Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints, but it also commonly causes systemic damage. The most frequent organs affected by RA are the lungs, heart, and the kidneys. Pulmonary complications are common, especially in patients who use Disease Modifying Antirheumatic Drugs (DMARDs) such as methotrexate and leflunomide. The most common extra-articular manifestation of RA are pleura effusions, pulmonary rheumatoid nodules, bronchiectasis, bronchiolitis, and the presence of infections. The pathophysiology of rheumatoid pulmonary nodules is currently not well understood, but there are several hypotheses that suggest a mixture of local injury, immune complexes, and proteolytic enzymes play a role. Computed Tomography (CT) of the chest and Positron Emission Tomography (PET) scan are the best studies to be requested for further diagnosis, mainly because they demonstrate superior specificity and sensitivity when compared to chest x-rays. The treatment of rheumatoid pulmonary nodules will depend always on the severity of the case, and will lead to a change in the medication of the RA. If necessary, patients can undergo surgical resection of the nodules.

Interstitial lung disease; Management; Nodules; Pulmonary nodules; Pulmonology; Rheumatoid arthritis; Rheumatology; Treatment

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by the destruction of articular joint structures. It is a systemic condition that also affects other organs, such as the heart, lungs, and kidneys [1]. Pulmonary complications are quite common and could include pleural effusion, rheumatoid nodules, bronchiectasis, obliterative bronchiolitis and opportunistic infections. These lung complications are the most common extra-articular manifestation of RA and could be detected in 40-70% of the cases [2]. Ellman and Ball first described lung disease in association with RA, and it is a particular clinical challenge [3]. There are often multiple pulmonary nodules and they involve both lungs, with a variation in their size, from few millimeters to 1 to 3 centimeters. Complications of these nodules involve their necrosis and rupture that subsequently results in secondary pneumothorax, bronchopleural fistula, hemorrhage, and empyema [4]. The rheumatoid nodules are usually asymptomatic, but once suspected, a more detailed examination must be done to exclude neoplasms, tuberculosis, and fungal infections [5]. Its pathophysiology is not well understood, although alveolar epithelial injury has been implicated [6]. Some risk factors for pulmonary rheumatoid nodules include history of smoking tobacco and a positive rheumatoid serology. They are most commonly located in the subpleural space, and usually asymptomatic. One of its consequences is the rupture of the nodules which could cause pleural effusion, pulmonary abscess, empyema, pneumothorax and bronchopleural fistula [7]. The diagnosis is suggested by a typical clinical vignette but cannot be confirmed without imaging tests (Chest X-Ray, CT Scan, MRI, etc.) [8]. The use of leflunomide for the treatment of RA, as well as methotrexate, have been related to the formation of pulmonary rheumatoid nodules as well. The latter is associated to methotrexate-induced accelerated nodulosis, which is characterized by the rapid onset or worsening of rheumatoid nodules. [9,10]. The treatment for pulmonary rheumatoid nodules still a challenge because surgical excision is rarely indicated. It is only used in specific situations where there is suspicion of complications. Clinical trials may be useful to collect additional data and generate clear treatment recommendations [11].

It is estimated that nearly 40% of patients with RA will develop some type of extra articular manifestation of RA, with pulmonary involvement. This is the most common complication and the second most common cause of death in this condition [12,13]. When discussing pulmonary involvement in rheumatoid arthritis, we understand the majority of lung structures are at risk of injury. Many patients with lung damage have an asymptomatic evolution. However, Chest X-Ray (CXR) and Computed Tomography (CT) show a high percentage of RA related effects in a large number of patients [14].

According to the literature, the most common CXR findings of RA patients are ground glass opacities, peribronchial opacity, and bronchiectasis. In addition, rheumatoid nodules are the only pulmonary manifestation specific to RA [14,15].

Several studies have been conducted to show the prevalence of rheumatoid nodules, but it is still inconclusive. One clinical series reported that only 2 of 516 patients presented with nodules on CXR. On the other hand, Rukenet al published a report in which 85 patients with RA underwent a CT scan. According to their results, 78.6% of subjects (66 out of 85) presented with pulmonary nodules. Results indicated that 34.5% of patients were asymptomatic and 76.6% had high rheumatoid factor titers. Furthermore, illustrated micronodules were more common among lifelong non-smoker RA patients compared to the small nodules found typically in RA patients who smoke [12].

Shunsukeet al performed a high-resolution CT on a total of 126 patients with RA (65 with early RA and 61 with longstanding RA). Fiftyone (51) subjects (40.4%) presented with either parenchymal micronodules, subpleural micronodules or nodules. They also reported that these findings were more common in the longstanding RA population, along with higher rheumatoid factor titers and a significantly lower FEV1/FVC ratio [15].

