Caplan Syndrome

Etiology

Previously, Caplan syndrome was primarily associated with occupational exposure to coal dust. However, experts now acknowledge that exposure to any respirable source of silica and asbestos can lead to this condition. Occupations at risk include coal miners, asbestos workers, gold miners, sandblasters, quarrymen, and carbon electrode manufacturing workers. In addition, workers in industries involving rubber dust, aluminum production, and silica-based scouring powder packing are at increased risk. Current industries such as jewelry polishing, denim jean production, fabrication of artificial stone benchtops, glass manufacturing, and glassware have created a resurgence of silicosis worldwide. There may also be a genetic component, although it remains undefined. Although experts believe smoking exacerbates lung findings, they have not established a direct causal relationship.

Epidemiology

Scant epidemiological data exist comparing subjects with and without pulmonary nodules and dust exposure. This lack of data and the rarity of the disease make it challenging to establish the true incidence of Caplan syndrome. The original studies by Caplan reveal that the prevalence of rheumatoid pneumoconiosis among coal workers is 0.4%.[2] More recent data report a prevalence of 0.89% among coal workers with pneumoconiosis in the United States and 0.74% in Japan.[2][3]

In patients with progressive massive fibrosis, the association between rheumatoid arthritis and silica exposure is more pronounced compared to those with simple pneumoconiosis.[2] Many epidemiological studies support the association between occupational exposure to respirable crystalline silica dust and the development of systemic autoimmune diseases, including rheumatoid arthritis.[2][4] A recent study from China reveals a prevalence of pneumoconiosis with connective tissue diseases at 13.8%, with a prevalence of pneumoconiosis with asbestosis and silicosis of 18.3% and 11.4%, respectively.[5] According to another study, the prevalence of antinuclear antibody seropositivity in patients with silica-associated pneumoconiosis is approximately 31.9%.[5]

Pathophysiology

The pathogenesis of rheumatoid pneumoconiosis remains unclear. However, researchers believe that exposure to inorganic dust triggers the immunological phenomena that favor the formation of pulmonary nodules that are histologically similar to the nodules associated with rheumatoid arthritis.[6] A clear link exists between occupational silica inhalation and autoimmune diseases. The proposed theory suggests that silica particles are engulfed by alveolar macrophages, triggering inflammation and activating fibroblasts. The macrophages degrade the silica, which new macrophages subsequently process. Through the pathogen-associated molecular pattern, silica-activated macrophages stimulate the production of various cytokines such as interleukin-1 and tumor necrosis factor-α. This innate immune system activation prompts dendritic cells to present antigens to CD4 T lymphocytes. This cycle of events perpetuates chronic immune activity and fibrosis, leading to the generation of autoantigens. Pneumoconiosis exacerbates the production of autoantibodies, immune complexes, and excessive immunoglobulins, including rheumatoid factor. In addition, anti-cyclic citrullinated peptide antibodies (ACPAs) are frequently observed in Caplan's syndrome, establishing a connection between silica exposure and ACPA-positive rheumatoid arthritis.[7] The range of frequencies observed after silica exposure implies substantial genetic participation and interaction with environmental factors in silica-induced autoimmunity.

Pulmonary nodules develop due to the stimulation of the bronchus-associated lymphoid tissue in the lungs. Silica, smoking, and autoimmune diseases such as rheumatoid arthritis all stimulate bronchus-associated lymphoid tissue. With chronic stimulation, bronchus-associated lymphoid tissues in the lungs mature with the formation of germinal centers. Although malignant transformation is possible, there is no evidence of silica-associated malignant lymphoma in the clinical literature.[7]

Histopathology

The histological characteristics allow clinicians to differentiate between rheumatoid arthritis nodules, Caplan nodules, and silicosis. Pulmonary nodules in patients with rheumatoid arthritis are round, well-defined opacities of variable size predominantly located in the upper lobes in a subpleural position. Histologically, a central area of brightly eosinophilic necrosis is surrounded by a zone of dark basophilic necrosis, followed by a layer of histiocytes in a palisade arrangement. The outermost layer contains granulation tissue and chronic inflammation.[6] 

A necrobiotic rheumatoid nodule that contains dust is a characteristic description of a Caplan nodule. The central necrotic area of Caplan nodules is surrounded by alternating layers of black coal dust and necrotic tissue. A zone of inflammatory cells containing polymorphonuclear granulocytes, macrophages, and giant cells surrounds the dust rings. In some cases, dust may be noted within the macrophages as well. This active zone of inflammation differentiates active Caplan nodules from silicotic nodules. The inflammatory zone is characterized by palisading cells, typically in lesser numbers compared to the typical nodules associated with rheumatoid arthritis.[2] In the absence of an active inflammatory zone, concentric rings of coal dust can help identify Caplan nodules from silicotic nodules.

