Pulmonary Nodules in Patients with Chronic Rheumatoid Arthritis: an with Lung Damage Have an Asymptomatic Evolution

Mendez Y, et al., J Pulm Med Respir Res 2019, 5: 029 DOI: 10.24966/PMRR-0177/100029 HSOA Journal of Pulmonary Medicine & Respiratory Research Review Article

Pulmonary Nodules In Patients Introduction Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease With Chronic Rheumatoid that is characterized by the destruction of articular joint structures. It is a systemic condition that also affects other organs, such as the heart, Arthritis: An Up-To-Date lungs, and kidneys [1]. Pulmonary complications are quite common and could include pleural effusion, rheumatoid nodules, bronchiecta- Review sis, obliterative bronchiolitis and opportunistic infections. These lung complications are the most common extra-articular manifestation of Yamely Mendez1*, Ismael Garcia1, Jane Thomas2, Rogelio RA and could be detected in 40-70% of the cases [2]. Ellman and Hernandez3, Alma Alicia Peña Maldonado1 and Salim Surani4 Ball first described lung disease in association with RA, and it is a 1Faculty of Medicine, Dr. Alberto Romo Caballero, Universidad Autonoma de particular clinical challenge [3]. There are often multiple pulmonary Tamaulipas, Houston, Texas, USA nodules and they involve both lungs, with a variation in their size, 2Department of Medicine, MD Anderson Cancer Center, Houston, Texas, from few millimeters to 1 to 3 centimeters. Complications of these USA nodules involve their necrosis and rupture that subsequently results 3Department of Pediatric Immunology, Allergy and Retrovirology, Baylor in secondary pneumothorax, bronchopleural fistula, hemorrhage, and College of Medicine, Houston, Texas, USA empyema [4]. The rheumatoid nodules are usually asymptomatic, but once suspected, a more detailed examination must be done to exclude 4Department of Medicine, Texas A&M University, Texas, USA neoplasms, tuberculosis, and fungal infections [5]. Its pathophysiology is not well understood, although alveolar epithelial injury has been Abstract implicated [6]. Some risk factors for pulmonary rheumatoid nodules Rheumatoid Arthritis (RA) is an autoimmune disease that affects include history of smoking tobacco and a positive rheumatoid serol- joints, but it also commonly causes systemic damage. The most ogy. They are most commonly located in the subpleural space, and frequent organs affected by RA are the lungs, heart, and the kid- usually asymptomatic. One of its consequences is the rupture of the neys. Pulmonary complications are common, especially in patients nodules which could cause pleural effusion, pulmonary abscess, em- who use Disease Modifying Antirheumatic Drugs (DMARDs) such pyema, pneumothorax and bronchopleural fistula [7]. The diagnosis as methotrexate and leflunomide. The most common extra-articu- is suggested by a typical clinical vignette but cannot be confirmed lar manifestation of RA are pleura effusions, pulmonary rheumatoid nodules, bronchiectasis, bronchiolitis, and the presence of infec- without imaging tests (Chest X-Ray, CT Scan, MRI, etc.) [8]. The tions. The pathophysiology of rheumatoid pulmonary nodules is cur- use of leflunomide for the treatment of RA, as well as methotrexate, rently not well understood, but there are several hypotheses that have been related to the formation of pulmonary rheumatoid nodules suggest a mixture of local injury, immune complexes, and proteo- as well. The latter is associated to methotrexate-induced accelerated lytic enzymes play a role. Computed Tomography (CT) of the chest nodulosis, which is characterized by the rapid onset or worsening of and Positron Emission Tomography (PET) scan are the best studies to be requested for further diagnosis, mainly because they demon- rheumatoid nodules. [9,10]. The treatment for pulmonary rheumatoid strate superior specificity and sensitivity when compared to chest nodules still a challenge because surgical excision is rarely indicated. x-rays. The treatment of rheumatoid pulmonary nodules will depend It is only used in specific situations where there is suspicion of com- always on the severity of the case, and will lead to a change in the plications. Clinical trials may be useful to collect additional data and medication of the RA. If necessary, patients can undergo surgical generate clear treatment recommendations [11]. resection of the nodules. Keywords: Interstitial lung disease; Management; Nodules; Pulmo- Epidemiology nary nodules; Pulmonology; Rheumatoid arthritis; Rheumatology; It is estimated that nearly 40% of patients with RA will develop Treatment some type of extra articular manifestation of RA, with pulmonary in- *Corresponding author: Yamely Mendez, Faculty of Medicine, Dr. Alberto volvement. This is the most common complication and the second Romo Caballero, Universidad Autonoma de Tamaulipas, Houston, Texas, USA, most common cause of death in this condition [12,13]. When discuss- Tel: 1956-999-0414; Email: [email protected] ing pulmonary involvement in rheumatoid arthritis, we understand Citation: Mendez Y, Garcia I, Thomas J, Hernandez R, Maldonado AAP, et al. the majority of lung structures are at risk of injury. Many patients (2019) Pulmonary Nodules In Patients With Chronic Rheumatoid Arthritis: An with lung damage have an asymptomatic evolution. However, Chest Up-To-Date Review. J Pulm Med Respir Res 5: 029. X-Ray (CXR) and Computed Tomography (CT) show a high percent- Received: July 11, 2019; Accepted: August 06, 2019; Published: August 13, age of RA related effects in a large number of patients [14]. 2019 According to the literature, the most common CXR findings of RA Copyright: © 2019 Mendez Y, et al. This is an open-access article distributed patients are ground glass opacities, peribronchial opacity, and bron- under the terms of the Creative Commons Attribution License, which permits un- restricted use, distribution, and reproduction in any medium, provided the original chiectasis. In addition, rheumatoid nodules are the only pulmonary author and source are credited. manifestation specific to RA [14,15]. Citation: Mendez Y, Garcia I, Thomas J, Hernandez R, Maldonado AAP, et al. (2019) Pulmonary Nodules In Patients With Chronic Rheumatoid Arthritis: An Up-To-Date Review. J Pulm Med Respir Res 5: 029.

