CHAPTER 42
Evaluation and Differential
Diagnosis of Polyarthritis
Ronald F. van Vollenhoven
KEY POINTS
The differential diagnosis of polyarthritis is extensive.
Diagnosing polyarthritis depends on an accurate medical
history, a thorough physical examination, and appropriately
chosen laboratory and imaging investigations.
Laboratory testing and imaging, when used correctly, can
lead to rapid diagnosis and diagnostic certainty.
An early (presumptive) diagnosis and appropriate
management will contribute to better outcomes.
“For the physician, it is essential to recognize what
diseases are and whence they come; which are long
and which are short; which are in the process of
changing into others; which are major and which are
minor.”
—Hippocrates
Diagnosing patients with musculoskeletal symptoms remains
one of the rheumatologist’s core responsibilities. Although
in the general field of medicine significant advances have
been made in the use of sophisticated laboratory analyses
and imaging modalities, in rheumatology, making correct
diagnoses remains as much an art as a science today as in
the days of Hippocrates. Moreover, for patients with poly-
arthritis, a purposeful and expeditious diagnostic workup
has gained in importance as the benefits of early interven-
tion have been identified for some specific diagnoses, most
notably rheumatoid arthritis (RA).
In this chapter I will review the current state of the art
of diagnosing polyarthritis in adults (the evaluation of chil-
dren with joint symptoms is covered in Chapters 106, 107,
and 108), with special reference to the proper use of labora-
tory testing and imaging but without detracting from the
central role of a detailed history and a thorough physical
examination.
DIFFERENTIAL DIAGNOSIS OF
POLYARTHRITIS
The differential diagnosis of polyarthritis, which is gener-
ally defined as arthritis occurring in four or more joints, is
large; however, information that is readily available at the
initial presentation will in many cases narrow the diagnosis
to a limited number of possibilities. Thus, when in early
spring polyarthritis of recent onset is seen in a young
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woman and is associated with febrile symptoms and a mac-
ulopapular rash, a viral diagnosis is very likely, and parvo-
virus B19 infection is a good guess. In contrast, if a
middle-aged man being treated with hemodialysis wakes up
one night with four hot, red, and swollen joints in his feet,
it does not take an expert diagnostician to suspect gout.
Nonetheless, surprises do occur, and it remains important
to consider the entire spectrum of possible diagnoses when
first evaluating the patient. Table 42-1 lists a comprehen-
sive differential diagnosis of polyarthritis. The most impor-
tant disease categories to be considered are outlined in the
next sections.
Viral Infections
Many different viral infections can cause a transient and
self-limiting polyarthritis. One may suspect that the rela-
tively common occurrence of self-limiting polyarthritis
without further explanation usually represents viral infec-
tion, even if it is not so diagnosed. Viral arthritis is usually
a symmetric polyarthritis of the small joints in the hands
and feet and may therefore trigger a workup for early RA.
The following viral infections are important to consider in
the evaluation of polyarthritis:
• Parvovirus B19, which occurs seasonally and often
appears in teenagers or young adults, is sometimes is
severe enough to trigger suspicions of RA. The discovery
that this infection can be associated with transient posi-
tivity for rheumatoid factor (RF) led to speculation that
parvovirus might be the cause of RA.1 Later studies
clearly ruled out that possibility.2,3 The course of parvo-
virus arthritis is self-limiting, but treatment may be
needed for several days or weeks.4
• Although rubella virus infection has become uncommon
as a result of vaccination, it may nonetheless be encoun-
tered from time to time in young adults, and diagnosis
is, of course, extremely important when pregnancy is an
issue. Rubella virus infection is self-limiting and usually
mild.5
• Hepatitis virus infection: Each of the hepatitis viruses
can cause polyarthritis as the first and sometimes only
clinical manifestation.6-8 The fact that RF can be positive
in persons with viral hepatitis may lead even experienced
clinicians astray.9
• HIV infection may cause polyarthritis, which may be the
first manifestation of HIV.10 Because early diagnosis and
treatment is very important, this disease must always be
considered. In contrast to most types of viral arthritis,
HIV-related polyarthritis can be severe.11
615
616 PART 5 EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

