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Rheumatoid nodules

Rheumatoid nodules
Author:
John M Davis, MD, MS
Section Editor:
James R O'Dell, MD
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: Jan 2024.
This topic last updated: Jan 03, 2024.

INTRODUCTION — The rheumatoid nodule is the most common cutaneous manifestation of rheumatoid arthritis (RA) and is most often seen in patients with seropositive RA and more severe disease [1-4]. Although nodules are most commonly found on pressure points (such as the olecranon process), they may occur at other sites, including within the lung and other internal organs.

The accelerated formation of multiple rheumatoid nodules may also occur in association with certain medications, particularly methotrexate; the presence of multiple subcutaneous rheumatoid nodules can infrequently be seen with only mild or no systemic manifestations of RA, a condition termed rheumatoid nodulosis.

The clinical and histopathologic features, diagnosis, and management of rheumatoid nodules will be reviewed here. The articular features and an overview of the systemic and nonarticular manifestations of RA are presented separately. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

EPIDEMIOLOGY

Frequency of subcutaneous rheumatoid nodules – Palpable nodules in the subcutaneous tissues have been reported at initial presentation in 7 percent of patients with rheumatoid arthritis (RA) [5] and historically were found at some time during the disease course in 30 to 40 percent of patients [6]. In Rochester, Minnesota, the cumulative incidence of rheumatoid nodules declined substantially from 31 percent for patients diagnosed between 1985 and 1999 to 16 percent for patients diagnosed between 2000 and 2014, essentially halving the incidence of rheumatoid nodules [7]. This decline has paralleled epidemiological shifts in risk factors for extraarticular disease manifestations, tobacco smoking, and seropositive disease, as well as initiation of modern treatment strategies. Further research is needed to understand why rheumatoid nodules are declining in incidence and to determine if this is occurring globally in patients with RA.

Associated findings – In general, patients with rheumatoid nodules tend to have a severe RA phenotype, with more rapid progression of joint destruction than other patients with RA [8]. The vast majority of nodule-formers have positive tests for rheumatoid factor [1]; limited data suggest that many patients with rheumatoid nodules have positive tests for anti-citrullinated peptide antibodies (ACPA) [9].

The presence of subcutaneous rheumatoid nodules is predictive of increased risk of cardiovascular disease as well as cardiovascular, respiratory, and all-cause mortality [10,11]. Patients with rheumatoid nodules are also at greater risk of hospitalization [12] due to complications of their disease or to comorbidities and to experience lower-extremity ulcers, which are associated with significant morbidity related to soft tissue, bone, and joint infections [13]. RA patients with nodules are also more likely to develop vasculitis [14]. Nodules are found in 75 percent of patients with RA-associated Felty syndrome [15]. (See "Clinical manifestations and diagnosis of Felty syndrome".)

Pulmonary nodules – The prevalence of pulmonary rheumatoid nodules in patients with RA depends in part on the methods used for detection. As an example, plain radiographs of the chest revealed rheumatoid nodules in only 2 of 516 patients with RA in one clinical series [16]. However, a study of open lung biopsies from 40 patients with suspected lung disease found rheumatoid nodules in 13 subjects (32 percent); in 8 of 13 patients, there were multiple nodules [17]. Accelerated pulmonary nodulosis associated with methotrexate and other medications may also be seen. (See 'Accelerated nodulosis' below.)

Nodules in other organs or tissues – Precise estimates of the prevalence and incidence of rheumatoid nodules in other organs or tissues are not available. The cumulative incidence of biopsy-confirmed rheumatoid nodules in the heart or elsewhere is reportedly <1 percent [18]. The most frequent visceral sites beyond the lungs are the cardiac valves. A systematic review revealed a greater than 12-fold increased odds of valvular nodules in patients with RA compared with non-RA control subjects [19], and RA patients with subcutaneous nodules have an increased frequency of valvular involvement [20]. The occurrence of rheumatoid nodules in the central nervous system (eg, on the meninges) is very rare based on scattered case reports in the literature [4].