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Several studies have been conducted to show the prevalence of receptor antagonist; IL-10, IL-15, IL-18, IL-12; E-selectin, Intracellu- rheumatoid nodules, but it is still inconclusive. One clinical series lar Adhesion Molecule (ICAM)-1, Platelet Endothelial Cell Adhesion reported that only 2 of 516 patients presented with nodules on CXR. Molecule (PECAM), and Vascular Cell Adhesion Molecule (VCAM) On the other hand, Rukenet al published a report in which 85 patients are the common factors among various rheumatoid nodules [28]. To- with RA underwent a CT scan. According to their results, 78.6% of gether these function to form a focal vasculitic reaction. Additionally, subjects (66 out of 85) presented with pulmonary nodules. Results fibroblasts produce Matrix Metalloproteinases (MMP), which serve indicated that 34.5% of patients were asymptomatic and 76.6% had in tissue remodeling and have known to be present in various pro- high rheumatoid factor titers. Furthermore, illustrated micronodules cesses of rheumatoid arthritis, including inflammation and formation were more common among lifelong non-smoker RA patients com- of nodules [29,30]. The above-mentioned cytokine profile, along with pared to the small nodules found typically in RA patients who smoke the generation of metalloproteinases within rheumatoid nodules is [12]. consistent with the Th1 granulomas [24]. Shunsukeet al performed a high-resolution CT on a total of 126 While the above mentioned are common features among rheu- patients with RA (65 with early RA and 61 with longstanding RA). matoid nodules in general, pulmonary nodules have certain distin- Fiftyone (51) subjects (40.4%) presented with either parenchymal mi- guishing features. For instance, Highton and colleagues immunohis- cronodules, subpleural micronodules or nodules. They also reported tochemically evaluated pulmonary rheumatoid nodules and found that these findings were more common in the longstanding RA pop- evidence of B-lymphocytes and features of lymphoid follicles among ulation, along with higher rheumatoid factor titers and a significantly them [31]. This is unlike the subcutaneous nodules, which are devoid lower FEV1/FVC ratio [15]. of such features. The findings suggested that while various inflamma- The risk of developing rheumatoid lung nodules is greater in pa- tory processes may be similar in rheumatoid arthritis, morphological tients with longer disease duration, history of smoking, high rheuma- findings may vary among and qualities of inflammatory lesions may toid factor titers, male gender, HLA-DRB1*04 and severe articular differ based on the site of tissue involved, as seen in the example of disease [15-17]. Another risk factor reported is the exposure to oc- the pulmonary rheumatoid nodules. This line of thought may help cupational dust (asbestos coal, silica) in RA patients, which causes us understand the phenomenon where pulmonary rheumatoid nodules a rapid development of multiple peripheral nodules associated with tend to decrease in size or vanish following therapy with rituximab, a mild-moderate airflow obstruction. This concomitant phenomenon is monoclonal antibody against CD20 which is mainly found on B cells called Caplan Syndrome [18-20]. [32]. Similar phenomenon has been found with the use of tocilizumab, an IL-6 receptor antibody [33]. IL-17A, however, is a common It is also important to acknowledge that