INTRODUCTION

Seronegative inflammatory arthritis refers to a group of conditions in which clinical evidence of noninfectious, active inflammation (Box 75-1) is noted in the joints, but serum autoantibodies, such as rheumatoid factor (RF) or anticyclic citrullinated peptide antibodies (anti-CCP), are absent. RF is widely used as a diagnostic marker for rheumatoid arthritis (RA), despite its presence in other inflammatory and infectious conditions. RF can also be detected in some healthy individuals. In recent years, anti-CCP antibodies have been shown to be as sensitive as RF in the diagnosis of RA, but with greater specificity.⁹ Seventy-five to eighty percent of patients with RA are seropositive for these autoantibodies.⁹ Therefore, the term seronegative inflammatory arthritis excludes RA.

Besides their distinction from RA, the seronegative inflammatory arthridites have several clinical features in common. They present with pain, limited motion and swelling of the affected joint, in the absence of trauma. When only one joint such as the elbow is initially involved, infection needs to be excluded. However, the elbow is often not the only diarthrodial joint involved in these conditions.

For the purposes of this discussion, the seronegative inflammatory arthridites will include spondyloarthropathies, crystalline arthropathies, and adult Still’s disease (Box 75-2).

SPONDYLOARTHROPATHIES

Spondyloarthropathies (SpA) are a group of inflam-matory disorders that includes ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease, and reactive arthritis, also known as Reiter’s syndrome. They share an increased prevalence of the human leukocyte antigen class I molecule B-27. Classically, the spondyloarthropathies manifest as an inflammatory arthritis of the spine and sacroiliac joints, but an asymmetric peripheral arthritis can occur as well. A key clinical feature distinguishing SpA from RA is the presence of enthesitis. Enthesitis refers to inflammation that is located at the sites of ligamentous insertion into bone, such as the Achilles tendon or plantar fascia. Table 75-1 illustrates several clinical differences between the SpA and RA. The relative frequency of elbow involvement in the SpA is shown in Table 75-2.

TABLE 75-1 Clinical Differences Between Spondyloarthropathies and Rheumatoid Arthritis

CCP, cyclic citrullinated peptide; HLA, human leukocyte antigen; IBD, irritable bowel disease.

TABLE 75-2 Elbow Involvement in Spondyloarthropathies

Aspiration of the elbow and subsequent synovial fluid (SF) analysis may be necessary to exclude infection in some cases, especially in monoarthritis. The injection of corticosteroids, such as triamcinolone and local anesthetic, into the joint space may also offer pain relief, and facilitate improvements in range of motion and overall joint function for patients with SpA.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of medical management of spondyloarthropathies. They reduce inflammatory features, and reduce joint pain and stiffness. The most common adverse events with the use of NSAIDs are gastrointestinal, and range from dyspepsia in 10% to 20% of patients to serious bleeding or gastroduodenal perforation in 7.3 to 13/1000 patients per year.¹⁰

If patients with SpA do not tolerate NSAIDs, are refractory to therapy, or have evidence of active disease or radiographic progression, the use of additional or alternative medications is indicated. These include sulfasalazine (SUSP) and methotrexate (MTX), which down-regulate the inflammatory activity that is associated with these conditions. Such medications require careful monitoring for potential adverse events, including increased risk for infection, hematologic abnormalities, and hepatotoxicity. For this reason, they should be prescribed and monitored only by physicians experienced in their administration.

If desired clinical outcomes are not achieved with NSAIDs, SUSP, or MTX, patients with spondyloarthropathies may be candidates for a new class of medications commonly referred to as biologics. Recently developed, they are monoclonal antibodies that bind to tumor necrosis factor-a, an important cytokine in the inflammatory pathway. These powerful medications can be associated with dramatic clinical improvements in patients with refractory spondyloarthropathies. Again, these medications should be administered and monitored under the guidance of a rheumatologist.

CRYSTALLINE ARTHROPATHIES

Crystalline arthropathies are a group of inflammatory arthritides associated with crystal deposition in the synovial space. The primary conditions included in this group are gout and pseudogout. Patients frequently present with an acute painful monoarthritis, which often is indistinguishable from septic arthritis. Timely aspiration to rule out infection and SF analysis to confirm the diagnosis is essential. The relative frequency of elbow involvement in crystalline arthropathies is shown in Table 75-3.

TABLE 75-3 Elbow Involvement in Crystalline Arthropathies

Gout is a common condition associated with the deposition of monosodium urate (MSU) crystals in the SF and synovial tissue. MSU crystals are by-products of an aberrant uric acid metabolism. Risk factors for gout include hypertension, renal insufficiency, obesity, type 2 diabetes mellitus, ethanol intake, lead exposure, and the use of diuretics, particularly thiazide diuretics.² The diagnosis is confirmed by finding the presence of the MSU crystals in SF under polarizing microscopy. Frequently, but not always, serum uric acid levels may be elevated during an acute gout attack.