Two different histopathological presentations characterize Caplan syndrome. The classic form consists of large nodules that show uniform necrosis with a background of mild pneumoconiosis. The silicotic type consists of smaller nodules with necrotic areas that retain some characteristics of a silicotic nodule. Patients with this form of Caplan syndrome present with frank silicosis with or without massive fibrosis.[2]

History and Physical

Patient History

Rheumatoid nodules and Caplan nodules are asymptomatic in most cases.[2] Clinicians identify many individuals after identifying an incidental lung nodule on radiographic imaging for other reasons.[8] Rheumatoid and Caplan nodules can undergo cavitation and rupture, leading to complications such as pleural effusion, pneumothorax, pyopneumothorax, bronchopleural fistula, hemoptysis, and infection.[2]

Caplan syndrome is characterized by the rapid development of multiple peripheral basilar nodules associated with mild airflow obstruction. Despite the presence of multiple pulmonary nodules, most patients with the classic form do not report symptoms. According to a case report, pulmonary function testing at diagnosis reveals a mild obstructive pattern with decreased forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio without recognizable pulmonary symptoms.[7]

Patients with the silicotic form are typically symptomatic. Affected patients may report pleuritic chest pain, a dry cough, shortness of breath, and fatigue. The symptoms are likely related to accelerated silicosis. Symptoms of rheumatoid arthritis are pain, morning stiffness, and swelling in numerous joints. The metacarpophalangeal and proximal interphalangeal joints of the fingers, interphalangeal joints of the thumbs, wrists, and metatarsophalangeal joints of the toes are commonly affected. Other synovial joints in the upper and lower extremities, including the elbows, shoulders, ankles, and knees, are commonly involved.

Physical Examination

Respiratory findings may be normal or include wheezing and crackles on lung examination. Typically, joint findings are symmetric, and clinicians observe swelling and pain upon palpation or during active and passive movement of the affected joint. Peripheral joints are affected in nearly every patient with rheumatoid arthritis. The hands are frequently the first area to be affected, and a reduced grip strength is often an early marker of disease. Some patients present with carpal tunnel. Joint deformities such as metacarpophalangeal subluxation, ulnar deviation or ulnar drift, swan neck, and boutonniere deformities of the fingers typically develop later in the disease process. Cervical spine involvement marked by pain and stiffness in the neck is also common.

Evaluation

Patients with pulmonary nodules should undergo a comprehensive assessment, including a detailed history and a thorough physical examination. Clinicians should pay particular attention to obtaining details about their occupational history, smoking habits, and family history.[7] In addition, inquiring about systemic symptoms such as fever, weight loss, joint pain and stiffness, dyspnea, and cough is crucial to the evaluation.

Clinicians must differentiate Caplan and rheumatoid nodules from malignant nodules. Advanced patient age and underlying risk factors help predict the malignant potential of a pulmonary nodule. Clinicians must remember that younger age without risk factors does not exclude the diagnosis of malignancy. Experts generally assign some risk of malignancy to pulmonary nodules in patients 35 and older. The following is a risk stratification of malignancy based on age.

• 35 to 39 years: 3%
• 40 to 49 years: 15%
• 50 to 59 years: 43%
• 60 years and older: Greater than 50%

Risk factors are smoking, family history, female sex, emphysema, prior malignancy, and exposure to asbestos.