TABLE 42-1 The Differential Diagnosis of Polyarthritis

Mechanism of Disease Types of Disease
Infections
Viral Parvovirus B19
Rubella virus
Hepatitis A, B, C
Human immunodeficiency virus
Alphaviruses, including Chikungunya infection
Bacterial Multiple infected joints in the presence of overwhelming sepsis
Initial phase of gonorrhea and chlamydia
Early phase of Lyme arthritis
Diseases triggered by infection but presumed autoimmune
Reactive arthritis After urogenital infections (Chlamydia and Ureaplasma); after gastrointestinal
infections (Yersinia, Shigella, Campylobacter, and Salmonella)
Acute rheumatic fever After infection with group A streptococcus
Autoimmune diseases
Primary arthritides Rheumatoid arthritis
Psoriatic arthritis
Spondyloarthropathies
Juvenile inflammatory arthritis
Transient and recurring polyarthritides Palindromic rheumatism
Recurrent symmetric seronegative synovitis with pitting edema (RS3PE syndrome)
Systemic autoimmune disease Systemic lupus erythematosus
Mixed connective tissue disease
Primary Sjögren’s syndrome
Progressive systemic sclerosis and limited scleroderma
Behçet’s disease
Sarcoidosis
Vasculitis
Autoinflammatory diseases Adult-onset Still’s disease
Familial Mediterranean fever and other cryopyrin-associated fever syndromes
Various genetic autoinflammatory conditions usually manifested first in childhood
Degenerative diseases Includes “erosive inflammatory osteoarthritis”
Osteoarthritis
Hypertrophic osteoarthropathy
Osteonecrosis
Metabolic diseases
Thyroid diseases Hypothyroidism
Hemochromatosis Hyperthyroidism (Graves’ disease; early phase of Hashimoto’s disease)
Hemoglobinopathies Sickle cell anemia
Hemochromatosis Thalassemiae
Crystal diseases Gout
Pseudogout
Deposition diseases Glycogen storage diseases; amyloid deposition in primary amyloidosis;
mucopolysaccharidoses; light- and heavy-chain deposition diseases; others
Drug-Induced diseases
Generalized vasculitic drug reactions, serum sickness

• Alphavirus infections, including Chikungunya arthritis:
In tropical countries, several alphaviruses (i.e., viruses
belonging to the family of togaviruses and the class of
arboviruses that are transmitted by mosquitos) are not
uncommonly encountered. These infections with fanci-
ful names such as Chikungunya12 (“bending up” in the
Akonde language), Sindbis,13 and O’nyong-nyong14
(meaning “severe joint pain” in the East African Acholi
language) are not always self-limiting and may some-
times be destructive. Ross River virus arthritis in Austra-
lia is also caused by an alphavirus.15 Until recently these
types of viral arthritis were rarely encountered in practice
outside tropical regions, but a remarkable change in the
epidemiology of Chikungunya virus arthritis is taking
place. As recently as 2013, this virus gained a foothold
in the Caribbean region, where more than a million
persons are since estimated to have been infected.16 Fre-
quent travel between that region and North America is
now making Chikungunya infection in general, and Chi-
kungunya arthritis more specifically, a diagnosis to be
reckoned with in daily practice in the United States and
Canada. Moreover, evidence indicates that the virus is
adapting to mosquito strains that are ubiquitous in the
United States, so the infection may become endemic in
the United States as well. Chikungunya infection almost
invariably causes moderate or severe myalgias and
arthralgias that frequently persist weeks or months after
other signs of the acute infection have subsided.17,18

