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
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

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 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 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 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 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
  • 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)

"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.

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