Continuing Medical Education: Synovitis.

Edited By: Gregory C. Gardner, M.D.
Last updated Thursday, February 10, 2005
The differential diagnosis of joint pain
Narrowing the differential diagnosis
When evaluating the patient with joint pain, I find it useful to consider six key concepts during the history
and physical examination that help me narrow my differential diagnosis. By narrowing the differential, one
can focus the work-up in a more expedient and cost efficient manner.
The six key concepts are:
1. Is the joint pain really an arthritis?
2. Is the condition acute or chronic?
3. Is the problem inflammatory or noninflammatory?
4. What is the pattern of joint involvement?
5. Are there associated systemic features?
6. What are the demographics of the patient that might make one diagnosis more tenable?
Articular, periarticular, or nonarticular?
There are a variety of structures that can become painful and might be interpreted as an arthritis by
patients. Causes of joint pain from outside the joint (structures inside the joint capsule) can be from
periarticular structures. The following is a list of structures around a joint that might present to you as
joint pain.
Periarticular causes of joint pain
1. Bursitis
2. Faciitis
3. Tendonitis
4. Ligament Injury
5. Epicondylitis
6. Myofacial Pain/Fibromyalgia
There are also a variety of nonarticular abnormalities affecting bone, nerve, or blood vessels that may
present as joint pain. Below is a list of such causes.
Nonarticular causes of joint pain
1. Tumors of Bone
2. Radiculopathy
3. Osteomyelitis
4. Neuroma
5. Nerve Entrapment
6. Vasculopathy
Differentiation of these problems from an arthritis requires careful physical examination which should
include:
1. Inspection of the joint area for evidence of swelling or redness
2. Passive range of motion of the joint(s) in the area noting pain, reduction of motion, or instability
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3. Active range of motion of the joint(s) in the area noting pain that was not there when the joint(s)
were passively moved
4. Resisted range of motion of the joint(s) in the area again noting pain
5. Palpation of the joint line(s) and surrounding structures noting tenderness, joint effusion(s), and
boney changes.
6. Most soft tissue problems do not hurt with passive motion while most forms of arthritis do.
7. Tendonitis is typically painful with active or resisted motion.
8. A bursitis is usually painful only with palpation.
9. Myofacial pain is also painful to palpation and may be widespread as in fibromyalgia.
Acute vs. chronic
Acute refers to conditions lasting less than 8 weeks while chronic signifies conditions that persist for a
longer period of time. Acute also suggests a rapid onset. Many acute disorders are also self-limited. This
division of acute and chronic can help focus the evaluation especially for conditions that have been present
for more than 8 weeks.
Inflammatory vs. noninflammatory
This is a very helpful point in limiting your differential diagnosis. Inflammatory disorders usually present
with morning stiffness that lasts longer than 30-40 minutes, stiffness that increases with rest, relief of
symptoms with exercise, some degree of swelling, and a synovial fluid WBC that is above 2000/mm3.
Most of the 2000 cells should also be PMNs.
Noninflammatory disorders usually present with only limited morning stiffness (< 15 minutes), pain with
use, relief of pain with rest, swelling may or may not be present, and synovial fluid WBC is typically less
than 2000/mm3.
An initial determination of the character of the synovial fluid at the bed side can be made by looking at the
fluid in a glass tube against newsprint. The print can still be read through noninflammatory fluid while
inflammatory fluid will obscure the print. The intensity of the synovial inflammation is only relatively
helpful in the differential diagnosis. Below is a chart of synovial fluid differentiated by cell count. An
important point to remember is that an infected joint may not have septic range WBC. If you at all suspect
infection send the fluid for gram stain and culture.
Table 1. Synovial fluid analysis
One other type of presentation in this regard is worthy of note. Fibromyalgia typically presents with
marked AM stiffness, pain with use and pain and stiffness at night so that it is not clearly inflammatory or
noninflammatory.
3 different classes
Rheumatologists spend a good deal of their training learning to recognize various forms of arthritis by
their pattern of joint involvement.
I divide the conditions into monoarticular (one joint only), pauciarticular (2-5 joints), and polyarticular
(more than 6 joints). These are not set in stone as there is some overlap but is a useful construct and has
withstood the test of time and medical students. The following lists are not all inclusive. They include the
Classification Clarity Wbc %Polys
Normal Transparent <200 <25
Noninflammatory Transparent <2000 <25
Inflammatory Translucent <75000 >50
Septic Opaque >75000 >75
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most common entities someone in the primary care setting would encounter. The purpose of this
differentiation is to focus the initial evaluation and help the "splitters" among us. The "don't
forget" (because of potential serious consequences) conditions are in italics and the most common causes
in each category are bold.