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 CHAPTER 42
Frank arthritis may also be seen, usually in a small joint
pattern that is difficult to differentiate from seronegative
RA.19
Bacterial Infections
Typically, bacterial infection causes a septic monoarthritis.
In rare cases, multiple joints can be seeded simultaneously,
but the clinical setting will usually clarify this from the
outset. Some bacterial infections behave atypically, such as
gonorrhea, which can cause polyarthritis in the small
joints in a relatively early phase20; this occurrence is
believed to be due to the dissemination of immune com-
plexes into the joints rather than to direct infection. Simi-
larly, Lyme disease, which was initially identified as a new
form of juvenile inflammatory arthritis, may cause polyar-
thritis in an early phase of the infection.21 In this disease,
both direct infection of the joints by Borrelia burgdorferi
and an autoimmune reaction triggered by that organism
may play a role; this possibility is discussed in more detail
in Chapter 110.
Several other bacterial infections may also lead to rheu-
matic syndromes through mechanisms other than direct
infection of the joints. A classic finding in rheumatic fever
after infection with group A streptococcus is a migratory
aseptic arthritis of the large joints (discussed further in
Chapter 115), and various gram-negative infections of the
gastrointestinal system (e.g., Shigella and Campylobacter)
and genitourinary tract (e.g., Chlamydia and Ureaplasma)
may trigger reactive arthritis.
Malignancy-Associated Polyarthritis
Although direct invasion of the joint by tumor cells or
metastases is very rare, polyarthritis can be a paraneoplastic
phenomenon.22 Relatively little is known about the epide-
miology or pathophysiology of this entity. Diagnostic clues
may be the rapid onset of a fulminant polyarthritis and
associated symptoms, such as weight loss and diffuse pain;
in the absence of an obvious clue, these cases can be diag-
nostically very challenging.23
Crystal-Associated Polyarthritis
Most cases of crystal deposition disease progress from
recurrent monoarticular episodes to oligoarticular and then
polyarticular phases, especially when left untreated. The
initial locations of the gout attack are usually the feet,
ankles, and knees, but the later polyarticular manifestations
may also involve the upper extremities. Thus gout in the
polyarticular phase can sometimes mimic RA, and this
may be particularly important to consider if patients are
partially treated with nonsteroidal anti-inflammatory drugs
(NSAIDs). The first presentation of gout is hardly ever
polyarticular, but in pseudogout, caused by the deposition
of calcium pyrophosphate dihydrate crystals, this presenta-
tion may sometimes occur. Pseudogout occurs mostly in
elderly persons and affects the knees and ankles, but also
the joints of the toes, and even the joints of the wrists and
hands; thus it can mimic many other diseases. The deposi-
tion of hydroxyapatite crystals can give rise to an inflamma-
tion of the shoulder (“Milwaukee shoulder”).
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EVALUATION AND DIFFERENTIAL DIAGNOSIS OF POLYARTHRITIS 617
Degenerative Arthritis
Although osteoarthritis (OA) is considered a degenerative
disease by many persons, some inflammation is often
detected in the affected joint. Less commonly, overt clini-
cal inflammation is present, and the moniker “erosive-
inflammatory OA,” although not very well defined, is
used.24,25 The presentation in this case may be a true
polyarthritis, although the experienced clinician will have
little difficulty recognizing this entity, based on the distri-
bution (predominantly the distal and proximal interpha-
langeal joints and frequently the first carpometacarpal
joint) and typical bony hypertrophy around the affected
joints.
Metabolic Diseases
Metabolic diseases such as hemochromatosis may cause pro-
gressive degenerative and inflammatory changes in multiple
joints,26 and a polyarticular presentation may on occasion
be encountered in primary amyloidosis27 and in other depo-
sition diseases as well.28-30 Both hypothyroidism and hyper-
thyroidism may be associated with a range of musculoskeletal
symptoms31,32; monoarticular or oligoarticular arthritis of
the large joints with large effusions is most typical of hypo-
thyroidism,33 and muscular symptoms are most typical of
hyperthyroidism,34 but frank polyarthritis occasionally may
be seen in both conditions.
Autoimmune Diseases
Autoimmune inflammation of the joints is the most impor-
tant concern for the rheumatologist when evaluating a
patient with new-onset polyarthritis. In addition to diseases
in which polyarthritis is the dominant manifestation, such
as RA and psoriatic arthritis (PsA), consideration must be
given to the spondyloarthropathies (SpAs) and to the sys-
temic inflammatory diseases for which polyarthritis may be
the first presenting manifestation, including systemic lupus
erythematosus (SLE), systemic vasculitis, Sjögren’s syn-
drome, progressive systemic sclerosis, Behçet’s disease, sar-
coidosis, and others.
Transient syndromes in which prominent polyarthritis is
self-limiting but recurrent include palindromic rheuma-
tism35 and the syndrome of recurrent symmetric seronega-
tive synovitis with peripheral edema (RS3PE syndrome).36
Autoinflammatory diseases with high fever, skin rashes,
lymphadenopathy, and polyarthritis are more commonly
diagnosed in the pediatric population but can on occasion
become manifest first in adults. Important considerations in
the patient with polyarthritis and fever are adult-onset
Still’s disease and cryopyrin-associated periodic syndromes
including familial Mediterranean fever.
Drug-Induced Arthritis and
Serum Sickness
Classic descriptions of a drug-induced vasculitis or “serum
sickness” include polyarthritis, which may variably be
inflammatory and oligoarticular or polyarticular.37 The clin-
ical setting is usually sufficient to make the diagnosis, and
the course is self-limiting.
618 PART 5 EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS
APPROACH TO THE PATIENT
WITH POLYARTHRITIS
History
Obtaining a thorough history remains a sine qua non
for diagnosis, even in this age of high-tech investigations.
The “seven dimensions” of the history of present illness
as encountered in documentation guidelines—location,
quality, quantity, duration, context, modifying factors, and