Radiographic Imaging

Clinicians should attempt to obtain all prior imaging studies for comparative analysis. Although the syndrome was initially diagnosed based on radiographic imaging, it can be challenging to differentiate Caplan from rheumatoid nodules and malignancy based on radiography alone. Computed tomography (CT) of the chest without intravenous contrast is the imaging modality of choice. Findings that suggest the presence of rheumatoid nodules over malignancy include the presence of satellite nodules, a smooth border, peripheral location, and pleural contact. Cavitation and calcification also favor rheumatoid nodules over malignancy. Nodule size is an independent predictor of malignancy. The risk of malignancy increases with size:

• Nodules less than 5 mm: Less than 1%
• Nodules 5 to 9 mm: 2% to 6% 
• Nodules 8 to 20 mm: 18%
• Nodules larger than 20 mm: More than 50%

Subsolid nodules are more likely to be malignant compared to solid nodules, and nodules that have remained stable are less likely to be malignant. In ambiguous cases, 18-fluorodeoxyglucose positron emission tomography (18-FDG PET) imaging may be performed as rheumatoid arthritis nodules are less FDG-avid compared to most malignancies. In this setting, FDG-avid lymph nodes are absent as well.[9] 18-FDG PET scanning is most helpful in distinguishing solid nodules larger than 8 mm. PET imaging is unreliable with subsolid nodules, and false positive and false negative results can occur.

Caplan nodules exhibit features similar to rheumatoid nodules on radiographic imaging. On CT, they vary in size from 0.5 to 5 cm and typically diffuse in the craniocaudal plane, with a higher prevalence in the middle to the outer one-third of the lungs in the axial plane. In most individuals, Caplan nodules evolve rapidly within a few weeks to months. They then appear to stabilize and persist without change over many years. In some cases, they heal with remnant asteroid scarring, or they may also cavitate and calcify.[2] Cavitation and calcification are quite common. Larger nodules, especially those that grow, can coalesce to form nodular consolidations of progressive massive fibrosis. With progressive massive fibrosis, scarring and architectural distortion are noted.[9]

Serum Markers

Seropositivity for antinuclear antibody, rheumatoid factor, and antineutrophil cytoplasmic antibodies is common in patients with Caplan syndrome. Seropositivity for rheumatoid factor is approximately 70%. In patients with a radiographic appearance of Caplan syndrome with no clinical evidence of rheumatoid arthritis, rheumatoid factor positivity drops to nearly 50%. Of note, approximately 25% of patients with silicosis are positive for rheumatoid factor, irrespective of rheumatoid arthritis.[2] The high antinuclear antibody titer typically reveals a homogeneous pattern in these patients.[3] ACPA may be positive in some cases.[10]

Pulmonary Function Testing

Pulmonary function tests often reveal a mild obstructive pattern in patients with Caplan syndrome.[7] However, there are documented cases of individuals exhibiting a mixed restrictive and obstructive pattern, particularly among those with progressive massive fibrosis. In patients with progressive massive fibrosis, pulmonary function testing typically reveals reduced vital capacity and significant airflow obstruction.[7] According to a study, however, adjusting for age, smoking, and mining exposure results in similar lung volumes and diffusion capacities in patients with classic Caplan syndrome and progressive massive fibrosis. The study indicates that patients with Caplan syndrome have less airflow obstruction compared to those with progressive massive fibrosis.[10]

Histology

The radiographic findings typical for this disease can be confused with rheumatoid arthritis–associated lung disease and silicosis, which are often present in conjunction with Caplan syndrome. A histological diagnosis is required in most cases to confirm Caplan syndrome.[11] Histological analysis showing centralized silica crystals within the nodule under polarized light is used to make a definitive diagnosis.[7] The peripheral location of these nodules allows CT-guided biopsies, which reveal typical rheumatoid nodule morphology consisting of central fibrinoid necrosis surrounded by a palisading mononuclear cell layer.[12] Caplan syndrome differs from rheumatoid arthritis nodules based on the presence of dust and silica crystal within the central necrotic region and in the concentric layers, which may refract light on microscopy.[13]

Treatment / Management

Therapeutic management of Caplan syndrome mainly involves supportive care. Patients should receive vaccinations against influenza and pneumococcal infections. Clinicians should administer oxygen and bronchodilators if necessary. Although most Caplan nodules remain stable without specific treatment, some may develop complications such as cavitation, superimposed infections, or bronchopleural fistulas. Although corticosteroids have been used in some cases to slow the progression of rapidly growing nodules, evidence supporting this approach is limited. Overall, therapy aims to minimize occupational exposure, promote the cessation of cigarette smoking, and adhere to evidence-based guidelines for managing rheumatoid arthritis.[10] (B3)