Monoarticular arthritis
Table 3. Causes of monoarthritis
Nongonococcal septic arthritis is the most serious cause of monoarthritis. The presentation is that of
an acute or subacute onset of mono- or rarely pauciarthritis. Large joints are usually affected especially
knees. Patients most often look systemically ill and will have fever, chills, and will have an elevated WBC
and ESR. Patients with underlying arthritis especially rheumatoid arthritis are at increased risk of septic
arthritis and may not have the usual symptoms due to antiinflammatory medications. The most common
organisms are Staphylococcus aureus, Streptococcus sp. and much less common are gram negatives but
think of the latter in the immunosuppressed or in IV drug users. The initial evaluation should include
arthrocentesis for gram stain and culture and WBC, blood cultures, as well as an ESR. The patient should
be admitted and IV antibiotics started while waiting for culture results. If there is any concern for a septic
joint do an arthrocentesis!
Gonococcal arthritis is seen in sexually active young adults and only 25% have local genitourinary
symptoms. Patients are usually systemically ill and have dermatitis, tenosynovitis, and migratory arthritis.
Blood cultures are positive in only 5%, GU cultures in 80%, and synovial fluid cultures in 30%. One often
resorts to treatment of presumptive gonococcal arthritis. Luckily, most strains that cause gonococcal
arthritis are penicillin sensitive although , resistant strains are emerging. Initial evaluation should include
the above cultures plus consideration of pharyngeal and rectal cultures. Patients often need a few days of
hospitalization then can be treated as an outpatient.
Endocarditis causes musculoskeletal symptoms in up to 40% of affected patients. Inflammatory low back
pain is common as is mono- or pauciarthritis. It is interesting to note that the fluid while inflammatory is
usually sterile. This is thought to be due to immune complex deposition in the synovium. Look for
peripheral signs of immune complex deposition such as cutaneous vasculitis, painful nodules, listen for a
murmur, check an ESR, blood cultures, CBC, cultures of synovial fluid, and if endocarditis is likely, admit
the patient and begin antibiotics. Of note, rheumatoid factor is frequently positive in these patients.
Crystals causing arthritis include urate, calcium pyrophosphate, and appatite. Urate gout is probably the
most common cause of acute inflammatory monoarthritis. Inflammation is usually intense and the patient
will relate a history of previous self-limited attacks. First MTP is a common site for urate gout and knee for
Inflammatory Noninflammatory
Infection
Disseminated gonorrhea
Other bacteria
Tuberculosis
Fungi
Lyme athritis
Endocarditis
Crystals
Monosodium urate
Calcium pyrophosphate
Hydroxyappatite
Spondyloarthropathy
Ankylosing spondylitis
Reiter's syndrome
Psoriatic arthritis
Miscellaneous
Palindromic rheumatism
Trauma/fracture
Osteoarthritis
Neoplasm
Osteonecrosis
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calcium pyrophosphate. Young women can have so called hydroxyappatite pseudopodagra affecting the
1st MTP. Patients can have a pauciarticular presentation with urate and pyrophosphate. For urate gout, a
history of ETOH use, history of kidney stones, or a family history of urate gout is helpful. Females rarely
get urate gout before menopause. There are some distinctive X-ray findings for calcium pyrophosphate
and appatite arthritis (chondrocalcinosis and fluffy calcification respectively) On examination, look for tophi
and synovial fluid analysis is very helpful in the definitive diagnosis of all but hydroxyappatite. A useful
hint to remember is that bugs, blood, and crystals (BBC) cause the most intense joint pain.
Palindromic rheumatism is an episodic condition usually affecting one joint at a time. The attacks can
be fairly intense and the fluid can be quite inflammatory. Attacks usually last several days and resolve.
With time, many individuals progress on to frank rheumatoid arthritis.
TB and fungi are relatively rare but any chronic monoarthritis without a diagnosis should be considered
for synovial biopsy and granulomatous synovitis considered.
Osteoarthritis is probably the overall most common cause of monoarthritis and trauma/internal
derangement of the knee is not far behind. Meniscal tears can cause chronic noninflammatory type pain
and may give symptoms of knee locking or giveway.