associations—all provide clues to the diagnosis. The loca-
tion of the symptoms makes it clear whether we are dealing
with a monoarticular, oligoarticular, or polyarticular disease,
but patients may sometimes focus on just one particularly
bothersome joint even though additional joints are
inflamed. The quality of the symptoms may provide some
information; for example, pain associated with persistent
morning stiffness is a notable feature of inflammation,
whereas the gel phenomenon—a more short-lived stiffness
when first starting to move—is typical of OA. Obviously, it
is important to ascertain the severity of the symptoms.
Asking the patient about the duration of symptoms, how
they first started, how they fluctuate during the day, and
what (s)he has done to find relief will come quite naturally.
It may be less intuitive, but at least as important, to ask
specifically about other symptoms, including fever and
weight loss, gastrointestinal symptoms, skin rashes and
mucosal lesions, ophthalmologic issues, and urogenital
symptoms. The probable cause of the polyarthritis fre-
quently becomes obvious after associated features that the
patient often does not believe are important have been
elicited by the clinician. Likewise, one must investigate risk
factors for infectious causes of polyarthritis, such as possible
exposures to infectious organisms, risk of sexually acquired
infections, and recent travel to tropical countries or to areas
where Lyme disease is endemic. Routinely inquiring about
these types of exposures minimizes the risk of missing an
important clue. Most practitioners now use a standardized
form to collect this information in advance of the patient
encounter.
Physical Examination
Rheumatologists take pride in their ability to detect inflam-
mation by simple clinical means, but they must hone this
skill continuously. An inflamed joint is typically swollen,
and upon palpation the swelling is soft or doughy rather
than hard (as in the osteoarthritic joint). This synovial
swelling may be quite obvious in some cases but is harder
to establish in others. Even experienced joint assessors will
not always agree where to draw the line between swollen
and not swollen. In one study, six rheumatologists achieved
complete agreement in only about 70% of cases,38 and other
studies have also highlighted the lack of complete agree-
ment between experienced specialists. Fortunately, one
such study also showed that specific training improves con-
sistency.39 Because it may not be in the patient’s interest to
define joints as swollen in borderline cases, I generally teach
my fellows to be restrained in assessing joint swelling. One
study suggested that the “squeeze test”—that is, pain on
lateral compression of the metacarpophalangeal (MCP) or
metatarsophalangeal joints—was more specific than other
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tests for arthritis, but a recent study found a low sensitivity
for this test.40,40a
In addition to swelling (“tumor”) and tenderness
(“dolor”), inflamed joints may exhibit other classic signs of
inflammation. Redness (“rubor”) is frequently seen over
joints that are affected by highly acute inflammation, such
as in septic arthritis or gout, but redness is seen only rarely
in RA and other autoimmune inflammations. Warmth
(“calor”) is more confidently assessed in larger than in
smaller joints but may be a useful clue, especially in the
knees, where the normal temperature gradient—with the
knee being slightly cooler than the proximal musculature—
may be reversed. Finally, impaired function is an almost
universal finding in inflamed joints, and here it is important
to distinguish between true limitations in range of motion
(contractures) and limitations solely caused by pain.
The proper technique for examining joint swelling has
been a matter of some discussion. The European League
against Rheumatism (EULAR) has published a set of rec-
ommendations for examining the joints, along with instruc-
tional images; this handbook may serve as a good starting
point for learning joint examination or for achieving stan-
dardization across different sites. Inflamed large joints often
have palpable effusions, and in the knee the signs of “fluid
wave” and “ballottement” can be elicited in the case of
moderate or large effusions. In the initial workup of the
patient with polyarthritis, a detailed examination and docu-
mentation of the individual inflamed joints, including those
in the feet, will be necessary to document the range of
movement (predictably decreased in the inflamed joint) or
early anatomic changes. Moreover, when first evaluating a
patient, a full joint examination must be performed, whereas
for follow-up purposes, a more limited but standardized joint
examination is recommended, the most practical one being
the 28-joint count, where the MCP and proximal interpha-
langeal (PIP) joints of both hands, the wrist, elbows, shoul-
ders, and knees are examined.41 It is good practice to
document such a standardized joint examination in the
medical record for most visits. The more extensive 44-joint
count and the even more comprehensive systematic joint
count based on 68 joints are rarely used in practice for long-
term follow-up of patients with arthritis.
Perhaps the two most useful pieces of information gained
from the physical examination of the affected joints are the
nature of the swelling (assuming swelling is present) and the
pattern of joint involvement. Synovial inflammation is pal-
pated as a soft, “doughy” swelling around the joint line,
obstructing the possibility of feeling the two apposed bony
edges. In contrast, hypertrophy emanating from these bony
edges, such as occurs in OA, is palpated as a hard structure.
Patterns of joint involvement that are easily recognized and
usually point at the correct diagnosis are the symmetric
involvement of wrists, MCP and PIP joints of the hands,
and the corresponding joints in the feet, suggesting RA;
the asymmetric involvement of predominantly the lower
extremity larger joints in reactive arthritis and SpA; and
involvement of multiple distal interphalangeal (DIP) joints
in OA but also in some patients with PsA and prominent
nail changes. The typical pattern of joint involvement in
various conditions is summarized in Table 42-2. The impor-
tant distinction between RA and OA is further illustrated
in Figure 42-1.
 CHAPTER 42 EVALUATION AND DIFFERENTIAL DIAGNOSIS OF POLYARTHRITIS 619