The risk of developing rheumatoid lung nodules is greater in patients with longer disease duration, history of smoking, high rheumatoid factor titers, male gender, HLA-DRB1*04 and severe articular disease [15-17]. Another risk factor reported is the exposure to occupational dust (asbestos coal, silica) in RA patients, which causes a rapid development of multiple peripheral nodules associated with mild-moderate airflow obstruction. This concomitant phenomenon is called Caplan Syndrome [18-20].

It is also important to acknowledge that some Disease-Modifying Anti-Rheumatic Drugs (DMARDs) might have a role in the development of rheumatoid lung nodules [10]. Sun-Hee Kim and Wan-Hee Yoo published a case report of a patient with multiple bilateral subpleural cavitary nodules after seven months of leflunomide [21]. In 2014, Kovacs et al. reported a case of a patient diagnosed with multiple rheumatoid nodules after 6 months of treatment with golimumab.

On the other hand, Toussirot et al reported a case series where only 1 out of 11 subjects developed new nodules after being reintroduced to TNF-α blocking agents [16]. Further studies may be necessary to establish a relationship between DMARDs and rheumatoid lung nodules. Until now the most commonly implicated agents are methotrexate, etanercept, infliximab and leflunomide [21-25].

Rheumatoid nodules may develop in multiple locations in the body and may be found in thecutaneous tissue or within internal organs. Despite its prevalence, the true pathogenesis of rheumatoid nodules is not well understood. Current hypothesis suggests a mixture of local injury, immune complexes and proteolytic enzymes may play a role [16]. Certain features have been found to be common among various forms of rheumatoid nodules, including pulmonary nodules. Primary among them is their appearance as granulomas with central necrosis, which consists of fibroblasts, surrounded by palisading lymphocytes and macrophages [26,27].

Lymphocytes generate IgG and IgM rheumatoid factors. The immunoglobulins, along with fibrin deposits and complement activation generate a variety of cytokines and adhesion molecules. Tumor necrosis factor (TNF)-ɑ, interferon (INF)-, interleukin (IL)-1; IL-1 receptor antagonist; IL-10, IL-15, IL-18, IL-12; E-selectin, Intracellular Adhesion Molecule (ICAM)-1, Platelet Endothelial Cell Adhesion Molecule (PECAM), and Vascular Cell Adhesion Molecule (VCAM) are the common factors among various rheumatoid nodules [28]. Together these function to form a focal vasculitic reaction. Additionally, fibroblasts produce Matrix Metalloproteinases (MMP), which serve in tissue remodeling and have known to be present in various processes of rheumatoid arthritis, including inflammation and formation of nodules [29,30]. The above-mentioned cytokine profile, along with the generation of metalloproteinases within rheumatoid nodules is consistent with the Th1 granulomas [24].

While the above mentioned are common features among rheumatoid nodules in general, pulmonary nodules have certain distinguishing features. For instance, Highton and colleagues immunohistochemically evaluated pulmonary rheumatoid nodules and found evidence of B-lymphocytes and features of lymphoid follicles among them [31]. This is unlike the subcutaneous nodules, which are devoid of such features. The findings suggested that while various inflammatory processes may be similar in rheumatoid arthritis, morphological findings may vary among and qualities of inflammatory lesions may differ based on the site of tissue involved, as seen in the example of the pulmonary rheumatoid nodules. This line of thought may help us understand the phenomenon where pulmonary rheumatoid nodules tend to decrease in size or vanish following therapy with rituximab, a monoclonal antibody against CD20 which is mainly found on B cells [32]. Similar phenomenon has been found with the use of tocilizumab, an IL-6 receptor antibody [33]. IL-17A, however, is a common cytokine in the rheumatoid synovial membrane, yet it is not seen in pulmonary nodules [34].

Studies are yet ongoing to identify factors that predispose patients to the development of these pulmonary rheumatoid nodules. No major associations have been found between the presence of major histocompatibility complex (MHC) alleles related to rheumatoid arthritis and rheumatoid nodules. Furthermore, HLA alleles were noted to be less crucial for nodules than they were for extra-articular disease as only a weak association was found with one HLA shared epitope allele (HLA-DR beta 1*0401) and the presence of rheumatoid nodules [35]. On the other hand, the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registry, provided 749 patients among whom the existence of at least one HLA-DRB1 allele encoding the shared epitope was related to IL4R single-nucleotide polymorphisms [36]. This is significant for the suggestion that poor responsiveness to IL-4 permits the Th-1 mediated inflammation and subsequently generates rheumatoid nodules, including those found in the lungs.

