the safety of the drugs being used; 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 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, and the presence of adverse
prognostic factors. (See 'Other considerations in RA management' above
and 'Prognosis' above.)