TABLE 42-2 The Typical Distribution of Joint Involvement in Some Commonly Encountered Forms of Polyarthritis
Rheumatoid Arthritis Osteoarthritis Psoriatic Arthritis Gout/Pseudogout
Large weight- Knees and ankles, usually Hips, knees, ankles Knees and ankles, usually Knees and ankles; wrists
bearing joints symmetric; hips only rarely asymmetric in pseudogout
Small joints MCP and PIP joints in the DIP, PIP, and first CMC Frequently DIP joints along Small joints of the
hands; MTP joints in the feet joints in the hands; first with nail involvement; feet; MCP joints in
MTP joint in the feet other small joints pseudogout
Spine Cervical spine Cervical spine and LS LS spine and SI joints No
spine

CMC, Carpometacarpal; DIP, distal interphalangeal; LS, lumbo-sacral; MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal;
SI, sacroiliac.

Osteoarthritis
Age of onset Most commonly occurs in individuals older than 50 years
Speed of onset Slow; over years
Systemic symptoms Lack of systemic symptoms
Joints painful without swelling or with hard, bone swelling
may affect joints symmetrically or asymmetrically;
Joint symptoms
affects small joints, large weight-bearing joints such as hips
and knees, and/or the spine

Stiffness Short-lived morning stiffness; “gel phenomenon”;

stiffness when starting movement after inactivity
Joint-space narrowing, subchondral sclerosis, cystic
Radiologic findings
changes, osteophytes
Lab findings Essentially normal findings; RF, anti-CCP negative

Rheumatoid arthritis
Usual age of onset is 40-60 years
Age of onset
May begin any time in life
Speed of onset May be sudden or gradual over weeks to months
Frequent fatigue, low-grade fever, anorexia, muscle/joint
aches, stiffness
Systemic symptoms
Extra-articular manifestations; rheumatoid nodules,
Sjögren’s syndrome
Joints are painful, swollen and stiff;
affects joints symmetrically;
Joint symptoms primarily affects small joints, but also affects large ones
Joints are swollen, warm, tender, and painful

Stiffness Morning stiffness > 45 minutes;

may recur after rest
Bony erosions, soft tissue swelling, angular deformities,
Radiologic findings periarticular osteopenia, joint-space narrowing
Elevated ESR and CRP; normocytic anemia; mild
Lab findings
leukocytosis; thrombocytosis; positive RF and/or anti-CCP

Figure 42-1 The typical distribution of joint involvement in rheumatoid arthritis and osteoarthritis. Note that hips can be involved in late rheumatoid
arthritis as well. CCP, Cyclic citrullinated peptide; CRP, C-reactive protein; DIP, distal interphalangeal; ESR, erythrocyte sedimentation rate; MCP, meta-
carpophalangeal; PIP, proximal interphalangeal; RF, rheumatoid factor. (From http://www.zoomout-ph.com/2012/02/rheumatoid-arthritis-concept-
map.html.)

The spine must be examined even if no symptoms are
reported to detect early signs of axial involvement in SpA.
Deep palpation of the large muscle groups around the
shoulders and hips sometimes reveals exquisite tenderness,
which, together with the patient’s age of 50 years or older and
a high erythrocyte sedimentation rate (ESR), might suggest
a diagnosis of polymyalgia rheumatica (PMR), in which case
some peripheral joint arthritis also may be present.
Furthermore, a general examination should be performed
with special attention to the skin and integuments (psoriasis

