Answer: D

Rheumatoid Nodules

Rheumatoid nodules (RNs) are extra-articular manifestations of rheumatoid arthritis, a chronic autoimmune disease of unknown etiology that affects primarily the joints. Rheumatoid arthritis is associated with several other extra-articular conditions, including vasculitis, atherosclerosis, anemia, Sjögren syndrome, and pulmonary nodules. However, RNs are the most common extra-articular manifestation, occurring in 20% to 30% of cases of rheumatoid arthritis.1,2 In patients with rheumatoid arthritis-associated Felty syndrome, the incidence of RNs rises to 75%.3 RNs can be associated with other connective tissue disorders, such as systemic lupus erythematosus.4

RNs occur more frequently in whites and are more common in men than in women.3 They usually affect those with a longer history of rheumatoid arthritis and a positive rheumatoid factor titer (90% of patients with RNs have this marker). In addition, patients with RNs may be more likely to have other systemic complications of rheumatoid arthritis.5 However, this does not definitively predict the severity of disease.6 Although rare, RN may be the first clinical symptom of rheumatoid arthritis.4 Other variations of rheumatoid arthritis-associated RNs include rheumatoid nodulosis, which is the presence of multiple RNs in an otherwise asymptomatic patient, and accelerated rheumatoid nodulosis, which is characterized by the rapid onset of numerous small nodules following methotrexate treatment.5

The histopathology of RNs is defined by 3 stages: acute inflammation, granulation, and necrosis. The lesions develop from small areas of granulated tissue into large nodules with necrotic centers. These nodules typically contain fat, cellular fragments, immunoglobulins, lymphocytes, neutrophils, eosinophils, and fibrinoid material.2 On histology testing, RNs display palisading necrobiotic granulomas and a central area of fibrin and are usually seen in the deep dermis. The nodules have 3 characteristic layers: a central eosinophilic zone of fibrinoid necrosis, a surrounding region of palisading granulomas with high levels of human leukocyte antigen-D related (HLA-DR)-expressing macrophages, and an outer border infiltrated by inflammatory cells.5

The pathogenesis of RNs is unknown, but current theories suggest that trauma to small vessels causes a local aggregation of immune complexes, which stimulates immune cells to release cytokines and other substances that promote the growth of these nodules.3 Evidence suggests that interleukin-17 and interleukin-23 are important for the onset of RNs.5 Patients with rheumatoid arthritis have a genetic predisposition for the development of RNs. Specifically, patients with the HLA-DR4 antigen haplotype are at higher risk for RNs, whereas patients displaying the HLA-DRw2 antigen are at lower risk.2

Clinically, these subcutaneous nodules usually occur in areas of the body that are subject to pressure or trauma, such as the elbow, upper forearm, digits, heels, and back.1 However, cases have been reported on other body sites, such as the mucosa of the mouth, penis, and vulva. In addition, nodules may develop on the visceral surfaces of the lungs, heart, throat, and liver.5 The nodules are firm, skin-colored papules that range in size from <5 mm to a few centimeters in diameter. Some are deep enough to adhere to underlying tendons or bursae, while others are epidermal and freely movable.4 Usually benign and painless, they can feel uncomfortable in certain areas of the body and are cosmetically distressing to many patients. If the skin over the nodules ruptures, possible complications include infection, ulceration, and gangrene.3 Additionally, nodules that are attached to the synovium may migrate to the skin and form a fistula, which requires treatment with synovectomy.2

RNs can usually be diagnosed based on clinical findings, such as the location of the nodules, associated vasculitis, and history of rheumatoid arthritis or other rheumatologic diseases. When this is not sufficient, laboratory findings and histology testing provide a reliable method of diagnosis.5 Many other conditions include nodular lesions; therefore, the differential diagnosis of RNs is complex. The differential diagnosis includes subcutaneous granuloma annulare (GA), fibromas, xanthomas, nodular scleroderma, synovial cysts, and tumoral calcinomas. These are often differentiated on histology or based on clinical differences.2

RNs may look similar histologically to deep GA, which makes this differential diagnosis more challenging. Several features can simplify this diagnosis, including location, pattern, presence of interstitial mucin, and fibrosis.2 For example, mucin deposition is very rare in RNs but is common in GA; this histologic difference is the most important method for differentiating these 2 nodular disorders.5

Because RNs are usually benign, treatment is not necessary. Draining, excising, or injecting the nodules may result in infection, so these methods should be avoided. The nodules will often regress with time and with typical rheumatoid arthritis treatments, such as nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, methotrexate, and cyclosporine.3 However, nodules may grow or worsen (eg, in accelerated rheumatoid nodulosis following methotrexate treatment). They may also be prone to ulceration and cause pain, discomfort, deformity, or issues with mobility, depending on location. In these cases, treatment options include corticosteroid injections into the nodules, surgical excision and grafting, and oral corticosteroid medications. These therapies have variable success.2

After a discussion of the various therapy options, the patient decided to wait and see whether the nodules would resolve over the next few months before trying a corticosteroid injection.

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