Presence in disorders other than rheumatoid arthritis – Rheumatoid nodules have also been noted in occasional patients with systemic lupus erythematosus, ankylosing spondylitis, granuloma annulare (GA), and chronic active hepatitis and have been found infrequently in healthy children and adults [15].

PATHOLOGY AND PATHOGENESIS

Histopathology — The histologic appearance of a typical rheumatoid nodule includes a central area of necrosis surrounded in turn by palisading macrophages and then lymphocytes (picture 1) [21-24]. Histologic features of focal vasculitis with associated immunoglobulin (Ig), fibrin deposition, and complement activation can be found in one-third of all rheumatoid nodules [15].

Lymphoid aggregates containing B lymphocytes and features characteristic of lymphoid follicles have been reported in pulmonary nodules [25]. This contrasts with the expected structure of subcutaneous nodules, from which B cells and lymphoid follicles are normally absent. Such B cell aggregates may also occur in diffuse rheumatoid arthritis (RA)-associated interstitial lung disease, such as nonspecific interstitial pneumonitis or usual interstitial pneumonitis [26].

Pathogenesis

Cytokines, proteinases, and other immune factors – A variety of products, particularly cytokines and other immunoreactants, are produced within rheumatoid nodules, and the fibroblasts in the nodules produce large quantities of metalloproteases [27]. Most of the cytokine profile, together with the ability of the tissue to produce metalloproteinases, establishes the rheumatoid nodule as a T helper 1 (Th1) granuloma [28-30]. The lymphocytes can generate IgG and IgM rheumatoid factor.

Examination for messenger ribonucleic acid (mRNA) transcripts for cytokines has revealed evidence for tumor necrosis factor (TNF) alpha, interferon gamma, interleukin (IL) 1 beta, IL-1 receptor antagonist, IL-10, IL-15, IL-18, and IL-12 (but not IL-2 or IL-4), as well as adhesion molecules E-selectin, intracellular adhesion molecule (ICAM) 1, platelet endothelial cell adhesion molecule (PECAM), and vascular cell adhesion molecule (VCAM). IL-17A is not found in rheumatoid nodules, in contrast to its presence in the rheumatoid synovial membrane [31]. Deposits of rheumatoid factor and the terminal components of complement are also found on the endothelium of small vessels within nodules [32].

Peptidyl arginine deiminases 2, 3, and 4 and myeloperoxidase have been shown to generate citrullinated and homocitrullinated antigens in necrotic tissue of rheumatoid nodules [33]. Neutrophils express these enzymes, and through the generation of neutrophil extracellular traps (NETs), they may contribute to autoantigen externalization that may be targeted by anti-citrullinated peptide antibodies (ACPA), contributing to the inflammatory process within rheumatoid nodules [34].

Immunogenetic factors – Human leukocyte antigen (HLA) alleles may be less important for development of nodules than for other extraarticular disease features. A meta-analysis of individual patient data from published studies showed no strong association between the presence of nodules and carriage of major histocompatibility complex (MHC) alleles (shared epitope) that are associated with RA, per se [35]. There was a weak association with only the HLADRbeta1*0401 shared epitope allele but not with other genotypes. This contrasts with a similar analysis of studies of RA-associated vasculitis, in which an association between vasculitis and a double dose of the shared epitope was found [36]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)

In contrast to the weak association with HLA, IL-4 receptor (IL4R) single-nucleotide polymorphisms are associated with rheumatoid nodules [37]. In a sample of 749 patients in the Consortium for Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry, the presence of IL4R single-nucleotide polymorphisms, either rs1801275 (odds ratio 8.1, 95% CI 1.6-40.9) or rs1805010 (odds ratio 2.74, 95% CI 0.80 to 9.41), was associated with the presence of rheumatoid nodules in patients with at least one HLA-DRB1 allele encoding the shared epitope [37]. The mechanism is unknown, but diminished responsiveness to IL-4 signaling could contribute to Th1-mediated inflammation. This association has not yet been replicated among African American individuals nor in other populations.