Apart from what is described above, another phenomenon is noted to develop pulmonary rheumatoid nodules. This relates to pulmonary nodules developing consequent to certain treatment of RA. It is generally known as accelerated pulmonary nodulosis. Here, following methotrexate, anti-TNF therapy, and leflunomide, there is remarkable increase in the volume and quantity of pulmonary nodules [37,38]. The mechanism, at least with the use of methotrexate, is thought to be the activation of adenosine A1 receptors by the drug, allowing for improved formation of multinucleated giant cells through enhanced cellular fusion.

Pulmonary nodules are discrete, small (<=30mm) lesions on imaging surrounded by pulmonary parenchyma which may contact the pleura but are not associated with lymphadenopathies or pleural disorders. Structurally, they are classified as solid or subsolid [39]. Based on their etiology, they may be benign or malignant. Malignant pulmonary nodules can include primary or metastatic lung cancer as well as a proportion of carcinoid tumors [40]. Benign pulmonary nodules may be benign tumors, infectious lesions, or non-infectious inflammatory lesions. Rheumatoid pulmonary nodules fall within the final category [41].

Thus, pulmonary rheumatoid nodules share some common features with the inflammatory processes found rheumatoid arthritis, while demonstrating differentiating attributes of their own.

Since pulmonary symptoms are the initial presentation in this pathology, X-ray is the initial diagnostic tool utilized. Nodules are described as a round opacity, that can be well or poorly defined, with presence of air around the circumference, on radiological imaging [39]. Following X-Rays, Computed Tomography (CT) of the chest and the Positron Emission Tomography (PET) scan are the next studies to be requested for further diagnosis.Both studies have a superior specificity and sensitivity when compared to X-rays [42,43]. CT scans have the advantage ofproviding more accurate characteristics, size and location of nodules [42]. PET scan is useful to determine if the nodule is benign or malignant by detecting its metabolic activity [43].

Pulmonary nodules can appear as single or multiple, frequently located around the periphery of superior lobes, under pleural regions and interlobular septa [39], the size may range from a few millimeters to 7cm [44,45]. In majority of the cases, a pattern of cavitary lesions are described in this nodules on imaging [46,47].

The priority in identifying a pulmonary nodule is to recognize appropriate differentials to rule out malignancy or microbial origin. For this purpose, further diagnostic techniques need to be implemented as testing with only imaging studies is insufficient for definitive diagnosis. Pathological confirmation by biopsy is mandatory [48].

Minimally invasive procedures are preferred for initial approach. Bronchoscopy allows for bronchial brush cytology and bronchial alveolar lavage from which samples can be cultured to rule out an infectious origin [49,50]. The endoscopic transbronchial lung biopsy obtains samples for pathologic diagnosis. Other methods include CT guided needle biopsy or transthoracic needle biopsy [42,43,51].

More invasive surgical procedures include needle aspiration or video-assisted thoracoscopic surgery [42]. Samples are sent for histological interpretation, classic findings of rheumatoid pulmonary nodules consist of a central zone of fibrinous necrosis with epithelial cells around it, with adjacent mononuclear cells, fibroblast, and vasculitis [30,46,47,52].

Rheumatoid nodules need to be differentiated from malignant nodules, particularly if it presents as single one, follow up with serial imaging studies and biopsy may be necessary to exclude malignancy.

The management of pulmonary rheumatoid nodules still not well established. This is due to lack of clinical data that could help in the development of standard treatment guidelines. Although, publication of case reports are helpful for treatment decisions, it is important to remember that pulmonary complications of RA are the second most common cause of mortality in these patients [53]. Imaging is necessary for establishing the diagnosis but is not sufficient for a definitive diagnosis. The uses of histopathologic tools are crucial to rule out other possible etiologies, particularly malignancies [30]. In some cases, patients require a change in their current RA treatment regimen to one causing less pulmonary damage. Multiple drugs currently used in treating RA are considered the standard of care, but have common patterns of lung toxicity. Methotrexate is a prime example of an RA drug propagating nodules. Its withdrawal has shown resolution of pulmonary nodules, but current data demonstrates that it is unclear if Methotrexate should be stopped [54]. Even though most pulmonary RA nodules are asymptomatic, the larger nodules may cavitate and case complications such as pleural effusions, spontaneous pneumothorax, or bronchopleural fistula. Currently, B-cell therapies like Rituximab may help decrease the size of the nodules, and in some cases reduce them in quantity [55].