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620 PART 5 EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS
and nail pitting in PsA), mucous membranes (ulcers in
reactive arthritis, Behçet’s disease, or SLE), lymph glands,
salivary glands, thyroid, heart, lungs, eyes, and other organs
based on specific suspicion.
Laboratory Investigation
After a comprehensive history and physical examination, a
laboratory workup will most likely be needed. Although
some tests can be ordered “routinely,” clearly many tests
should be ordered on the basis of the possible differential
diagnosis at this stage, at which time most often the possi-
bilities already have been narrowed down considerably.
Inflammation can be reflected by several routine mea-
sures, including leukocytosis and neutrophilia, normocytic
anemia (“of chronic disease”), and thrombocytosis. The
latter in particular may be a strong indicator of systemic
inflammation of significant duration and severity. The
ESR is typically elevated in patients with inflammation,
although it lacks specificity or sensitivity for any single
diagnosis, and the same applies to the C-reactive protein
(CRP). A normal ESR or CRP argues against infectious
causes for the polyarthritis but does not preclude a rheuma-
tologic diagnosis, whereas extremely high ESR or CRP
values should trigger suspicion of a more serious disease
underlying the polyarthritis.
Serologic testing is one of the rheumatologist’s most trea-
sured domains. The demonstration of rheumatoid factors
(IgM antibodies binding to IgG; RF) in the 1940s was one
of the first indications that RA was an autoimmune
disease42,43—a concept considered inadmissible for many
decades. RFs are indeed commonly seen in RA but are not
more than 60% to 70% sensitive, and in the setting of an
undiagnosed polyarthritis, the test must be interpreted with
caution because several viral infections can cause polyar-
thritis with a positive RF, including parvovirus and hepatitis
B and C. Moreover, RF can be positive in a wide range of
rheumatologic diseases—not only RA but also Sjögren’s
syndrome, scleroderma, SLE, and vasculitis, for example.
Nonetheless, in an early undifferentiated arthritis clinic,
the presence of RF conferred a considerably increased risk
of the development of persistent disease and radiologic
damage.44-47 In other words, although RF is useful in the
diagnostic process, it must not be relied upon blindly;
however, once the diagnosis of RA is established, the pres-
ence of RF suggests a worse prognosis.
More recently, it has become standard to test for antibod-
ies against citrullinated proteins using an assay based on
cyclic citrullinated peptides (CCPs). The test is therefore
often called the anti-CCP test, but the antibodies that are
detected should more properly be called anti-citrullinated
protein antibodies (ACPA) because the CCP is a laboratory
construct that does not exist in nature. Regardless, anti-
CCP or ACPA are about equally sensitive for RA as RF but
are much more specific.48,49 Combined testing for RF and
ACPA is the current standard for evaluating a patient with
polyarthritis when RA is a possible diagnosis, and the speci-
ficity of the combined positivity was indeed 100% in one
study,49 although of course the sensitivity was reduced.
Other serologic tests can be useful in the evaluation of
the patient with polyarthritis but must be interpreted with
even greater caution. Anti-nuclear antibodies (ANAs) are
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positive in many autoimmune diseases, as well as in various
infections, malignancies, drug-induced conditions, and so
on. When ANAs are tested by immunofluorescence on
human cell lines, they can be helpful in that a negative test
provides a strong argument against a diagnosis of SLE,
whereas a positive test will allow further testing for more
specific autoantibodies (but does not prove that the patient
has any particular disease). ANA by enzyme-linked immu-
nosorbent assay (ELISA) methods may have more false-
negative results. Antibodies against extractable nuclear
antigens (ENAs) can point in the direction of various sys-
temic inflammatory diseases, whereas anti-Ro/La (SS-A/
SS-B) will point to Sjögren’s syndrome, and anti-neutrophil
cytoplasmic antibodies (ANCA) will point to systemic
vasculitis.
Testing for specific infectious causes of polyarthritis can
and should also be performed on the basis of clinical suspi-
cion at this stage. Testing for hepatitis virus, HIV, and
various other viruses can be considered, but it would be
excessive to test for all viruses in all patients. The same can
be said for serologic testing for Lyme disease or for enteric
or urogenital pathogens.
Genetic Testing
The HLA-B27 gene marker is found in approximately 3%
to 8% of the population, but it is found in more than 90%
of patients with ankylosing spondylitis and in 50% to 80%
of patients with other SpAs. It has been argued that the
HLA-B27 test is not useful because of the prevalence of this
gene marker in healthy persons, but this argument does not
do justice to the subtle “probabilistic” process of diagnosis;
in the right clinical setting, a positive HLA-B27 test can
raise the diagnostic likelihood from modest to high. More-
over, the HLA-B27 test only needs to be performed once,
making it a rather cost-effective way to obtain an additional
diagnostic clue.
Other genetic tests have not yet become useful in rheu-
matology practice. Determining whether the patient has the
“shared epitope” (a constellation of HLA-DR genes that
confer an elevated risk for RA) is not yet part of standard
care. A genetic test exists for hereditary hemochromatosis,
that is, the HFE gene; this test can be performed in the right
clinical setting.
Synovial Fluid Analysis
If at all possible, synovial fluid should be obtained and
analyzed in the initial workup of polyarthritis. The fluid
from an inflamed but aseptic joint typically is yellow and
turbid and contains 5000 to 50,000 white cells/mm3, mostly
neutrophils. Higher leukocyte counts suggest bacterial
infection but may also occur in crystal diseases, whereas
lower counts would be expected in degenerative diseases.
Crystal arthritis can be definitively diagnosed by demon-
strating intra-cellular crystals in the joint aspirate.
Imaging and Additional Diagnostic Procedures
Although conventional radiography is not often the key to
making a diagnosis in the patient with polyarthritis, order-
ing plain radiographs of some of the affected joints may
 CHAPTER 42 EVALUATION AND DIFFERENTIAL DIAGNOSIS OF POLYARTHRITIS 621

