Rheumatoid Nodules

6/3/2014 Rheumatoid nodules
http://www.uptodate.com/contents/rheumatoid-nodules?topicKey=RHEUM%2F7523&elapsedTimeMs=2&source=search_result&searchTerm=nodulo+reumatoid 1/9
Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Authors
Peter H Schur, MD
Carl Turesson, MD, PhD
Section Editor
RN Maini, BA, MB BChir, FRCP,
FMedSci, FRS
Deputy Editor
Paul L Romain, MD
Rheumatoid nodules
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2014. | This topic last updated: jul 24, 2012.
INTRODUCTION The rheumatoid nodule is the most common cutaneous manifestation of rheumatoid arthritis
(RA) [1,2]. Although nodules commonly are found on pressure points (such as the olecranon process), they may
occur at other sites, including ones within internal organs of the body. Thus, bedridden patients can develop
nodules on the occiput and ischial areas, and nodules occasionally form on the Achilles tendon and vocal cords [3].
Rheumatoid "nodulosis" is characterized by multiple nodules on the hands and multiple subchondral bone cysts
known as "geodes" [4]. These nodules tend to occur on extensor surfaces adjacent to joints, elbows, and fingers,
as well as the forearm, metacarpophalangeal and proximal interphalangeal joints, occiput, back, heel, and other
areas [5].
The clinical and histopathologic features, diagnosis, and treatment 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 features of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of
rheumatoid arthritis".)
PREVALENCE AND CLINICAL SIGNIFICANCE
Subcutaneous nodules Palpable nodules in the subcutaneous tissues have been reported at initial
presentation in 7 percent of patients with RA [6] and are found at some time during the disease course in 30 to 40
percent of patients [7]. The vast majority of nodule formers have positive tests for rheumatoid factor [1]. Nodules are
found in 75 percent of patients with RA-associated Feltys syndrome [5]. RA patients with nodules are also more
likely to develop vasculitis [8]. Limited data suggest that many patients with rheumatoid nodules have a positive
test for antibodies to citrulline containing peptides (eg, anti-CCP) [9]. 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
[10]. Rheumatoid nodules have also been noted in occasional patients with systemic lupus erythematosus,
ankylosing spondylitis, granuloma annulare, and chronic active hepatitis, and they have been associated with
antiphospholipid antibodies in patients with RA, as well as in healthy children and adults [5].
The size of the nodules varies from 2 mm to 5 cm; they are firm, nontender, and moveable in subcutaneous tissue
(picture 1) [5].
In many cases, the nodules are neither symptomatic nor a cosmetic concern. However, rheumatoid nodules can be
painful and/or disfiguring, can interfere with function, and can 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.
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 and is
discussed in more detail elsewhere. (See "Major side effects of low-dose methotrexate", section on 'Nodulosis'.)

Nodulosis has also occasionally been associated in RA patients with treatment with azathioprine, etanercept, and
RA leflunomide [5].
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 film radiographs of the chest revealed rheumatoid nodules in
only 2 of 516 patients with RA in one clinical series [11]. 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 [12]. Accelerated pulmonary nodulosis has been reported to follow anti-tumor necrosis factor (anti-
TNF) therapy and leflunomide treatment [13-15]. These can mimic infection or malignancy.
Nodules are generally located in subpleural areas or in association with interlobular septa [16]. Pulmonary
rheumatoid nodules are generally asymptomatic but can lead to complications including pleural effusion,
pneumothorax, pyopneumothorax, bronchopleural fistula, and hemoptysis. These and other aspects of rheumatoid
nodules in the lungs are discussed in more detail elsewhere. (See "Overview of lung disease associated with
rheumatoid arthritis", section on 'Rheumatoid lung nodules'.)
Lymphoid aggregates containing B lymphocytes and features characteristic of lymphoid follicles have been reported
in pulmonary nodules [17]. 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 RA-associated
interstitial lung disease, such as nonspecific interstitial pneumonitis or usual interstitial pneumonitis [18].
Consistent with these histopathologic features, 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 [19].
Cardiac nodules Rheumatoid nodules may develop in the pericardium, myocardium, and valvular structures
[20]. They may be noted on echocardiograms [21]. 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 [22]. Stroke or
other manifestations of arterial embolization may result from nodules on a heart valve [23-25].
Central nervous system nodules Rheumatoid nodules rarely may affect the central nervous system. This is
discussed in detail elsewhere. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Rheumatoid
nodules'.)