MSU crystals are long, needle-shaped, and demonstrate strong negative birefringence under compensated polarized light. That is, they appear bright yellow under the polarizing microscope. During an attack of gout, MSU crystals are often found within white blood cells from synovial fluid. If a tophus is aspirated and examined, the crystals are often found outside the cells as well.

Pseudogout is another crystalline arthropathy characterized by an acute monoarthritis, similar to, but often more insidious, than acute gout. The diagnosis of pseudogout is made when calcium pyrophosphate (CPPD) crystals are deposited in the joint. Most CPPD crystal formation is associated with degenerative joint disease.

In contrast to MSU crystals, CPPD crystals are rhomboid shaped and exhibit positive birefringence under compensated polarized light, appearing blue. They also can be intracellular or extracellular but are more difficult to identify than MSU crystals because they are smaller and much less bright. In addition, low concentration of CPPD crystals in synovial fluid can lead to a false-negative report.

Treatment of acute gout focuses on excluding infection and confirming the diagnosis. Acute medical therapies include NSAIDs, a brief course of oral corticosteroid (<10 days), intra-articular corticosteroid injection, or oral colchicine. Often the treatment for acute gout depends on minimizing risk of adverse events because one treatment is not clearly superior to another. A key principle is to avoid a rapid change in the serum uric acid level during an acute attack.

Management of chronic gout focuses on carefully lowering serum uric acid levels. Medications that facilitate the excretion of uric acid, such as probenecid, may be used. More often, medications that decrease uric acid production, such as allopurinol are used. Consistent with the principle of not changing the uric acid level during an acute attack, the initiation of allopurinol is not indicated during an acute attack of gout. Rather, it should be started at least 2 months, if possible, after an acute attack has resolved, and dosed according to the patient’s creatinine clearance. As with the treatment of SpA, these medications should be administered and monitored by a physician familiar with them.

Patients with chronic gout may develop tophi. Tophi are deposits of MSU crystals in the subcutaneous tissues, which are often very painful. The olecranon bursa is a frequent location for tophi in patients with chronic gout. Figure 75-1 depicts such an example. A radiograph of a patient with tophaceous gout is seen in Figure 75-2.

FIGURE 75-1 Olecranon bursitis with tophi in a 68-year-old man. Acute olecranon bursitis is a very common clinical manifestation of gout. Often this presentation is rather dramatic and may be a common location for tophi as well.

FIGURE 75-2 Radiograph of right elbow demonstrating soft tissue swelling and erosion of the olecranon consistent with gout.

(Courtesy of R.G. Swee, M.D.)

As mentioned previously, an acute pseudogout attack presents clinically in a similar manner to an acute gout attack. It is not surprising then, that the treatment is almost identical and includes NSAIDs, a short course of oral corticosteroid or an intra-articular corticosteroid injection. In the workup after an initial pseudogout episode, metabolic abnormalities of calcium metabolism should be excluded. Between acute episodes, physiciansshould address degenerative joint disease that is often associated with pseudogout.

ADULT STILL’S DISEASE

Adult Still’s disease (ASD) is a rare form of seronegative inflammatory arthritis. It shares many clinical features with systemic-onset juvenile RA, which accounts for about 10% of the cases of juvenile RA. Hallmarks of ASD are its extra-articular features including high fever, rash, adenopathy and serositis, and the absence of autoantibodies. ASD can potentially cause a destructive arthritis. The frequency of elbow involvement in chronic ASD ranges from 4% to 44%.^3,11

The diagnosis of ASD is frequently made in the clinical setting of a fever of unknown origin. Clinical and exclusion criteria are described in Table 75-4.¹² The characteristic salmon-colored evanescent maculopapular rash of ASD is frequently observed at the time of the fever spikes and tends to be located on the trunk. The fevers are more prominent during the afternoon and evening hours as depicted in Figure 75-3.

TABLE 75-4 Criteria for Diagnosing Adult Still’s Disease (ASD)

^*Diagnosis of ASD requires five criteria, at least two major.

ANA, antinuclear antibody text; RF, rheumatoid factor; WBC, white blood cells.

Data from Yamaguchi, M., Ohta, A., Tsunematsu, T., Kasukawa, R., Mizushima, Y., Kashiwagi, H., Kashiwazaki, S., Tanimoto, K., Matsumoto, Y., Ota, T., and Akizuki, M.: Preliminary criteria for classification of adult Still’s disease. J. Rheumatol. 19:424, 1992.

FIGURE 75-3 Fever curve in adult Still’s disease demonstrating late afternoon and evening peaks.

Treatment of the arthritis of ASD resembles the treatment of RA. Typically NSAIDs and oral corticosteroids are used to treat arthritis, fever, and constitutionalsymptoms. MTX may be used to help reduce the need for systemic steroids.

SUMMARY

Seronegative inflammatory arthritides are common conditions that can involve the elbow. Frequently, arthrocentesis and synovial fluid analysis are needed to exclude the possibility of infection. Once infection is excluded, a specific diagnosis is confirmed either by documenting the presence of crystals in synovial fluid or by recognition of characteristic clinical features. Medical therapies are based on careful assessment of prognosis and risk-benefit ratio.