some Disease-Modifying cytokine in the rheumatoid synovial membrane, yet it is not seen in Anti-Rheumatic Drugs (DMARDs) might have a role in the develop- pulmonary nodules [34]. ment of rheumatoid lung nodules [10]. Sun-Hee Kim and Wan-Hee Yoo published a case report of a patient with multiple bilateral sub- Studies are yet ongoing to identify factors that predispose patients pleural cavitary nodules after seven months of leflunomide [21]. In to the development of these pulmonary rheumatoid nodules. No ma- 2014, Kovacs et al. reported a case of a patient diagnosed with multi- jor associations have been found between the presence of major his- ple rheumatoid nodules after 6 months of treatment with golimumab. tocompatibility complex (MHC) alleles related to rheumatoid arthritis On the other hand, Toussirot et al reported a case series where only and rheumatoid nodules. Furthermore, HLA alleles were noted to be 1 out of 11 subjects developed new nodules after being reintroduced less crucial for nodules than they were for extra-articular disease as to TNF-α blocking agents [16]. Further studies may be necessary to only a weak association was found with one HLA shared epitope al- establish a relationship between DMARDs and rheumatoid lung nod- lele (HLA-DR beta 1*0401) and the presence of rheumatoid nodules ules. Until now the most commonly implicated agents are methotrex- [35]. On the other hand, the Consortium for Longitudinal Evaluation ate, etanercept, infliximab and leflunomide [21-25]. of African-Americans with Early Rheumatoid Arthritis (CLEAR) registry, provided 749 patients among whom the existence of at least Pathophysiology one HLA-DRB1 allele encoding the shared epitope was related to Rheumatoid nodules may develop in multiple locations in the body IL4R single-nucleotide polymorphisms [36]. This is significant for and may be found in thecutaneous tissue or within internal organs. the suggestion that poor responsiveness to IL-4 permits the Th-1 me- Despite its prevalence, the true pathogenesis of rheumatoid nodules diated inflammation and subsequently generates rheumatoid nodules, is not well understood. Current hypothesis suggests a mixture of local including those found in the lungs. injury, immune complexes and proteolytic enzymes may play a role Apart from what is described above, another phenomenon is noted [16]. Certain features have been found to be common among various to develop pulmonary rheumatoid nodules. This relates to pulmonary forms of rheumatoid nodules, including pulmonary nodules. Primary nodules developing consequent to certain treatment of RA. It is gen- among them is their appearance as granulomas with central necrosis, which consists of fibroblasts, surrounded by palisading lymphocytes erally known as accelerated pulmonary nodulosis. Here, following and macrophages [26,27]. methotrexate, anti-TNF therapy, and leflunomide, there is remarkable increase in the volume and quantity of pulmonary nodules [37,38]. Lymphocytes generate IgG and IgM rheumatoid factors. The im- The mechanism, at least with the use of methotrexate, is thought to munoglobulins, along with fibrin deposits and complement activation be the activation of adenosine A1 receptors by the drug, allowing for generate a variety of cytokines and adhesion molecules. Tumor ne- improved formation of multinucleated giant cells through enhanced crosis factor (TNF)-ɑ, interferon (INF)-γ, interleukin (IL)-1β; IL-1 cellular fusion.

