Rheumatoid Nodules: Symptoms, Causes and Treatment

Rheumatoid nodules are a classic yet enigmatic feature of rheumatoid arthritis (RA), most commonly appearing in those with more severe or long-standing disease. While they are often harmless, their presence can signal a distinct disease phenotype and may complicate management decisions. Understanding their symptoms, underlying causes, and modern treatment strategies is vital for patients and clinicians alike. In this article, we provide a comprehensive overview of rheumatoid nodules, synthesizing recent research and clinical insights.

Symptoms of Rheumatoid Nodules

Rheumatoid nodules can be alarming to discover, yet their symptoms and clinical course are quite distinctive. Most patients notice them as firm lumps under the skin, but their presentation can vary depending on their location and underlying disease activity. Recognizing these symptoms not only helps with diagnosis but can also guide further management.

Location	Appearance	Sensation	Source(s)
Subcutaneous	Firm, non-tender	Usually painless	1 4
Pulmonary	Cavitating nodules	Cough, chest pain (sometimes)	3 5
Scleral	Nodules on eye	May cause vision issues	6
Multiple Sites	Recurrent, multiple	Variable	4 7

Table 1: Key Symptoms

Typical Presentation

Rheumatoid nodules are most frequently found as firm, round lumps beneath the skin, often over pressure points such as the elbows, forearms, or fingers. These subcutaneous nodules are usually painless and non-tender, which can make them easy to overlook unless they become large, infected, or interfere with movement 1 4.

Subcutaneous Nodules

• Location: Most commonly on extensor surfaces—elbows, forearms, fingers, and sometimes the Achilles tendon.
• Texture: Firm, rubbery, or hard; not usually attached to underlying bone.
• Mobility: Usually movable under the skin.
• Sensation: Typically painless, though discomfort can occur if the nodule presses on nerves or becomes inflamed 1 4.

Pulmonary Nodules

While less common, rheumatoid nodules can develop in the lungs. These can show up as cavitating nodules seen on imaging or can rarely cause symptoms like cough, chest pain, or shortness of breath. Sometimes, they can be mistaken for infections or malignancies, making diagnosis more difficult 3 5.

Ocular and Other Manifestations

Nodules can also appear in unusual locations such as the sclera of the eye (scleromalacia perforans), leading to vision changes or discomfort. These are rare but important to recognize, as they may indicate more aggressive disease 6.

Disease Course and Complications

Rheumatoid nodules can vary in size and number over time. They may remain stable, enlarge, regress spontaneously, or recur after treatment. Occasionally, they can ulcerate, become infected, or cause mechanical problems depending on their location 4 7. Multiple or recurrent nodules are more common in patients with active, seropositive RA 3 4.

Causes of Rheumatoid Nodules

Understanding why rheumatoid nodules form is a complex puzzle, involving immune system dysregulation, environmental exposures, and genetic predisposition. While not all patients with RA develop nodules, certain risk factors and pathogenetic mechanisms have been identified.

Risk Factor	Mechanism/Contribution	Notable Findings	Source(s)
Seropositivity	High RF/ACPA titers	Higher risk of nodules	3 4
Smoking	Increases risk	Associated with nodular RA	3 5
Cadmium exposure	Pulmonary nodule trigger	Distinct nodular phenotype	3
Immune response	Granuloma formation	IL-23/IL-17 axis involved	4 7

Table 2: Core Causes and Risk Factors

Autoimmunity and Seropositivity

A strong link exists between the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) and the development of rheumatoid nodules. Individuals with high RF and ACPA titers are more likely to form nodules, suggesting that nodular RA may be a distinct, seropositive subtype of the disease 3 4.

Environmental Factors: Smoking and Cadmium

Smoking is a well-established risk factor for both RA and the development of nodules. Research suggests that cigarette smoke (and its cadmium content) may trigger formation of pulmonary nodules, which in turn can promote the generation of autoantibodies and subsequent subcutaneous nodule formation 3.

Key points:

• Smokers with RA are twice as likely to develop nodules compared to non-smokers.
• Cadmium inhalation (from cigarettes or environmental exposure) is linked to pulmonary granuloma (nodule) formation, potentially preceding joint disease 3.