PATHOLOGY AND PATHOGENESIS The histologic appearance of a typical rheumatoid nodule includes a
central area of necrosis surrounded in turn by palisading macrophages and then lymphocytes (picture 2) [26-29].
The fibroblasts produce large quantities of metalloproteases [30]. The lymphocytes can generate IgG and IgM
rheumatoid factor. Histologic features of focal vasculitis with associated immunoglobulin, fibrin deposition, and
complement activation can be found in one-third of all rheumatoid nodules [5].
Examination for mRNA transcripts for cytokines revealed evidence for tumor necrosis factor alpha, interferon
gamma, interleukin-1 beta (IL-1beta), interleukin-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-1 (ICAM-1), PECAM, and VCAM.
IL-17A is not found in rheumatoid nodules, in contrast to its presence in the rheumatoid synovial membrane [31],
but most of the cytokine profile, together with the ability of the tissue to produce metalloproteinases, establishes
the rheumatoid nodule as a Th1 granuloma [32-34]. (See "Role of cytokines in rheumatic diseases".)
Deposits of rheumatoid factor and the terminal components of complement are also found on the endothelium of
small vessels within nodules [35]. 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. There was a very weak association with only the
HLADR1*0401 shared epitope allele but not with other genotypes [36]. 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 [37], suggesting that genetic factors may be less important for development of nodules than for
other extra-articular disease features. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
As noted above, a complication of methotrexate therapy in some patients with RA is the increased formation of
rheumatoid nodules, a pro-inflammatory effect that occurs even when synovial inflammation is suppressed [38].
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 [39]. (See
"Major side effects of low-dose methotrexate", section on 'Nodulosis'.)
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 [6].
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 [40,41] and other severe extra-articular manifestations of RA [42,43].
DIAGNOSIS In a patient with 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. In the absence of symptoms related to the presence of the nodule, no additional diagnostic testing
is necessary.
Rheumatoid nodules in viscera may be more difficult to diagnose with confidence. As an example, a rheumatoid
nodule in the lung may not be definitively diagnosed until lung cancer has been excluded by biopsy or excision.
(See "Overview of lung disease associated with rheumatoid arthritis", section on 'Rheumatoid lung nodules'.)
The finding of a nodule with the histologic characteristics described above for rheumatoid nodules (see 'Pathology
and pathogenesis' above) is nearly pathognomonic of RA. However, nodules with a similar histologic appearance
rarely occur in some patients with systemic lupus erythematosus and in otherwise healthy children [44-48].
Differential diagnosis
Subcutaneous nodules The differential diagnosis of subcutaneous rheumatoid nodules should include
fibromas caused by chronic trauma from shoes or repetitive use of hand tools, subcutaneous granuloma annulare
(pseudo rheumatoid nodules), xanthomatosis, sarcoidosis, gouty tophi, pseudogout tophi [49], cutaneous
extravascular necrotizing granulomas (Churg-Strauss granulomas), tumoral calcinosis, fibromas unrelated to
chronic trauma, xanthomas, subcutaneous sarcoidosis, lupus panniculitis, nodular (keloidal) scleroderma,
metastatic tumors, histoplasmosis, amyloidosis, ganglion cysts, foreign body granulomas, basal cell skin cancer,
epidermoid cysts, synovial cysts, necrobiotic granulomas, and necrobiosis lipoidica [1,5]. However, the concurrent
presence of active RA with high rheumatoid factor titers points strongly toward rheumatoid nodules.
Lung nodule or nodules As noted above, 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. The approach to a patient with RA
and an asymptomatic pulmonary nodule is similar to that for others with solitary nodules. If radiographic stability of
the lesion cannot be demonstrated conclusively by review of prior chest radiographs, or if prior studies are
unavailable, then consideration can be given to additional investigations; these include continued observation with
serial imaging studies, biopsy of the lesion, and surgical excision. An approach to diagnosis of a solitary pulmonary
nodule is presented separately. (See "Diagnostic evaluation and management of the solitary pulmonary nodule".)
Rheumatoid nodulosis is one of several benign and malignant diseases that are associated with the presence of
multiple pulmonary nodules. A discussion of the causes of multiple pulmonary nodules and an approach to
diagnosis are presented separately. (See "Differential diagnosis and evaluation of multiple pulmonary nodules".)