A French study evaluated antibodies to the five immunodominant citrullinated epitopes within human fibrin (alpha-36-50cit, alpha-171-185cit, alpha-501-515cit, alpha-621-635cit, and beta-60-74) for association with HLA genotype and clinical phenotypes among 184 patients with ACPA-positive RA [38]. Anti-citrullinated fibrin alpha-501-515 antibodies in high titer were associated with rheumatoid nodules and correlated with HLA-DRB1*0401 and positive rheumatoid factor. The findings suggest a potential role for immune complexes containing anti-citrullinated fibrin alpha-501-515 antibodies and rheumatoid factor in the pathogenesis of rheumatoid nodules [38].

Exogenous risk factors – Extrinsic risk factors, including drugs and cigarette smoking, appear to be implicated in some patients. A complication of methotrexate therapy in some patients with RA is the increased formation of rheumatoid nodules, a proinflammatory effect that occurs even when synovial inflammation is suppressed [39,40] (see 'Accelerated nodulosis' below). Among susceptible individuals, this complication may be due to the activation of adenosine A1 receptors by methotrexate, which leads to enhanced cellular fusion and the formation of multinucleated giant cells [41]. It is unknown if activation of adenosine pathways is involved in nodulosis associated with other medications.

Cigarette smoking may increase the risk of developing rheumatoid nodules. This was illustrated in a study of 1589 patients with early RA in which those with nodules were compared with age- and sex-matched RA controls [5]. Those with nodules were significantly more likely to have ever smoked cigarettes (odds ratio 7.3, 95% CI 2.3-24.6). Smoking is also associated with vasculitis [42,43] and other severe extraarticular manifestations of RA [18,44].

CLINICAL MANIFESTATIONS

Subcutaneous nodules — Subcutaneous nodules are the most common form of rheumatoid nodule and are most commonly found on pressure points or areas of repeated trauma, such as the olecranon process and other extensor areas (eg, on the hands and fingers), but occur at other sites as well. The size of the nodules varies from 2 mm to 5 cm; they are firm, nontender, and may either be moveable in subcutaneous tissue or bound down to underlying fascia or periosteum (picture 2) [15]. Nodules are more common in patients with severe rheumatoid arthritis (RA); bedridden patients can develop nodules on the occiput and ischial areas, and nodules occasionally form on tendons and ligamentous tissues, such as the Achilles tendon and vocal cords [45].

In many cases, the nodules are neither symptomatic nor a cosmetic concern. However, rheumatoid nodules can be painful and/or disfiguring, interfere with function, or cause compressive neuropathies. Some patients find the nodules more distressing than the arthritis. The nodules may also ulcerate and thus serve as a site for local infection or other distant infectious complications by hematogenous spread of bacteria.

Pulmonary nodules — Nodules in the lungs in RA are generally located in subpleural areas or in association with interlobular septa [46]. Pulmonary rheumatoid nodules are generally asymptomatic but can lead to complications, including pleural effusion, pneumothorax, pyopneumothorax, bronchopleural fistula, or hemoptysis.

Consistent with their histopathologic features, which can differ from subcutaneous nodules in that they may contain B lymphocytes and features of lymphoid follicles (see 'Histopathology' above), reduction in size or even disappearance of pulmonary rheumatoid nodules may sometimes be seen in patients with severe RA treated with the B-cell-depleting agent rituximab [47].

Rheumatoid nodules in the lungs, their complications, and rheumatoid nodules associated with pneumoconiosis (Caplan syndrome) are discussed in detail elsewhere. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Rheumatoid lung nodules'.)

Cardiac nodules — Rheumatoid nodules may develop in the pericardium, myocardium, and valvular structures [48]. The presence of subcutaneous nodules is associated with valvular thickening, nodules, and insufficiency, mainly of the mitral and aortic values on echocardiography [20]. Symptoms related to the presence of nodules are rare, but syncope or death due to heart block from a lesion situated in the conduction system can occur [49]. Stroke or other manifestations of arterial embolization may result from nodules on a heart valve [50-52].

