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10 Articles in Volume 17, Issue #7
Abuse-Deterrent Opioids: Why Rush to Judgment?
Alcohol Screen Recommended to Reduce Opioid-Induced Respiratory Depression Overdose
Ehlers-Danlos Syndrome: An Emerging Challenge for Pain Management
Guide to Laboratory Testing in Patients With Suspected Rheumatic Disease
Letters to the Editor: Arachnoiditis, Hormone Testing, Ehlers-Danlos Syndrome
Neurocognitive Disorders: Pain Expression in the Face of Mental Deficits
Preemptive and Preventive Analgesia for Chronic Postsurgical Pain
The Effects of Religion and Spirituality on Coping Efficacy for Death and Dying
Topical Nonsteroidal Anti-inflammatory Drugs and Nephrotoxicity: Is There a Safer Option?
Transformative Care for Chronic Pain and Addiction

Guide to Laboratory Testing in Patients With Suspected Rheumatic Disease

Differentiating rheumatic disorders can be difficult. This guide will assist PCPs in selecting which tests to order and why.

A simple paradigm can be useful during the initial evaluation of any patient with a suspected rheumatic disease. Is the patient presenting with joint swelling, or rather only with joint pain? In other words, is the problem more likely arthritis vs an arthralgia (Figure 1)?1

In general, primary care providers (PCPs) should be prepared to recognize possible rheumatic diseases and to provide a rapid referral to a rheumatologist. Importantly, the earlier therapy is initiated, the better the long-term outcome for the patient. Therefore, a timely diagnosis is central to optimal management.2 This article will review which diagnostic laboratory tests should or should not be ordered when making a diagnosis of rheumatic disorders.

A guide to the proper tests when diagnosing rheumatic diseases.

Basic Principles

The differential diagnosis of rheumatic disease may seem complex at first but can be subdivided into 3 discernible categories: inflammatory arthritis, non-inflammatory arthritis, and non-articular pain. If the swelling is associated with inflammation, inflammatory arthritis should be suspected. When there is no evidence of joint inflammation, non-inflammatory arthritis is much more likely (Figure 1).

The most common types of inflammatory arthritis affecting 1 to 2 joints include crystal-induce—either gout or pseudogout and joint infection. These are definitively diagnosed by a synovial fluid analysis. The most common inflammatory arthritis affecting multiple joints is rheumatoid arthritis (RA).3 However, there are many other forms of inflammatory polyarthritis, such as psoriatic arthritis and arthritis associated with inflammatory bowel disease, making the differential diagnosis more difficult. Most cases of non-inflammatory arthritis, whether monoarticular or polyarticular, are related to osteoarthritis (OA).

In contrast, arthralgias (non-articular pain) may be regional or generalized, but there is no obvious joint or soft-tissue inflammation. Examples of focal arthralgias include many types of tendonitis, bursitis, and muscle strain. Fibromyalgia is the most common widespread soft-tissue pain.

When to Order Lab Tests

Joint Swelling

Any time that joint swelling is found, especially if it is of recent origin, the affected joint should be aspirated. The PCP (if qualified) can perform the joint aspiration in the office. Identifying monosodium urate or calcium pyrophosphate (CPPD) crystals in the synovial fluid provides a definitive diagnosis of gout or pseudogout. Seeing bacteria on gram-stain smear or by culture is the only way to be certain of the diagnosis of bacterial arthritis.

In other joint effusions, a synovial fluid analysis will not provide an exact diagnosis but can give important clues as to the etiology of the joint swelling. Based primarily on the number of cells in the aspirate sample, joint effusions are classified as non-inflammatory, inflammatory, or highly inflammatory (purulent) (Table 1). For example, non-inflammatory joint effusions are relatively acellular, usually containing less than 1,000 cells/mm3, whereas inflammatory effusions, such as seen in RA or psoriatic arthritis, usually contain 5,000 to 20,000 cells/mm3. Septic arthritis should always be suspected if the synovial fluid cell count is greater than 50,000 cells/mm3 and mainly polymorphonuclear leukocytes (polys), although sometimes non-septic, inflammatory arthritis or crystal-induced effusions may be in that range. Bloody joint effusions are primarily related to joint trauma or bleeding disorders.