TREATMENT
Accelerated nodulosis If the formation of rheumatoid nodules is suspected to be due to use of methotrexate,
discontinuing treatment with this agent can be considered. A decision to stop or continue methotrexate therapy
depends on several factors, including the success with which RA disease activity other than nodulosis has been
controlled by methotrexate, the availability of other disease modifying antirheumatic drugs (DMARDs) and biologic
response modifying agents (eg, anti-tumor necrosis factor alpha agents, anakinra), safety of alternative drugs, and
cost concerns. Discontinuation of methotrexate and a change to an alternative DMARD or biologic response
modifier may be appropriate, while some patients and their clinicians may decide to continue methotrexate.
Regression of nodules has been noted in patients who received various DMARDs or colchicine; however, a review in
2002 found insufficient evidence to conclude that any specific treatment was beneficial for methotrexate associated
nodulosis [50].
For patients with symptomatic accelerated nodulosis in the setting of methotrexate treatment, for whom there are
viable alternative treatments, we suggest the discontinuation of methotrexate and a change to an alternative
DMARD or biologic response modifier. Patients whose articular disease activity is well-controlled and whose
nodulosis is only a cosmetic concern may choose to continue methotrexate therapy.
Subcutaneous nodules Asymptomatic nodules require no specific treatment. However, those that are painful,
that interfere with function, or that cause nerve entrapment may require an intervention. Direct injection of the nodule
with a mixture of glucocorticoids and local anesthetic may be beneficial and is recommended. Surgical excision
may be necessary for nodules that are causing serious complications. One patient without RA, but with nodules
consistent with rheumatoid nodulosis on biopsy, has been reported to respond to topical tacrolimus after failing to
respond to topical corticosteroids [51].
Glucocorticoid injection 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 RA. Patients were randomly
assigned for each injection to receive either methylprednisolone or placebo, and assessment was blinded [52]. A
>50 percent loss in nodule volume occurred in a significantly greater proportion of those who received glucocorticoid
injections when compared with placebo injections (9 of 12 versus 1 of 12, respectively). Similar findings were later
reported in a study of 20 patients (one nodule each) of comparable design, but, instead of methylprednisolone,
triamcinolone hexacetonide was injected and was found to be superior to placebo [53].
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?".)
Surgical excision Indications for surgical treatment of rheumatoid nodules include skin erosion and
infection, pain or neurologic dysfunction arising from pressure on a peripheral nerve, and limitation of motion
because of the location of the lesion [48]. Recurrence of nodules at the same site is frequently seen.
As noted (see 'Lung nodule or nodules' above), surgical resection of pulmonary nodules is sometimes indicated.
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, to rhythm disturbances, or to embolic events.
SUMMARY AND RECOMMENDATIONS
Rheumatoid nodules are a common extra-articular manifestation of RA, with subcutaneous nodules
occurring at some time in 30 to 40 percent of patients. (See 'Subcutaneous nodules' above.)
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
cytokines. (See 'Pathology and pathogenesis' above.)
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.)
Rheumatoid pulmonary nodules present a more difficult diagnostic challenge. When an asymptomatic single
lung nodule is discovered, we recommend 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 and management of the solitary pulmonary nodule".)
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.)
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 "Differential diagnosis and evaluation of multiple pulmonary nodules".)
For an asymptomatic subcutaneous nodule, targeted therapy is not necessary. For symptomatic nodules,
we recommend local injection of glucocorticoids and a local anesthetic as the initial treatment (Grade 1B).
(See 'Glucocorticoid injection' above.)
A complication of methotrexate therapy in some patients with RA is the increased formation of rheumatoid
nodules. In patients for whom there are viable alternative treatments, we suggest discontinuation of
methotrexate and a change to an alternative DMARD or biologic response modifier (Grade 2C). Patients
whose articular disease activity is well-controlled and whose nodulosis is only a cosmetic concern may
choose to continue methotrexate therapy.
For patients with symptomatic subcutaneous nodules that have resulted in complications (eg, skin
ulceration, nerve compression) and that either are not appropriate for steroid injection or have not responded
to local injection, surgical excision may be necessary. (See 'Surgical excision' above.)
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Topic 7523 Version 6.0
GRAPHICS
Rheumatoid nodules
Rheumatoid nodules are firm, nontender lesions that typically occur in
areas of trauma in individuals with rheumatoid arthritis. Nodules are
present near the elbows in this patient.
Reproduced with permission from: www.visualdx.com. Copyright Logical
Images, Inc.
Graphic 74194 Version 3.0
Rheumatoid nodule
Biopsy of a nodule from a patient with rheumatoid arthritis showing an
area of geographic stellate necrobiosis with extensive fibrin deposition
surrounded by a palisading histiocytic rim.
Courtesy of Cynthia Magro, MD.
Graphic 69272 Version 1.0

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