Other noncutaneous sites

Central nervous system – Rheumatoid nodules may rarely affect the central nervous system. This is discussed in detail elsewhere. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Rheumatoid nodules'.)

Other organs – Rheumatoid nodules have also been described in case reports to rarely occur in other organs and tissues, including the oral mucosa and the lip [53,54], thyroid gland [55], lymph nodes [56], liver [57-59], and kidneys [57,60].

Accelerated nodulosis — A poorly understood phenomenon is that some patients treated for RA with methotrexate have a noticeable increase in the size and number of rheumatoid nodules. This is referred to as accelerated nodulosis. Typically, patients with this condition rapidly develop numerous small subcutaneous nodules primarily over the fingers, hands, or wrists, though other sites have been described, such as elbows, scalp, Achilles tendon, larynx, and lungs [61,62]. Nodulosis has also occasionally been associated in RA patients with treatment with azathioprine, etanercept, leflunomide [15], and tocilizumab [63].

The onset of methotrexate-induced accelerated nodulosis has been described as early as one month and as long as eight years after the initiation of methotrexate therapy [61,62]. Nodules associated with methotrexate therapy are otherwise similar in their morphology and clinical manifestations to usual RA nodules.

Exploratory analyses has suggested that patients with polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and adenosine A2a receptor (ADORA2A) genes may have an increased frequency of methotrexate-induced nodulosis, supporting potential causal roles for the folate and adenosine pathways in the pathogenesis of nodulosis [64].

Accelerated pulmonary nodulosis has been reported to follow methotrexate, anti-tumor necrosis factor (TNF) therapy, and leflunomide treatment [65-68]. These can mimic infection or malignancy.

Rheumatoid nodulosis — Rheumatoid nodulosis is the term used for a variant of polyarthritis associated with features of palindromic rheumatism, radiologic subchondral bone cysts, and subcutaneous rheumatoid nodules [69,70]. Patients typically exhibit multiple subcutaneous nodules, particularly on the hands, and multiple subchondral bone cysts known as "geodes" [71]. The nodules tend to occur on extensor surfaces adjacent to joints, elbows, and fingers, and can affect the forearm, metacarpophalangeal and proximal interphalangeal joints, occiput, back, heel, and other areas [15]. Many of the affected patients have minimal clinical and radiographic joint disease without chronic synovitis, but a minority may go on to develop chronic, erosive RA [70].

DIAGNOSIS

Subcutaneous nodules — In a patient with rheumatoid arthritis (RA), a slowly developing, firm, painless, subcutaneous nodule located at a pressure point is almost certainly a rheumatoid nodule. These can be movable or bound down to underlying fascia or periosteum. Thus, in patients with typical asymptomatic subcutaneous nodules, further evaluation is usually not required to establish the diagnosis. However, a biopsy is indicated in patients with unusual or complicated presentations. As examples, patients with nodules that exhibit progressive rapid growth, unusual location, ulceration, or a suspected alternative diagnosis such as infection or malignancy should undergo surgical excision of the entire nodule.

The finding of a nodule with characteristic histologic findings on biopsy is nearly pathognomonic for RA and rheumatoid nodules (see 'Histopathology' above). However, nodules with a similar histologic appearance rarely occur in some patients with systemic lupus erythematosus and in otherwise healthy children [72-76].

Pulmonary nodules — Rheumatoid nodules in the lung parenchyma are more difficult to diagnose with confidence than subcutaneous nodules, but the radiologic features are helpful in making the diagnosis. Computed tomography (CT) is usually necessary for further evaluation of pulmonary infiltrates or nodules identified on a screening chest radiograph. Typical findings on CT imaging include the presence of multiple nodules, smooth borders, satellite nodules, cavitation, and peripheral or subpleural location, occasionally with an associated subpleural rind of confluent soft tissue [77]. A biopsy is often required to confirm the diagnosis and to exclude malignancy, infection, or other abnormalities. (See 'Differential diagnosis' below.)