Immunopathology and Granuloma Formation

On a microscopic level, rheumatoid nodules are composed of a core of fibrinoid necrosis surrounded by palisading macrophages and fibroblasts—a type of granuloma. Their formation involves:

• Activation of the immune system, especially the IL-23/IL-17 axis.
• Chronic inflammation leading to cell death, granuloma formation, and deposition of immune complexes 1 4 7.
• Some studies hypothesize that vascular inflammation (vasculitis) may play a role, but evidence is inconsistent 2 7.

Medications and Other Triggers

Certain medications, such as methotrexate, have been implicated in the development or worsening of nodules in some patients, although the reasons are not fully understood 5 7. The pathogenesis likely involves complex interactions between immune mechanisms and medication effects.

Histopathological Progression

Rheumatoid nodules evolve through several histological stages:

• Acute inflammation
• Granulomatous inflammation with minimal necrosis
• Necrobiotic granulomas with central necrosis and palisading cells
• Advanced "ghost" lesions with cystic or calcified areas 4

Treatment of Rheumatoid Nodules

Managing rheumatoid nodules requires a tailored approach, as these lesions can be persistent, recurrent, and sometimes resistant to standard therapies. Treatment decisions are based on nodule size, location, symptoms, and underlying RA activity.

Approach	Application	Effectiveness/Notes	Source(s)
Corticosteroids	Systemic/topical/injection	May shrink nodules, but variable response	5 6 7
Disease-modifying antirheumatic drugs (DMARDs)	Methotrexate, etc.	Control underlying RA, but some may worsen nodules	5 6
Surgery	Excision	For problematic nodules	4
Experimental	Targeted immunotherapy, siRNA	Promising but investigational	7

Table 3: Overview of Treatment Strategies

Medical Management

Corticosteroids

• Systemic corticosteroids (e.g., prednisone) or local corticosteroid injections may reduce nodule size, particularly for inflamed or symptomatic nodules 5 6.
• Topical corticosteroids are sometimes used for superficial lesions.
• Responses are variable, and nodules can recur after cessation of therapy 6.

DMARDs

• Methotrexate is commonly used to control RA but can paradoxically be associated with the development or worsening of nodules in some patients 5.
• Other DMARDs and biologics may be considered based on the individual’s disease course and medication history.

Surgical and Procedural Options

• Surgical excision is considered for nodules that are painful, infected, ulcerated, or causing functional impairment. However, recurrence is common, and surgery is generally reserved for problematic cases 4.
• Aspiration or drainage may be performed if a nodule becomes infected or forms an abscess.

Emerging and Experimental Therapies

Novel approaches are under investigation:

• Targeted immunotherapy using small interfering RNA (siRNA) directed at the IL-23/IL-17 axis, delivered via advanced microneedle patches, shows promise in reducing nodule size and number in experimental settings 7.
• Combination strategies—such as corticosteroids plus gene silencing—may offer future options for stubborn or recurrent nodules 7.

Monitoring and Supportive Care

• Regular monitoring is essential, especially for nodules in critical locations (e.g., lungs, eyes).
• Histopathological evaluation is crucial for atypical nodules to exclude infection, malignancy, or other causes 4 5.
• Patient education and shared decision-making are key, balancing nodule management with overall RA control.

Conclusion

Rheumatoid nodules are a complex extra-articular manifestation of RA, reflecting the interplay of immune, environmental, and genetic factors. While often painless, they can signal a more severe disease subtype and occasionally lead to complications. Diagnosis and management require a nuanced approach, tailored to the individual’s symptoms, risk factors, and overall disease activity.

Key Takeaways:

• Rheumatoid nodules are most commonly firm, painless lumps under the skin but can also occur in the lungs, eyes, and other tissues 1 3 4.
• High seropositivity (RF, ACPA), smoking, and cadmium exposure are major risk factors; nodular RA may be a distinct subtype 3 4.
• The pathogenesis involves immune-mediated granuloma formation, with the IL-23/IL-17 axis playing a central role 4 7.
• Treatment options include corticosteroids, DMARDs, surgical removal, and emerging targeted therapies; responses vary and recurrence is common 5 6 7.
• Accurate diagnosis and tailored management are essential for optimal outcomes, especially in atypical or problematic cases 4 5.

By recognizing the unique features and challenges of rheumatoid nodules, clinicians and patients can work together to manage this intriguing manifestation of rheumatoid arthritis more effectively.