Volume 5 • Issue 2 • 100029 J Pulm Med Respir Res ISSN: 2573-0177, Open Access Journal DOI: 10.24966/PMRR-0177/100029 Citation: Mendez Y, Garcia I, Thomas J, Hernandez R, Maldonado AAP, et al. (2019) Pulmonary Nodules In Patients With Chronic Rheumatoid Arthritis: An Up-To-Date Review. J Pulm Med Respir Res 5: 029.

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Pulmonary nodules are discrete, small (<=30mm) lesions on im- Treatment aging surrounded by pulmonary parenchyma which may contact the pleura but are not associated with lymphadenopathies or pleural dis- The management of pulmonary rheumatoid nodules still not well established. This is due to lack of clinical data that could help in the orders. Structurally, they are classified as solid or subsolid [39]. Based development of standard treatment guidelines. Although, publication on their etiology, they may be benign or malignant. Malignant pulmo- of case reports are helpful for treatment decisions, it is important to nary nodules can include primary or metastatic lung cancer as well remember that pulmonary complications of RA are the second most as a proportion of carcinoid tumors [40]. Benign pulmonary nodules common cause of mortality in these patients [53]. Imaging is neces- may be benign tumors, infectious lesions, or non-infectious inflam- sary for establishing the diagnosis but is not sufficient for a definitive matory lesions. Rheumatoid pulmonary nodules fall within the final diagnosis. The uses of histopathologic tools are crucial to rule out category [41]. other possible etiologies, particularly malignancies [30]. In some cases, patients require a change in their current RA treatment regimen to Thus, pulmonary rheumatoid nodules share some common fea- one causing less pulmonary damage. Multiple drugs currently used tures with the inflammatory processes found rheumatoid arthritis, in treating RA are considered the standard of care, but have common while demonstrating differentiating attributes of their own. patterns of lung toxicity. Methotrexate is a prime example of an RA Diagnosis drug propagating nodules. Its withdrawal has shown resolution of pulmonary nodules, but current data demonstrates that it is unclear if Since pulmonary symptoms are the initial presentation in this Methotrexate should be stopped [54]. Even though most pulmonary pathology, X-ray is the initial diagnostic tool utilized. Nodules are RA nodules are asymptomatic, the larger nodules may cavitate and described as a round opacity, that can be well or poorly defined, with case complications such as pleural effusions, spontaneous pneumo- presence of air around the circumference, on radiological imaging thorax, or bronchopleural fistula. Currently, B-cell therapies like Rit- [39]. Following X-Rays, Computed Tomography (CT) of the chest uximab may help decrease the size of the nodules, and in some cases and the Positron Emission Tomography (PET) scan are the next stud- reduce them in quantity [55]. ies to be requested for further diagnosis.Both studies have a superi- Nevertheless, pulmonary nodules seem to occur in <1% of the pa- or specificity and sensitivity when compared to X-rays [42,43]. CT tients with RA, some patients develop them, and the treatment seem scans have the advantage ofproviding more accurate characteristics, to be depending on the case. For example, Venerito and colleagues re- size and location of nodules [42]. PET scan is useful to determine if ported a case where a 45-year old female with RA developed pulmo- the nodule is benign or malignant by detecting its metabolic activity nary nodules, and she was under inadequate response to a 12-month [43]. 