As an example, a rheumatoid nodule in the lung may not be definitively diagnosed until lung cancer has been excluded by biopsy or excision. The evaluation of solitary and multiple pulmonary nodules is discussed separately. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Rheumatoid lung nodules' and "Diagnostic evaluation of the incidental pulmonary nodule".)

DIFFERENTIAL DIAGNOSIS

Subcutaneous nodules – Numerous conditions can be associated with nodules or cysts that may potentially resemble rheumatoid nodules, depending upon their anatomic location and consistency. However, the concurrent presence of active rheumatoid arthritis (RA) with positive rheumatoid factor or anti-citrullinated peptide antibodies (ACPA) together with distribution over extensor surfaces and other pressure points strongly suggests rheumatoid nodules, and the distinction can usually be made clinically without further testing. When a biopsy is required, the distinction between rheumatoid and other nodules can usually be made based upon the histologic findings.

The differential diagnosis for the most common causes of subcutaneous nodules includes fibromas caused by chronic trauma from shoes or repetitive use of hand tools, subcutaneous granuloma annulare (GA), gouty tophi, and calcinosis [1,15]:

Subcutaneous granuloma annulare – Subcutaneous GA, also known as "pseudorheumatoid nodules," can be seen in adults but are more common in children. These are typically <4 cm in diameter, single or multiple, and most commonly located on the scalp, hands, anterior tibia, or feet (see "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis"). Histopathologic features may resemble rheumatoid nodules, including a lymphohistiocytic infiltrate, often in an interstitial or palisaded pattern, but the presence of mucin deposition is suggestive of GA [78].

Gouty tophi – Gouty tophi should be suspected in a patient with a history of acute mono- or oligoarticular arthritis, most commonly involving the great toe metatarsophalangeal (MTP) joints or other lower extremity joints; hyperuricemia; and the physical appearance of tophi, which is often characteristic, with a white to yellow coloration of the subcutaneous monosodium urate deposits (see "Clinical manifestations and diagnosis of gout"). The diagnosis can be confirmed when necessary by aspiration and polarized microscopy showing needle-shaped, negatively birefringent crystals.

Calcinosis cutis – Calcinosis cutis refers to dystrophic calcification at sites of microtrauma or inflammation, which typically occurs in patients with systemic sclerosis, dermatomyositis, or overlap connective tissue diseases (see "Calcinosis cutis: Etiology and patient evaluation"). These lesions are composed of calcium hydroxyapatite and typically manifest as multiple subcutaneous papules or nodules that are yellow-white in the hands, elbows, or feet but may also occur in soft tissues of the trunk or legs. Calcinosis lesions may ulcerate and exude chalky white material. These nodules may be evident on plain radiography.

Rare mimickers of rheumatoid nodules include epithelioid sarcoma, infectious granuloma, necrobiosis lipoidica diabeticorum, and tumoral calcinosis [79]. In patients in whom the diagnosis is uncertain, referral to a medical dermatologist for further evaluation may be warranted.

Lung nodule(s) – The most important diagnosis to exclude in a patient with RA and a pulmonary nodule is non-small cell lung cancer at a potentially curable stage. Features on chest CT that suggest malignancy rather than rheumatoid nodules include solitary nodules, spiculated borders, central location, and presence of air bronchograms in the region [77]. On positron emission tomography (PET) imaging, malignant nodules present with substantially higher fluorodeoxyglucose (FDG) avidity than rheumatoid nodules, and malignant nodules are associated with FDG-avid draining lymph nodes whereas rheumatoid nodules are not [77].

Accelerated pulmonary nodulosis that follows methotrexate, anti-tumor necrosis factor (TNF) therapy, and leflunomide treatment can mimic infection or malignancy [65-68].