Avascular necrosis is caused by trauma, alcohol abuse, steroid use, divers, and in patients with
hemaglobinopathies. Pain is initially out of proportion to X-rays. Hips, knees and shoulders are usually
involved. Early diagnosis is by MRI scan.
Synovial neoplasm to remember and is pigmented villonodular synovitis. It can cause dark bloody
effusions and is diagnosed by MRI/arthroscopy.
Pauciarticular arthritis
Table 4. Causes of pauciarthritis
Rheumatic fever - In many of these conditions systemic features play an important role in the
differential diagnosis. Rheumatic fever is certainly one of these although most adults with rheumatic fever
present with only arthritis. The pain is usually out of proportion to the swelling and the symptoms tend to
be migratory. Other Jones criteria include carditis, erythema marginatum, chorea, and subcutaneous
nodules. Be sure to listen for a murmur and check ASO/streptozyme. The ASO should be followed serially
and remember that a positive test still does not prove rheumatic fever. Throat cultures are usually
negative by the time rheumatic fever occurs. One often spends time ruling out other diseases even with a
suspicion for rheumatic fever due to the lack of definitive diagnostic testing. The presence of carditis
though, is very compelling and can be made by echocardiogram.
Lyme arthritis is a late manifestation of lyme disease and usually presents with recurrent attacks of
mono- or pauciarthritis especially including the knee. In this condition, the swelling is often out of
Inflammatory Noninflammatory
Infection
Endocarditis
Disseminated gonorrhea
Rheumatic fever
Lyme disease
Crystals
Monosodium urate
Calcium pyrophosphate
Spondyloarthropathy
Sarcoidosis
Miscellaneous
Polymyalgia rheumatica
Osteoarthritis
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proportion to the pain!. A history of exposure and the characteristic rash of Lyme disease are important.
By time the arthritis is present, the vast majority of patients have a positive Lyme antibody test. One may
have to treat presumptively for at least one course of antibiotics in some marginal cases.
Spondyloarthropathies are characterized by their association with the HLA-B27 gene (except the
peripheral arthritis of psoriatic arthritis). Features of these illness that are helpful in the diagnosis include
inflammatory low back pain, history of inflammatory eye disease (uveitis, iritis, conjunctivitis), urethritis,
cervicitis, diarrhea, a variety of hyperkeratotic rashes, and diffuse swelling of digits called sausage digits.
Joints most often affected are the large joints of the lower extremities. In my experience, the most
common cause of inflammatory pauciarthritis is a spondyloarthropathy, especially Reiter's disease or
psoriatic arthritis. Up to 7% of patients with psoriasis will have arthritis.
Sarcoidosis frequently presents with pauciarthritis. One typical presentation is called Lofgren syndrome
and consists of erythema nodosum, hilar adenopathy, and pauciarthritis usually affecting the large joints
of the lower extremities. A chronic destructive form also exists and is often seen along with extensive
bone cysts on X-ray. Other important features include uveitis and skin lesions.
Polymyalgia rheumatica will be discussed below.
Polyarticular arthritis
Table 5. Causes of polyarthritis
Viruses are a common cause of acute self limited arthritis. The ones to remember include hepatitis B,
parvovirus B19, and rubella. HIV can cause a variety of rheumatologic syndromes but polyarthritis is
unusual. Viral arthridities are usually symetrical and cause more pain than swelling. They usually are self
limited and are associated with rash. The prodrome of hepatitis B can be polyarthritis even before liver
function tests are abnormal. Be sure to check for hepatitis B surface antigen. The arthritis usually goes
away by the time the patient has clinical hepatitis. Hepatitis C is being recognized as a common infection.
It can cause a symmetric polyarthritis that is often accompanied by a positive rheumatoid factor thus
being confused with rheumatoid arthritis. There are no nodules with hepatitis C nor does it cause erosive
joint changes. Parvovirus will be discussed below.
Rheumatoid arthritis is a relatively common disease affecting 1-2% of the US population. Remember
that rheumatoid factor is seen in only 70% of patients and may not appear for 1 year. RA is a symmetric
arthritis and almost always affects the small joints of the hands and feet.