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 remis- Pulmonary nodules can appear as single or multiple, frequently sion and the larger nodule appeared with regression on a high-resolu- located around the periphery of superior lobes, under pleural regions tion CT scan. The rapid improvement of the pulmonary nodules and and interlobular septa [39], the size may range from a few millimeters the also a recovery of the arthritis, could be a hint that janus kinase to 7cm [44,45]. In majority of the cases, a pattern of cavitary lesions inhibition may be effective in these cases [56]. Another agent reported are described in this nodules on imaging [46,47]. with less pulmonary damage is the leflunomide, which inhibits the key enzyme of the pyrimidine synthesis in activated lymphocytes. The priority in identifying a pulmonary nodule is to recognize ap- During its development and testing in clinical trials, the lung toxicity propriate differentials to rule out malignancy or microbial origin. For reported was quite rare [57]. this purpose, further diagnostic techniques need to be implemented as testing with only imaging studies is insufficient for definitive diagno- In 2003, Kaiser et al reported that etanercept had no effect in pul- sis. Pathological confirmation by biopsy is mandatory [48]. monary rheumatoid nodules. The patients evaluated in this study received etanercept 25 mg twice weekly and prednisone 7.5 mg/day for Minimally invasive procedures are preferred for initial approach. 17 months. In this case, the nodules did not improve with treatment Bronchoscopy allows for bronchial brush cytology and bronchial and a lung biopsy revealed necrotizing areas with chronic inflam- alveolar lavage from which samples can be cultured to rule out an matory cells. Furthermore, mycobacterial DNA was detected after infectious origin [49,50]. The endoscopic transbronchial lung biopsy which etanercept was discontinue. In this case, the development of obtains samples for pathologic diagnosis. Other methods include CT pulmonary rheumatoid nodules was unrelated to etanercept usage and guided needle biopsy or transthoracic needle biopsy [42,43,51]. 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 More invasive surgical procedures include needle aspiration or with RA that had 4 pulmonary rheumatoid nodules unchanged in size video-assisted thoracoscopic surgery [42]. Samples are sent for histo- since 1999. These nodules appeared during the usage of methotrexate logical interpretation, classic findings of rheumatoid pulmonary nod- treatment. Due to this complication, methotrexate was discontinued ules consist of a central zone of fibrinous necrosis with epithelial cells and etanercept was started. After 21 months of therapy, the patient around it, with adjacent mononuclear cells, fibroblast, and vasculitis had a remarkable improvement in her joint pain, and the size of the [30,46,47,52]. pulmonary nodules decreased significantly [59]. Rheumatoid nodules need to be differentiated from malignant Rituximab has also been linked to a lesser degree of lung dam- nodules, particularly if it presents as single one, follow up with serial age in RA patients [60]. The probable efficacy of this medication is imaging studies and biopsy may be necessary to exclude malignancy. supported by the presence of B lymphocytes in the periphery of the