nonetheless be useful. Such radiographs may reveal unex-
pected findings that provides diagnostic clues; in addition,
radiographs may provide an indication of the severity of
inflammation (juxta-articular osteopenia) and form a base-
line for future evaluation, and in some cases, they may
establish the diagnosis, such as when typical erosions are
found and the diagnosis of RA can be made. Typical “clues”
on plain radiographs are summarized in Table 42-3.
Magnetic resonance imaging (MRI) has become an
important diagnostic modality in musculoskeletal diseases
and has largely replaced computerized tomography, conven-
tional tomography, and scintigraphy in this setting. MRI
combines several very favorable attributes: It is noninvasive
and carries minimal risk; it offers unparalleled structural
detail in soft tissues; and it can be adapted to demonstrate
inflammation, such as by T2 weighting, fluid-attenuated
inversion recovery (FLAIR) sequencing, and the use of con-
trast media. The disadvantages of MRI are that it is quite
time consuming for the patient and may be associated with
physical and psychological discomfort (e.g., lying still in an
uncomfortable position and claustrophobia); the images it
provides are not as good for bone as for other tissues; only
TABLE 42-3 Clues to Diagnosis on Plain Film Radiographs
Finding Disease Suggested
Juxta-articular osteopenia Early RA
Joint-space narrowing RA, PsA, or OA
Subchondral sclerosis OA
Eburnation OA
Entheseal calcifications PsA, SpA
Bony erosions RA, gout
Osteophytes OA
Chondrocalcinosis Pseudogout
OA, Osteoarthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SpA,
spondyloarthropathy.
a relatively limited region can be imaged at one time;
and both acquisition and pass-through costs are very high.
Some of these disadvantages are lessened for low-magnetic-
strength “office” MRI.50 With use of a device that can be
operated easily in a general practice setting, images of rea-
sonable quality can be obtained and at a lower cost. However,
the region that can be imaged is small, and image acquisi-
tion time is significantly longer. Based on all these consid-
erations, when initially evaluating a patient with
polyarthritis, the use of MRI will only rarely be indicated.
Use of musculoskeletal ultrasound examination (MSUS)
has been increasing rapidly in the past several years. MSUS
combines several attractive features: It is easily accommo-
dated in the practice setting and even adds to the patient-
physician interaction, images of good quality can be obtained
and evaluated in real time based on the clinical situation,
inflammation is readily detected with use of Doppler tech-
nology, and the costs are surmountable. Inflammation is
easily identified using MSUS, as demonstrated in Figure
42-2. Distinct disadvantages of MSUS are that it requires
an experienced physician or physician assistant to perform
the procedure, it remains rather more subjective compared
with MRI, and soft tissue structures can be “hidden” from
view by overlying bone. Nonetheless, MSUS has increas-
ingly become a valuable tool in rheumatology practice. Sen-
sitivity and specificity have been shown to be similar to
MRI.51-53 Moreover, when assessing patients with polyarthri-
tis, MSUS has proven useful to increase the diagnostic
certainty on the part of the rheumatologist, both in terms
of establishing that polyarthritis is truly present54 in cases
where there may be doubt and in establishing a more defini-
tive diagnosis.55
Fluorescence optical imaging (FOI; “Rheumascan”) is
approved in Europe for evaluating arthritis in the hands.
The technique is based on the intravenous injection of a
fluorochrome, after which images of the hands are taken in
rapid succession with a specially adapted camera. FOI has
been used at some European centers, and several recent
studies have demonstrated that it has similar sensitivity and

Skin Fat Tendon

Bone surface
Effusion
Synovial thickening within
B MCP 2 the joint capsule

Normal MCP joint

High frequency Bone erosions of

musculoskeletal metacarpal head
ultrasound
(MSUS) imaging MCP 2
Doppler activity within the
A C joint capsule

Figure 42-2 Musculoskeletal ultrasound examination can complement the clinical examination. A, A normal metacarpophalangeal (MCP) joint.
B, Synovial thickening in “gray scale” mode and an effusion. C, A distinct Doppler signal in the synovium, indicating inflammation. (Original photographs
courtesy Mr. Yogan Kisten, the Karolinska Institute.)

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622 PART 5 EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