No currently available therapy has demonstrated efficacy in patients with severe symptomatic disease. A recent case using rituximab, methotrexate, and prednisolone to alleviate symptoms in a patient with symptomatic Caplan syndrome reveals a notable improvement in rheumatoid arthritis–associated joint pain, but pulmonary symptoms remained unaffected. Another recent case report suggests that treatment with rituximab, initiated for rheumatoid arthritis symptoms, contributed to stabilizing Caplan nodules. However, it did not appear to alter the evolution of these nodules. Further study is needed to establish a treatment consensus for Caplan syndrome.[14](B3)

Animal studies reveal that organic dust exposure in specific human leukocyte antigen (HLA) phenotypes increases proinflammatory responses, resulting in elevated cytokine and chemokine levels. This enhanced lung inflammation in HLA-DR4+ mice produces pathologic features consistent with rheumatoid arthritis–associated lung disease, including Caplan syndrome. In these animal models, researchers reported enhanced production of citrulline and malondialdehyde-acetaldehyde (MAA)–modified lung proteins, and serum and bronchus-associated lymphoid tissue anti-MAA antibodies. Further study is necessary to determine if specific cytokine-targeted therapies may benefit the pulmonary findings of Caplan syndrome in these individuals.[15]

No evidence-based guidelines exist regarding the long-term management of Caplan nodules. An individualized follow-up plan is required based on the Caplan syndrome type and the radiographic severity of these nodules. Patients with the silicotic form warrant close follow-up as they likely have significant airflow abnormalities. Patients with larger and greater numbers of nodules warrant close follow-up to monitor for complications such as hemoptysis or pneumothorax.[7](B3)

Differential Diagnosis

The differential diagnoses of Caplan syndrome include lymphoma, tuberculosis, sarcoidosis, primary or metastatic lung malignancy, rheumatoid arthritis–associated pulmonary nodules, silicosis without Caplan syndrome, and asbestosis.[7][16]

Prognosis

Based on case reports and older studies in patients with Caplan syndrome, the prognosis depends on the extent of antigen exposure, exacerbating factors such as cigarette smoking, and the severity of lung damage. Severe respiratory disability is a rare finding in patients with Caplan syndrome, but some patients can progress to develop progressive massive fibrosis. Most current literature is unable to differentiate morbidity and mortality associated with Caplan syndrome from that of concomitant cigarette smoking and underlying rheumatoid arthritis. The former is particularly difficult due to the lag time between occupational exposure to Caplan syndrome–associated antigens and an official diagnosis of Caplan syndrome.

A recent study from Korea attempts to differentiate between patients with underlying rheumatoid arthritis and those with underlying rheumatoid arthritis and prior silica exposure. The study calculates the standardized hospital admission ratio by dividing the observed hospital admissions in silica-exposed workers by the reference population. They report that the standardized hospital admission ratio was higher in the silica-exposed group. They also noted that silica-exposed workers without a diagnosis of pneumoconiosis had a higher standardized hospital admission ratio compared to the general population, suggesting that the severity of rheumatoid arthritis is increased with silica exposure.[17]

Complications

Complications associated with Caplan syndrome are exceedingly rare. Nodule cavitation with superimposed infections or bronchopleural fistula formation are the most commonly reported complications of this disease.[2] The current literature is filled with sporadic cases of other complications occurring in patients with Caplan syndrome, such as chronic non-malignant renal disease,[7] parkinsonism,[18] amyloid A amyloidosis,[19] and mitral valve disease.[20]

Many of these complications are commonly associated with rheumatoid arthritis. In addition, the lag time between exposure and diagnosis makes it particularly difficult to establish a causal link. Without robust data, researchers find assigning these complications to Caplan syndrome difficult. 

Clinical studies consistently identify an increased risk of developing lung cancer, particularly non–small cell lung cancer, with silica exposure. However, most studies have been unable to exclude other factors, such as cigarette smoking. As such, making an inference regarding the risk of lung cancer in patients with Caplan syndrome becomes challenging.[21]

Cavitation of the nodules with subsequent colonization by Aspergillus can occur.[2] There have been case reports of patients developing mild pulmonary hypertension without any worsening of Caplan nodules on CT imaging.[7]