Diagnosis of systemic lupus erythematosus is aided greatly by the ANA testing. A negative ANA plus
a negative antiSSA antibody rules out SLE! On the other hand, a positive ANA does not mean SLE! One
has to look for other features to go along with the positive ANA not just fatigue and arthralgias. I usually
am not impressed with an ANA of less than 1:160 and look for the presence of other autoantibodies as
Inflammatory Noninflammatory
Viruses
Parvovirus
Hepatitis B
Rubella
Hepatitis C
Autoimmune diseases
Rheumatoid arthritis
Systemic lupus erythematosus
Sjogren's syndrome
Scleroderma
Polymyositis/Dermatomyositis
Serum sickness
Antibiotics
Primary osteoarthritis
Secondary osteoarthritis
Hemachromatosis
CPPD
Ochronosis
Acromegaly
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well as objective evidence of inflammation on laboratory testing and examination. Urgent cases of SLE
include those with new onset or exacerbation of nephritis or cerebritis.
Secondary causes of osteoarthrits especially metabolic causes, are conditions I keep in the back of my
mind when I see a patient with clinical osteoarthritis in a symmetric pattern but in places atypical for
primary OA. These include the shoulders, elbows, wrists, and MCP joints. The most important cause is
idiopathic calcium pyrophosphate disease and less common, but with more significant implications, is
hemachromatosis. I usually check a calcium, FE, TIBC, and TSH in a patient with what may be a
secondary cause of OA without other explanation (old RA) and or significant chondrocalcinosis on X-ray.
Serum sicknesses are actually in this day and age serum sickness-like reactions. Symptoms include rash
often uriticarial, and inflammatory arthritis affecting large joints. Fever is common and laboratory
abnormalities include mild hypocompletemia and normal eosinophil count. The process is self limited
resolving in 1-3 weeks after exposure. Typical causes of serum sickness-like reactions are antibiotics
especially penicillins and sulfa drugs.
Systems and related diseases/syndromes
There are a variety of systemic features that can help in the differential diagnosis of joint pain/arthritis.
Finding these requires a complete review of systems and a good general examination with emphasis on
the skin, eyes, heart, lungs, GI, GU, and nervous system. Below is a list of some of the
diseases/syndromes for which systemic features are important in the differential diagnosis.
Skin
Gout
Spondyloarthropathy
Sarcoidosis
Lyme disease
Disseminated gonorrhea
Rheumatic fever
Viral syndromes
Rheumatoid arthritis
Systemic lupus
Serum sickness
Eyes
Spondyloarthropathy
Sarcoidosis
Rheumatoid arthritis
Heart
Spondyloarthropathy
Lyme disease
Endocarditis
Systemic lupus
Rheumatic fever
Rheumatoid arthritis
Lungs
Tuberculosis
Fungi
Sarcoidosis
Systemic lupus
Rheumatoid arthritis
GI/GU
Spondyloarthropathy
Systemic lupus
Gout
Endocarditis
CNS/PNS
Sarcoidosis
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Lyme disease
Systemic lupus
Demographics and related conditions
There are features of the history that can help you focus the differential diagnosis. Knowing which
diseases are more common in certain patient groups may move certain conditions to the top of your list.
Below is listed some items worthy of note.
Age
Younger
Spondyloarthropathy
Disseminated gonorrhea
Older
Polymyalgia rheumatica
Gout
Osteoathritis
Gender
Men
Gout
Spondyloarthropathy
Women
Rheumatoid arthritis
Systemic lupus
Race
Africans
Sarcoidosis
Systemic lupus
Europeans
Polymyalgia rheumatica
Lifestyle
Bacteria
Gout (ETOH overuse)
Endocarditis (IDU)
Disseminated gonorrhea
Lyme disease (outdoors)
Avascular necrosis (ETOH overuse)
Other illness
Bacteria: immunosuppression, rheumatoid arthritis
Gout: renal disease, medications, obesity
Tuberculosis & fungi: immunosuppresion
Avascular necrosis: steroid use
Laboratory testing
Finally, after having gone through the above process, you are ready for some directed laboratory testing.
Try to select your tests based on your history, review of systems, and examination. Avoid the "Arthritis
Panel" approach to patients with arthritis. This can give you information you don't need and may misdirect
your evaluation. Remember in most cases, time is on your side and all tests don't have to be ordered at
once. Concentrate on the potentially most serious conditions and those most easily tested for and add
tests as needed. I have included a handout on laboratory testing at the end of this section that might be
helpful.