specificity to MSUS.56-59 However, its use is limited to the
hands, and the injection can in rare instances cause allergic
reactions. The device is not yet approved in the United
States.
FORMAL CRITERIA AND THEIR ROLE IN
CLINICAL DIAGNOSIS
“Classification criteria” have been developed for many
rheumatologic diseases, perhaps most notably for RA. These
criteria were developed originally to achieve uniformity
between clinicians in different health care settings, regions,
or countries, and primarily so for epidemiologic or other
research purposes. They were explicitly not developed as
diagnostic criteria. Nonetheless, the very existence of these
criteria has led to changes in the way RA and other rheu-
matologic diseases are perceived, and many clinicians do, in
fact, rely on the classification criteria for making clinical
diagnoses. The most recent classification criteria for RA,
which were developed internationally under the auspices of
the American College of Rheumatology (ACR) and the
EULAR, were quite significantly different from previous
versions60 (Table 42-4). First, it was recognized that if a
radiograph showed incontrovertible evidence for RA, then
the diagnosis could be made and no other evidence was
needed. Unfortunately, the criteria did not make it entirely
clear exactly how certain the radiographic evidence would
TABLE 42-4 The 2010 American College of Rheumatology/
European League against Rheumatism Classification Criteria for
Rheumatoid Arthritis*
Criteria
Joint involvement
2-10 large joints
1-3 small joints (with or without involvement of
large joints)
4-10 small joints (with or without involvement of
large joints)
>10 joints (with at least 1 small joint)
Serology (at least 1 test result is needed for
classification)
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
Acute-phase reactants
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
Duration of symptoms
<6 wk
≥6 wk
*Target population (patients who can be evaluated using these criteria):
those who have at least one joint with definite clinical synovitis (swelling),
with the synovitis not better explained by another disease.
• A score of 6 or greater is needed for classification of a patient as having
definite rheumatoid arthritis.
• If incontrovertible radiographic evidence of rheumatoid arthritis exists,
the diagnosis can be made even if the criteria provided are not fulfilled.
• If a patient has previously fulfilled the criteria for rheumatoid arthritis,
the diagnosis is maintained even if the criteria are not fulfilled on
current re-examination.
ACPA, Anti-citrullinated protein antibodies; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; RF, rheumatoid factor.
have to be, and most radiologists agree that there can be
considerable variations in the interpretations of radio-
graphic findings.
When radiographic evidence is lacking, the classification
of RA is based on a system of points, where the number and
nature of the inflamed joints, combined with several other
characteristics, determines whether the patient “has” or
“does not have” RA. It remains critically important to
emphasize that these criteria were benchmarked on the
opinions of expert clinicians and were shown to have sen-
sitivity and specificity in the 90% range, indicating that in
1 in 10 patients, an experienced clinician will disagree with
the criteria. This is not to belittle the importance of these
criteria but to underscore that their use should not replace
the clinical judgment of a competent specialist.
Similar considerations apply to other rheumatologic
diagnoses, with the added caveat that classification criteria
for diseases such as PsA,61 ankylosing spondylitis,62 and
gout63 usually achieve sensitivity and specificity lower than
that for RA.
PRELIMINARY DIAGNOSES, WORKING
DIAGNOSES, PRESUMPTIVE
TREATMENTS, AND REASSESSMENTS:
A LONGITUDINAL VIEW
Even after applying all possible diagnostic acumen and each
and every available test, the diagnosis may not be entirely
clear. All clinicians are familiar with the fact that medical
diagnostics remains, to some extent, a probabilistic venture.
Nonetheless, there comes a point where a preliminary diag-
nosis must be made, the patient must be informed, and a
course of treatment must be chosen. This situation poses
Score some challenges in terms of patient-physician communica-
tion. Understandably, clinicians may not want to appear
1 uncertain when speaking with their patients, but nonethe-
2 less, it may be better to be frank and say something to the
3 effect that “I think it is likely that you have X, but we
cannot be certain. There are no further tests right now to
5 be done, and I propose that we start treatment with Y. We
will reassess in a few weeks’ or months’ time.”
Most important, a time point for reassessment must be
0 chosen. This point could be a few weeks or several months
2 into the future, depending on the situation, but by explicitly
3
marking this point, the patient will have greater acceptance
if a preliminary diagnosis must be revised.
0
1
DIFFERENTIAL DIAGNOSIS OF
0 POLYARTHRITIS: FUTURE PERSPECTIVES
1
Modern rheumatologic diagnostics, applied in the setting of
a clinic with experienced specialists, will achieve a final
diagnosis in 60% to 90% of patients presenting with new-
onset polyarthritis.64,65 It does seem likely that further
advances can be made in diagnosing specific rheumatologic
disorders earlier, especially RA; the interest in this possibil-
ity is based not only on the desire to achieve an expeditious
diagnosis but also on the potential for very early interven-
tion, taking advantage of a presumed “window of opportu-
nity” and thereby achieving better long-term results for the
patient.66 However, if this earlier diagnosis is to be achieved,

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 CHAPTER 42
it may well have to done in the pre-clinical phase, before
the patient actually has polyarthritis.
In summary, for the patient with polyarthritis, a diagnosis
often can be made rapidly and confidently. Additional
refinements in tools for diagnosing polyarthritis will most
likely be forthcoming, and when combined with better
access to medical specialty care for persons with serious
musculoskeletal symptoms, excellent results will increas-
ingly be achieved.
The references for this chapter can also be found on
ExpertConsult.com.
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