Nevertheless, pulmonary nodules seem to occur in <1% of the patients with RA, some patients develop them, and the treatment seem to be depending on the case. For example, Venerito and colleagues reported a case where a 45-year old female with RA developed pulmonary nodules, and she was under inadequate response to a 12-month therapy with 20 mg of Methotrexate per week. She was started on Baricitinab 4 mg per day and after 4 months, the disease was in remission and the larger nodule appeared with regression on a high-resolution CT scan. The rapid improvement of the pulmonary nodules and the also a recovery of the arthritis, could be a hint that janus kinase inhibition may be effective in these cases [56]. Another agent reported with less pulmonary damage is the leflunomide, which inhibits the key enzyme of the pyrimidine synthesis in activated lymphocytes. During its development and testing in clinical trials, the lung toxicity reported was quite rare [57].

In 2003, Kaiser et al reported that etanercept had no effect in pulmonary rheumatoid nodules. The patients evaluated in this study received etanercept 25 mg twice weekly and prednisone 7.5 mg/day for 17 months. In this case, the nodules did not improve with treatment and a lung biopsy revealed necrotizing areas with chronic inflammatory cells. Furthermore, mycobacterial DNA was detected after which etanercept was discontinue. In this case, the development of pulmonary rheumatoid nodules was unrelated to etanercept usage and may be a confounding factor of latent tuberculosis reactivation [58]. However, in 2009, Derot et al reported a case of a 60-year-old woman with RA that had 4 pulmonary rheumatoid nodules unchanged in size since 1999. These nodules appeared during the usage of methotrexate treatment. Due to this complication, methotrexate was discontinued and etanercept was started. After 21 months of therapy, the patient had a remarkable improvement in her joint pain, and the size of the pulmonary nodules decreased significantly [59].

Rituximab has also been linked to a lesser degree of lung damage in RA patients [60]. The probable efficacy of this medication is supported by the presence of B lymphocytes in the periphery of the pulmonary rheumatoid nodules, suggesting the role of B cells in this RA-related extra-articular involvement. No new nodules appeared in the 10 patients receiving rituximab from the French Autoimmunity and Rituximab/Rheumatoid Arthritis registry [61]. Another case series reported the use of Rituximab, in 3 RA patients whom the anti-TNF-α therapy seemed to be associated with the development of pulmonary rheumatoid nodules. On those 3 cases, the mentioned therapy was interrupted and subsequently Rituximab was administered: 1000 mg initially, followed by another 1000 mg in the next 2 weeks. However, 3 months after the interruption of the anti-TNF-α therapy, there was no spontaneous regression of the pulmonary rheumatoid nodules, but also there were not worsening either [62]. More recently, a prospective study involving 28 patients supports that Rituximab is effective in stabilizing ILD, including pulmonary nodulosis, and the lung function. These patients were evaluated with the six-minute walking test to evaluate the oxygen requirement and underwent bronchoscopy to exclude any type of infections (including TB). 14 of 28 treated with this drug for more than 1 year, but the benefits started to appear in the first 6 months [63].

Surgical management is an alternative in patients whose lung nodules represent a higher risk of complication. Thoracoscopic nodule resection can be performed and the specimen must undergo a complete evaluation to rule out malignancies, especially in patients with history of smoking [64]. 10 to 30% of the resected nodules are often benign. The addition of a new medication for the medical treatment of rheumatoid arthritis will be required in approximately 38% of the post-operative patients, as well as the discontinuation of certain medications that could be associated with generation of the pulmonary rheumatoid nodules [65].

Pulmonary rheumatoid nodulosis is a complication of RA. The nodule formation may fluctuate with the course of the disease or may be related to the drugs used to manage RA. Making an accurate diagnosis is required to rule out other causes of pulmonary nodules, such as malignancies or infections. Diagnosis with imaging is the best way to confirm the presence of nodulosis, but a lung biopsy is mandatory to confirm the histopathological features of the nodule. The treatment will consist of changing the basal treatment of RA to another one that has been documented to cause lesser damage to the lung tissue (Abatacept, Etanercept, Rituximab). It is important to mention that Methotrexate have been associated with accelerated nodulosis and its complications (recurrent pneumothorax). Patients prescribed this medication may need to be followed with chest x-rays. However, further investigation with clinical trials is essential to corroborate this hypothesis. Surgical treatment is generally used when there is high risk of nodule rupture, hemorrhage, tension pneumothorax or other complication with potential for patient mortality.

All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.

No potential conflicts of interest. No financial support.