Download
Arthritis Case Histories (PDF) (0.01 MB)
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"Newer" forms of arthritis
Parvovirus arthropathy is a recently recognized cause of acute and chronic joint symptoms. In 1975, the
parvovirus was isolated from human tissue. In 1981, this virus was associated with aplastic crisis in people
with hemaglobinopathies, 1n 1983, with 5th disease, 1984 with nonimmune hydrops in prognancy, 1985
with an acute and chronic arthropathy, and 1987 with bone marrow suppression in immunocompromised
individuals. The virus is a small, single stranded DNA virus that grows in erythrocyte precursor cells.
Presently, detection of infection depends on serologic confirmation of an IgM response to the virus and one
need to check for infection within the first 8 weeks. Newer methods of detection are being developed as is
a method for culture.
The acute arthropathy consists of polyarthralgias/polyarthritis that may come on over night. There is
usually significant stiffness and pain and only mild synovitis. Joint symptoms are much more common in
adult women than men and the characteristic rash of childhood 5th disease is unusual in adults but a fine
evanesent macular is frequently present on the extremities and trunk. The symptoms last 1-3 weeks and
in most cases dissappear without sequela. In up to 1/3 of affected females the symptoms may continue or
recur at various intervals. Symptoms have been recorded up to 4 years to date. One can usually treat the
symptoms with NSAIDs. It is important to ask individuals with chronic or recurring inflammatory sounding
arthralgias about possible exposure to the virus ie exposure to 5th disease. There is some interest in the
parvovirus as a possible trigger of rheumatoid arthritis or systemic lupus erythematosus.
PMR with synovitis or seronegative rheumatoid arthirtis. In recent years, it has become evident that there
is a group of individuals over the age of 60 who present with symmetrical polyarthritis, are seronegative
for rheumatoid factor, and present with considerable shoulder and hip stiffness. This group has an
excellent response to low dose steroids and do not show the progressive destructive course so common of
true rheumatoid arthritis. Their symptoms resemble more the course of polymyalgia rheumatica (PMR). It
is well recognized that PMR can have have coexixting joint effusions often pauciarticular, but this group
who are between RA and PMR, have a polyarticular presentation. The response to low dose steroids is as
dramatic as that for PMR and relapses can occur as well as actual temporal arteritis. Besides the absence
of rheumatoid factor, another clue to help distinguish this syndrome from RA is the lack of involvement of
the MTP joints.
It is important to remember that except for a few emergent conditions (septic arthritis, endocarditis) and
urgent conditions (multisystem SLE) there is time to watch and evaluate the patient. I try to order tests
sequentially rather than "shotgun" approach at the outset. I have been reminded by several patients the
financial burden I placed on them by trying to cover all bases early on. By keeping in mind the 6 key
concepts of arthritis evaluation, one can hopefully have an easier time making sense of the swelling!
Suggested references
1. Primer on the Rheumatic Diseases. Ed, Schumacher HR Jr. Tenth Edition, Arthritis Foundation,
Atlanta, 1995.
2. Textbook of Rheumatology. Eds, Kelly WN, Harris ED, Ruddy S, Sledge CB. Fourth Edition, WB
Saunders, Philadelphia, 1993.
3. Clinical Rheumatology. Ed, Moskowitz R, Third Edition, WB Saunders, Philadelphia, 1989.
4. Gardner GC: Polymyalgia rheumatica, temporal (giant cell) arthritis, and Takayasu's arthritis. In:
Treatment of Rheumatic Diseases, Weisman MH, Weinblatt ME (Editors). Philadelphia, WB
Saunders, pp 154-171, 1995.
5. Barland P, Lipstein E: Selection and use of laboratory tests in the rheumatic diseases. Am J Med
1996; 100(suppl 2A):16S-23S.
6. Churchill MA, Geraci JE, Hunder GG: Musculoskeletal manifestations of bacterial endocarditis. Ann
Int Med 1977; 87:754-759.
7. Steere A: Lyme Disease. N Eng J Med 1989; 321:586-596.
8. Kahn MA (ed): Ankylosing spondylitis and related spondyloarthropathies. Spine. State of the Art
Reviews 1990;4:497-688.
Surgery for arthritis at the University of Washington
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If you are interested in making an appointment to discuss this procedure, you can request an appointment
using our online referrals website. To request a referral online, please click here. You can also call 206-
598-4288 (outside the Seattle area: 800-440-3280) to make an appointment.

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