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Rheumatoid nodules are the common extra-articular manifestation of rheumatoid arthritis (RA).
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Systemic RA medications are not proven therapy for rheumatoid nodules; paradoxically, methotrexate and possibly other systemic therapies can induce or exacerbate nodule formation.
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Regardless of location, rheumatoid nodules have a consistent histologic appearance with a central area of fibrinoid necrosis, surrounded by palisading macrophages that are CD68+ and enclosed by a granulation layer.
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Subcutaneous
Rheumatoid Nodules
Section snippets
Key points
Rheumatoid nodules
Rheumatoid nodules are one of the most common extra-articular manifestations noted in RA. These nodules are usually encountered on extensor surfaces and areas of pressure or repetitive trauma, most notably the olecranon and dorsal aspect of the hand (Fig. 1). However, they can develop on any tendon/ligament-like structures such as the Achilles tendon and vocal cords. In bedbound patients, these nodules can also be seen on the occiput and ischium. The prevalence is estimated at 10%, although the
Prevalence of rheumatoid nodules
Studies indicate that rheumatoid nodule incidence is highest during initial RA presentation, with approximately 7% of patients demonstrating nodules at the time of diagnosis.10 The overall occurrence rates have been reported in as many as 35% of individuals,6 In a study examining Asian and Hispanic populations placing overall prevalence at approximately 17%, prevalence was higher in the Hispanic population.11 Most patients with rheumatoid nodules have positive RF factor.12 In patients with
Histopathology
The histologic appearance of rheumatoid nodules is specific and representative of an immune-mediated granulomatous process, which exhibits a central area of necrosis surrounded by palisading epithelioid macrophages enclosed by granulation tissue containing lymphocytes and histiocytes.14, 15, 16 The area of central necrosis contains a large population of HLA-DR+ staining material likely from necrosing endothelial cells and macrophages. Of the surrounding palisading cells, the vast majority stain
Risk factors and pathogenesis
Numerous studies have evaluated the risk factors and associations for the development of rheumatoid nodules. The one clear modifiable risk factor is smoking. In a study of 420 consecutive patients with RA, smoking conferred an odds ratio (OR) of 1.8 (confidence interval [CI], 1.0–2.9) for rheumatoid nodules.21 Additional studies show that ever smokers had an OR of 7.3 (CI, 2.3–24.6) of developing rheumatoid nodules, with no difference noted between men and women.22
The presence of elevated level
Systemic location of rheumatoid nodules
Rheumatoid nodules rarely occur in the lung or cardiac structures. The radiographic prevalence of pulmonary rheumatoid nodules is less than 1% on radiologic studies20, 22, 28 but have been reported at nearly 30% on autopsy specimens.20 Predisposing risk factors are similar to those of subcutaneous nodules, including smoking and RF positivity.29 Multiple nodules are more common than single nodules and are predominantly located in middle and superior peripheral lobes. Approximately 50% of these
Rheumatoid nodules in other diseases
With initial descriptions dating back to the 1870s, there are long-standing reports of rheumatoid-like nodules documented in rheumatic fever. However, an early comparative study from 1933 provides an excellent review of these conditions. The nodules were more commonly found at the extensor surface of the knees and elbows, similar to those seen in RA, and were associated with more severe disease, including cardiac complications.38 This finding was supported by a study that showed that 90.4% of
Accelerated nodulosis
Methotrexate is considered the first-line therapy for moderate or severe RA and is highly effective as monotherapy or in combination with other DMARDs or biologic agents. Although methotrexate is usually well tolerated, methotrexate-induced accelerated nodulosis, characterized by the rapid onset or worsening of rheumatoid nodules in association with methotrexate, has been recognized as a rare side effect. Other DMARDs and biologic agents have also been implicated. A systematic review of
Rheumatoid nodulosis
Rheumatoid nodulosis is characterized by the development of rheumatoid nodules in patients without chronic synovitis. This condition was initially described in 1949,7 and Couret and colleagues52 established the diagnostic criteria in 1988. The criteria require multiple biopsy proven nodules, recurrent joint symptoms without chronic synovitis or radiographic findings, and no or mild systemic manifestations. A modified criteria presented in 2003 included these criteria, adding positive RF and a
Treatment of rheumatoid nodules
During the past 23 to 30 years, advances in RA treatment have led to a remarkable improvement in patient’s symptoms, function, outcomes, and quality of life, particularly in patients with moderate to severe disease. Aggressive therapy with DMARDs such as methotrexate, along with biologic agents that specifically target key inflammatory cytokines and pathways, has dramatically changed the prognosis for this patient group. However, there are little data to support the impression that rheumatoid
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