Blood testing

The only appropriate rheumatology “screening” laboratory tests are the acute phase reactants, either the erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP). These tests are almost always elevated in any inflammatory rheumatic disease. Therefore, they provide clues as to whether the patient has an inflammatory or non-inflammatory rheumatic condition. They also are helpful in tracking treatment efficacy in inflammatory diseases, such as polymyalgia rheumatica (PMR) or RA. Furthermore, these tests are simple and inexpensive. However, they are not specific and are most helpful when a patient has no physical findings suggestive of systemic inflammation, as illustrated in the following case studies.

Case Study 1

A 64-year-old man presented to the office feeling “very stiff and achy” for the past 2 weeks. He had a low-grade fever on 2 readings at home and has lost 5 pounds due to a lack of appetite over in last few weeks. He noted being especially stiff in the morning and feeling exhausted.

The patient’s physical examination was quite unremarkable: both strength testing and joint exam were normal. He was afebrile at the time of this visit.

What laboratory testing and treatment would be appropriate?

In this case, the patient presented with a characteristic history of PMR. I would recommend an initial ESR and a CRP blood test. A highly elevated ESR or CRP would help to confirm the clinical suspicion of PMR. It is possible that this patient may also be anemic and have thrombocytosis. A modest anemia and thrombocytosis would also be indicative of an inflammatory disease.

Treatment with low doses of prednisone should rapidly improve the patient’s symptoms and, within a few weeks, the ESR/CRP would be expected to return to normal.

Case Study 2

A 45-year-old female patient was referred, by her dermatologist, to be evaluated for hair loss and fatigue. She had no history of rash, joint swelling, or significant systemic symptoms.

Prior testing included a positive antinuclear antibody (ANA). She stated that she had been losing clumps of hair for 10 months. She also complained of being “tired and run-down” and often felt achy.

Her physical examination, including scalp and skin, was unremarkable, as was the joint examination.

Would any additional testing be appropriate?

In contrast to Case 1, a normal ESR or CRP in the patient from Case 2 would suggest a non-inflammatory cause of her symptoms, most likely fibromyalgia. A specialist, such as a rheumatologist, may be satisfied that the ANA is “false-positive,” since at least 20% of healthy women are known to have a positive ANA screening result (Table 2). Very elevated ANA titers would much less likely present as false positive. However, further immune serologic testing may be necessary.

Rheumatoid Factor

As discussed in a past article in Practical Pain Management,1 the PCP’s role in diagnosing RA, a positive rheumatoid factor, and anticyclic citrullinated peptide (anti-CCP) antibody is present in 70% to 80% of RA patients.1 Higher levels of either ANA or anti-CCP findings would be more suggestive of RA and more likely to reflect greater, more aggressive disease activity. However, positive rheumatoid factor is also present in many acute and chronic inflammatory diseases, as well as in a small percentage of healthy subjects.

Given its relatively poor specificity, a rheumatoid factor would not need to be obtained by the PCP but could be obtained during a rheumatology consultation. Indeed, there is evidence that a positive rheumatoid factor obtained in primary care performed badly in excluding the diagnosis of RA, thereby delaying a rheumatology referral.4 In contrast, the anti-CCP antibody has greater specificity for RA and may be a reasonable test to initiate in the primary care setting.

Other Serum Tests: When to Order

Patients with systemic lupus erythematosus (SLE or lupus) are best diagnosed by a constellation of multi-system signs and symptoms. Laboratory tests would be confirmatory but never diagnostic. Nearly 100% of patients with SLE are ANA positive, usually at high titer serum dilutions. The indirect immunofluorescence ANA test is the most common technique used in most laboratories and is reported by its endpoint titer and by its pattern. Other serologic techniques, using solid phase assays, better identify specific autoantibodies. For example, immune tests that identify anti-DNA or Sm antibodies are quite specific for SLE.