• Page 4 of 7 • pulmonary rheumatoid nodules, suggesting the role of B cells in this References RA-related extra-articular involvement. No new nodules appeared in the 10 patients receiving rituximab from the French Autoimmunity 1. Hallowell RW, Horton MR (2014) Interstitial Lung Disease in Patients and Rituximab/Rheumatoid Arthritis registry [61]. Another case se- with Rheumatoid Arthritis: Spontaneous and Drug Induced. Drugs 74: ries reported the use of Rituximab, in 3 RA patients whom the an- 443-450. ti-TNF-α therapy seemed to be associated with the development of 2. Habib HM, Eisa AA, Arafat WR, Marie MA (2011) Pulmonary involve- pulmonary rheumatoid nodules. On those 3 cases, the mentioned ther- ment in early rheumatoid arthritis patients. Clin Rheumatol 30: 217-221. apy was interrupted and subsequently Rituximab was administered: 3. 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Gómez Herrero H, Arraiza Sarasa M, Rubio Marco I, García de Eulate plete evaluation to rule out malignancies, especially in patients with Martín-Moro I (2012) Nódulos pulmonares reumatoides: forma de pre- history of smoking [64]. 10 to 30% of the resected nodules are often sentación, métodos diagnósticos y evolución, a propósito de 5 casos. Re- umatol Clin 8: 212-215. benign. The addition of a new medication for the medical treatment of rheumatoid arthritis will be required in approximately 38% of the 9. Yoshikawa GT, Dias GA da S, Fujihara S, Silva LF e, Cruz L de BP, et al. post-operative patients, as well as the discontinuation of certain med- (2015) Formation of multiple pulmonary nodules during treatment with ications that could be associated with generation of the pulmonary leflunomide. J Bras Pneumol 41: 281-214. rheumatoid nodules [65]. 10. Akiyama N, Toyoshima M, Kono M, Nakamura Y, Funai K, et al. (2015) Methotrexate-induced Accelerated Pulmonary Nodulosis. Am J Respir Conclusions Crit Care Med 192: 252-253. Pulmonary rheumatoid nodulosis is a complication of RA. The 11. Tilstra JS, Lienesch DW (2015) Rheumatoid Nodules. Dermatol Clin 33: nodule formation may fluctuate with the course of the disease or may 361-371. be related to the drugs used to manage RA. Making an accurate diag- 12. Yuksekkaya R, Celikyay F, Yilmaz A, Arslan S, Inanir A, et al. (2013) nosis is required to rule out other causes of pulmonary nodules, such Pulmonary involvement in rheumatiodarhtirits: multidetector computed as malignancies or infections. Diagnosis with imaging is the best way tomography findings. Acta Radiologica 54:1138-1149. to confirm the presence of nodulosis, but a lung biopsy is mandatory 13. Turesson C, OO’ Fallon WM, Crowson CS, Gabriel SE, Matteson EL to confirm the histopathological features of the nodule. 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However, fur- Abnormalities on High-Resolution Computed Tomography in Patients ther investigation with clinical trials is essential to corroborate this with Early versus Longstanding Rheumatoid Arthritis. J Rheumatol 35: hypothesis. Surgical treatment is generally used when there is high 1513-1521. risk of nodule rupture, hemorrhage, tension pneumothorax or other 16. Toussirot E, Berthelot J, Pertuiset E, Bouvard B, Gaudin P, et al. (2009) complication with potential for patient mortality. Pulmonary Nodulosis and Aseptic Granulomatous Lung Disease Occur- ring in Patients with Rheumatoid Arthritis Receiving Tumor Necrosis Fac- Author contributions tor-α Blocking Agent: A Case Series. The Journal of Rheumatology 36: 2421-2427. All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and criti- 17. 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Conflict of Interest 18. King TE Jr, Kim EJ, Kinder BW (2011) Connective tissue diseases. In: Interstitial Lung Disease (5th ed.) Schwarz MI, King TE Jr (Eds). People’s No potential conflicts of interest. No financial support. Medical Publishing House-USA, Shelton, CT: 689.

Volume 5 • Issue 2 • 100029 J Pulm Med Respir Res ISSN: 2573-0177, Open Access Journal DOI: 10.24966/PMRR-0177/100029

Citation: Mendez Y, Garcia I, Thomas J, Hernandez R, Maldonado AAP, et al. (2019) Pulmonary Nodules In Patients With Chronic Rheumatoid Arthritis: An Up-To-Date Review. J Pulm Med Respir Res 5: 029.

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Volume 5 • Issue 2 • 100029 J Pulm Med Respir Res ISSN: 2573-0177, Open Access Journal

DOI: 10.24966/PMRR-0177/100029

Citation: Mendez Y, Garcia I, Thomas J, Hernandez R, Maldonado AAP, et al. (2019) Pulmonary Nodules In Patients With Chronic Rheumatoid Arthritis: An Up-To-Date Review. J Pulm Med Respir Res 5: 029.

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