Additional investigations are usually required to establish the diagnosis in patients in whom radiographic stability of a solitary lesion cannot be demonstrated conclusively by review of prior chest radiographs or if prior studies are unavailable; the evaluation may include continued observation with serial imaging studies, biopsy of the lesion, or surgical excision. The approach to a patient with RA and an asymptomatic pulmonary nodule is similar to that for others with solitary nodules and is described in detail separately, as are the causes of multiple pulmonary nodules and their evaluation. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

MANAGEMENT

General approach — Treatment decisions depend upon several factors, including:

The potential role of methotrexate as a cause of accelerated nodulosis

The presence or absence of symptoms, including pain, nerve compression, infection, mechanical dysfunction, or other complications

Response to initial therapeutic interventions

Methotrexate-induced accelerated nodulosis — For patients with symptomatic accelerated nodulosis associated with methotrexate treatment, and for whom there are reasonable alternative treatments, we suggest the discontinuation of methotrexate and a change to an alternative synthetic or biologic disease-modifying antirheumatic drug (DMARD). The decision whether to switch therapies in patients whose articular disease activity is well controlled and whose nodulosis is only a cosmetic concern is based upon patient preferences regarding the relative risks and benefits of switching to one of the available alternative DMARD therapies, route and frequency of administration, and cost concerns. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Nodules commonly require 6 months (range, 1 to 13 months) to regress after discontinuation of methotrexate [62]. In a review of several case series and multiple case reports, approximately 70 percent of cases of accelerated nodulosis resolved with stopping the methotrexate [61]. Nodules that are symptomatic or impinging upon local structures and causing dysfunction should be approached and treated as described for typical rheumatoid nodules. (See 'Initial therapy' below.)

Regression of nodules has also been noted in case series and reports of patients who received various other nonbiologic DMARDs or colchicine [61]. Subsequent case reports suggested that rituximab may be effective treatment for some cases of severe subcutaneous nodulosis [80], and rituximab, tocilizumab, and baricitinib could cause regression of pulmonary rheumatoid nodules [81-84]. The author prefers to switch to interleukin (IL) 6 receptor antagonists or rituximab in cases of persistent nodules with moderate or high disease activity.

Subcutaneous nodules without accelerated nodulosis

Initial therapy — For patients with symptomatic subcutaneous nodules, including those that are painful, interfere with function, or cause nerve entrapment, we suggest local injection of the nodule with a mix of glucocorticoids and a local anesthetic as the initial treatment. Asymptomatic nodules require no specific treatment. A long-acting glucocorticoid (eg, 0.1 to 0.3 mL of methylprednisolone or triamcinolone hexacetonide 40 mg/mL) and local anesthetic (eg, 1 percent lidocaine) in a 1:1 mixture by volume are typically used for injection. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

Local injection is contraindicated for nodules that are ulcerated or exhibit signs of localized infection or cellulitis. Caution should be exercised prior to injecting a nodule in patients with a history of severe skin or soft tissue infections or septic arthritis or for nodules overlying prosthetic joints.

Local glucocorticoid injection of rheumatoid nodules is often effective in decreasing their size. This was illustrated in a study of 24 nodules in 11 patients with rheumatoid arthritis (RA). Patients were randomly assigned for each injection to receive either methylprednisolone or placebo, and assessment was blinded [85]. A >50 percent loss in nodule volume occurred in a greater proportion of those who received glucocorticoid injections (9 of 12 versus 1 of 12). Similar benefits were subsequently reported in a randomized trial involving 20 patients with symptomatic nodules (one nodule each), which employed triamcinolone hexacetonide and lidocaine for injection, compared with lidocaine alone [86]. The only adverse effect in either trial was pain at the injection site. Nodules typically regress in size over one to three weeks.

Resistant to initial therapy or nodules causing serious complications — Nodules that are causing serious complications and in symptomatic patients who have not responded after four to six weeks to local injection should generally be surgically excised. Indications for early surgical treatment of rheumatoid nodules, rather than trying a local injection, include skin erosion and infection, severe pain or neurologic dysfunction arising from pressure on a peripheral nerve, and marked limitation of motion because of the location of the lesion [76]. Recurrence of nodules at the same site is frequently seen.

Visceral nodules — Surgical resection of pulmonary nodules is sometimes indicated for diagnostic purposes and is also sometimes performed because of related complications from the nodule(s). Surgical or intravascular approaches to cardiac nodules should be undertaken only when there is firm evidence that the nodules are contributing to abnormal cardiac function, rhythm disturbances, or embolic events.