Serologic tests that can be helpful in other systemic, autoimmune diseases include the Scl and anti-centromere antibodies in scleroderma, the anti-Ro/SSA and anti-La/SSB antibodies in Sjogren’s syndrome, and the anti-Jo-1 antibody in autoimmune myositis.

Antiphospholipid antibodies are present in patients with SLE or with other autoimmune diseases who may have manifestations of the antiphospholipid syndrome (APS). Clinically, APS presents as unexplained venous or arterial thrombosis, adverse events related to pregnancy, thrombocytopenia, and other autoimmune symptoms.

The presence of anticardiolipin antibodies is usually confirmed by the enzyme-linked immunoassay (ELISA), although the presence of the lupus anticoagulant or an abnormal activated partial thromboplastin time (aPTT) are often present.

Case Study 3

A 56-year-old woman with a 3-week history of generalized body ache, fatigue, and shortness of breath presented to the office. While her physician was taking the patient’s history, she reported that for the last 2 weeks she had been unable to eat. She was experiencing right foot and left hand numbness, and a skin rash.

Initial laboratory testing revealed a leukocytosis, a very elevated ESR, and hematuria. On physical examination, there was palpable purpura over both lower legs and evidence of sensory and motor abnormalities on the neurologic examination.

Would any additional laboratory testing be indicated?

This patient case offers a characteristic presentation of systemic vasculitis (Table 3). In this situation, laboratory evidence of antineutrophilic cytoplasmic antibodies (ANCA) would confirm the suspicion of vasculitis. The 2 main ANCA detected by immunofluorescence are antibodies to proteinase 3 (PR3) or cytoplasmic ANCA. These are present in 60% to 90% of patients with granulomatosis with polyangiitis (Wegener’s disease). Antibodies to myeloperoxidase (MPO) or perinuclear ANCA (p-ANCA) are present in 50% to 80% of patients with microscopic polyangiitis.

The enzyme-linked immunosorbent assay (ELISA) is more specific although less sensitive for ANCA testing in suspected vasculitis. ANCA positivity is present in renal-limited vasculitis, eosinophilic granulomatosis/polyangiitis (Churg-Strauss syndrome), various gastrointestinal autoimmune diseases, and drug-induced systemic vasculitis. Although the degree of ANCA positivity may reflect disease activity, most observers do not recommend using changes in ANCA values as the sole determinant of therapeutic decisions.

Is There Value in Uric Acid Testing?

In general, the degree of hyperuricemia correlates with the propensity to develop gout over a patient’s lifetime. However, during an acute attack of gout, obtaining a blood serum uric acid test is not very helpful, since 20% to 30% of patients will be normo-uricemic at the time of an attack.  

Furthermore, medications to lower serum uric acid should never be started until the attack has completely subsided. Therefore, the diagnosis of gout should be made by the classic clinical picture and, when possible, confirmed by identification of uric acid crystals in the synovial fluid or tophus aspirate.


The only pathognomonic laboratory tests for rheumatic disease are the identification of synovial fluid crystals in gout or pseudogout or a positive culture in septic arthritis. Screening blood tests should be discouraged other than an ESR or CRP that may help to assess whether an inflammatory, systemic disease is present. The predictive value of a positive ANA and rheumatoid factor test is related to the clinical likelihood of the presence of that disease. More specific autoimmune tests for SLE and the other systemic connective tissue diseases are available but may best be ordered in consultation with a specialist.

In contrast, testing for antiphospholipid antibodies and for ANCA are appropriate tests in the initial diagnostic evaluation of possible APS or systemic vasculitis. A serum uric acid level would not be helpful in the clinical setting to diagnose acute gout.

Last updated on: September 27, 2017
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