PROGNOSIS — Patients with rheumatoid nodules may have a worse prognosis of their rheumatoid arthritis (RA) articular and extraarticular manifestations than patients without nodules, given the association with more severe and seropositive disease and other extraarticular complications (see 'Epidemiology' above). However, RA nodules may not have independent predictive value for radiographic progression at five years following diagnosis after accounting for anti-citrullinated peptide antibodies (ACPA) and radiographic damage at diagnosis [8].

Symptoms and complications associated with subcutaneous nodules can usually be addressed effectively by appropriate treatment interventions, although recurrence is common despite surgical excision (see 'Management' above). Among 11 patients, surgical excision of rheumatoid nodules was successful in 100 percent, and significant improvements in pain, stiffness, and physical function, along with high patient satisfaction, were reported [87]. Rarely, visceral nodules, particularly those in the lung and heart, and even less often in the central nervous system, may directly cause significant morbidity.

SUMMARY AND RECOMMENDATIONS

Epidemiology – Rheumatoid nodules are a common extraarticular manifestation of rheumatoid arthritis (RA). Historically, subcutaneous nodules have occurred at some time in 30 to 40 percent of patients, but limited evidence suggests that the incidence is declining over the past two decades. Patients with rheumatoid nodules tend to have a greater incidence of severe disease phenotypes, including propensity for joint destruction, development of other extraarticular manifestations, and increased cardiovascular, pulmonary, and all-cause mortality. (See 'Epidemiology' above.)

Pathology – Wherever rheumatoid nodules are found, they have a similar histologic appearance. Characteristic features include a central area of necrosis surrounded by concentric layers of palisading macrophages and lymphocytes. As is the case for the synovitis of RA, the pathogenesis is uncertain but involves multiple components of innate and adaptive immunity. (See 'Pathology and pathogenesis' above.)

Diagnosis – The diagnosis of subcutaneous lesions can be made from their proximity to pressure points, generally intact overlying skin, and firm to hard nature on palpation, often with fixation to the underlying periosteum. Although the histopathologic features are nearly pathognomonic, biopsy is rarely necessary for diagnosis of rheumatoid nodules located in or beneath the skin. (See 'Diagnosis' above.)

Pulmonary nodules – In patients found to have an asymptomatic single lung nodule, we perform a thorough evaluation to exclude a potentially resectable lung cancer. An approach to diagnosis in this setting is discussed in more detail elsewhere. (See "Diagnostic evaluation of the incidental pulmonary nodule" and 'Pulmonary nodules' above.)

The presence of multiple pulmonary nodules requires thorough evaluation to exclude treatable infectious and potentially curable neoplastic diseases. The differential diagnosis and evaluation of such patients is presented separately. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

Cardiac nodules – Rheumatoid nodules in the myocardium can cause heart block; lesions located on or near the heart valves may cause regurgitation or embolic events. (See 'Cardiac nodules' above.)

Management – For symptomatic nodules, we suggest local injection of glucocorticoids and a local anesthetic as the initial treatment (Grade 2B). For an asymptomatic subcutaneous nodule, therapy targeted to treating the nodule is not necessary. (See 'General approach' above and 'Subcutaneous nodules without accelerated nodulosis' above.)

A complication of methotrexate therapy in some patients with RA is the increased formation of rheumatoid nodules. In patients for whom there are reasonable alternative treatments, we suggest discontinuation of methotrexate and a change to an alternative targeted synthetic or biologic disease-modifying antirheumatic drug (DMARD) (Grade 2C). Patients whose articular disease activity is well controlled and whose nodulosis is only a cosmetic concern may choose to continue methotrexate therapy. (See 'Methotrexate-induced accelerated nodulosis' above.)

For patients with symptomatic subcutaneous nodules that have resulted in complications (eg, skin ulceration, nerve compression) and that either are not appropriate for glucocorticoid injection or have not responded to local injection, surgical excision may be necessary. (See 'Resistant to initial therapy or nodules causing serious complications' above.)

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