Advertisement

Multiple fibrotic lung nodules in a patient with primary Sjögren's syndrome

Published:December 16, 2022DOI:https://doi.org/10.1016/j.amjms.2022.12.007

      Abstract

      Evaluation of bilateral lung nodules noted on imaging poses a diagnostic challenge to clinicians as it can have many differentials from benign to malignant causes. It becomes especially critical to identify them right when there are underlying autoimmune conditions and risk factors for infection. However, a thorough investigation can lead to the recognition of rare associations as described below. We present here a 57-year-old woman who was admitted to the hospital with shortness of breath. Imaging with a computed tomography (CT) scan showed that she had 8 bilateral cystic pulmonary nodules with focal areas of ground-glass opacity and mediastinal lymphadenopathy. Fibrobronchoscopy and histopathological studies were done on the right middle lobe lung nodule demonstrated that the lung nodule was fibrotic with reactive inflammation but showed no malignant cells. Upon further detailed history and chart review, it was noted that the patient had a history of dry eyes leading to an autoimmune workup showing positive antinuclear antibodies (ANA), anti-Ro, and anti-La antibodies with no follow-up since then. This lead to the suspicion that these nodules could be related to underlying Sjögren's syndrome. Initial inpatient management with intravenous steroids showed significant improvement in her symptomatology. Hence, we present this rare association of lung nodules with Sjögren's syndrome and its management for awareness of this condition.

      Keywords

      Introduction

      Sjögren's syndrome (SS) is a chronic multisystem autoimmune disease originally described by Gougerot in 1926.
      • Gougerot H.
      Insuffisance progressive et atrophie des glandes salivaires et muqueuses de la bouche, des conjonctives (et parfois des muqueuses nasale, laryngée, vulvaire) sécheresse de la bouche, des conjonctives, etc).
      It is characterized mainly by keratoconjunctivitis sicca and mouth dryness secondary to lymphocytic infiltration of exocrine glands.
      • Fox RI.
      Sjögren's syndrome.
      Pulmonary involvement in SS is not uncommon, occurring in approximately 10 to 20% of patients,
      • Palm O
      • Garen T
      • Berge Enger T
      • et al.
      Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
      • Nannini C
      • Jebakumar AJ
      • Crowson CS
      • et al.
      Primary Sjögren's syndrome 1976–2005 and associated interstitial lung disease: a population-based study of incidence and mortality.
      • Kreider M
      • Highland K.
      Pulmonary involvement in Sjögren syndrome.
       although lung nodules are a rare pulmonary manifestation of Sjögren's syndrome, malignancy and infectious causes need to be ruled out as well. We present here a rare case of pulmonary nodules which were thought to be related to a malignancy; however, a biopsy of the lung nodule which was most suspicious of malignancy showed that it was of fibrotic nature and a remote history of dry eyes prompted an autoimmune workup revealing the cause to be related to Sjögren's syndrome.

      Case presentation

      A 57-year-old female with a past medical history of cirrhosis of the liver, hepatitis C infection (completed treatment), and pancytopenia presented to the hospital due to shortness of breath, productive cough, and chest pain which had progressively worsened over the past few days. Shortness of breath was present during the past few months and had progressively worsened. A review of old records indicated that the patient had a total of 8 bilateral lung nodules for the past 2 years. They were of different characteristics- a subpleural 5mm left upper lobe nodule, a spiculated right middle lobe 7 mm nodule, left lower lobe 8 mm subpleural nodule, an 11 mm ground glass left lower lobe nodule, an 8 mm left lower lobe subpleural nodule, a 12 mm right middle lobe nodule with central cavitation, a tiny subpleural lingular nodularity, and a 13 mm right lower lobe solid calcified nodule. (Fig. 1a). The lesions were characterized as infectious/inflammatory/malignant.. The patient was being followed by pulmonology and was awaiting a lung biopsy before she was admitted to the hospital. She had two admissions over the past year for obstructive pneumonia and was treated with appropriate antibiotics. Upon admission, the patient's respiratory status was stabilized, and workup was started for an acute infectious process. Repeat computed tomography (CT) chest showed similar lung nodules with some consolidation, tree-in-bud and ground-glass opacities in both lungs with a predominance in right upper lobe (Fig. 1b). Tuberculosis was ruled out by 3 negative acid-fast bacilli (AFB) smears. The patient was started on broad-spectrum antibiotics. Her sputum cultures grew methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, so antibiotics were de-escalated. After antibiotics her consolidation improved on chest X-ray (not shown) but nodular lesions persisted. Bronchoscopy was done and the right middle lobe spiculated nodule was biopsied, which ruled out malignancy and showed reactive bronchial cells with macrophages, congo red staining was negative. Detailed medical chart review and further comprehensive history noted treatment for dry eyes in the past, suggesting possible autoimmune etiologies. In the meantime, labs were positive for ANA, SSA, and SSB antibodies. Rheumatology was of the opinion that findings could be related to Sjögren's syndrome; hence, the patient was started on steroids. She showed dramatic improvement after steroids, and was discharged home with a follow-up to rheumatology. We do believe that the repeated pulmonary infections seen in our patient were a result of the underlying Sjögren's and the resultant inability to clear thick secretions.
      Fig 1
      Fig. 1Chest computed tomography (CT) scan showing multiple pulmonary nodules, in the right lung anterior upper lobe (arrows) (A) and the left lung upper lobe (arrows) (B).

      Discussion

      Sjögren's syndrome can occur either as a primary disorder or in association with other connective tissue diseases (secondary SS). It is the second most common systemic autoimmune disorder after rheumatoid arthritis, with an estimated prevalence of 0.5% with a female preponderance (10 to 1 female/male ratio approx.). About 0.4 million to 3.1 million adults in the United States had primary SS in 2005.
      • Helmick CG
      • Felson DT
      • Lawrence RC
      • et al.
      Estimates of the prevalence of arthritis and other rheumatic conditions in the United States.
      The etiopathogenesis of Sjögren's syndrome is not well understood, but it is believed to be multifactorial, combining environmental factors like viral infections (cytomegalovirus, HIV, Human T-cell leukemia virus, and hepatitis C virus),
      • Martel C
      • Jauberteau M-O
      • Vidal E
      • et al.
      Pathophysiology of primary Sjögren's syndrome.
      a genetic predisposition as suggested by genome-wide association studies,
      • Lessard CJ
      • Li H
      • Adrianto I
      • et al.
      Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome.
      and hormonal imbalance, leading to an autoimmune epithelitis characterized by chronic glandular inflammation secondary to a deregulated innate and acquired immune response.
      • Tapinos NI
      • Polihronis M
      • Tzioufas AG
      • et al.
      Sjögren's syndrome. Autoimmune epithelitis.
      Several studies have found an abnormal activation and proliferation of B-cells, promoting plasma cells that secrete pathogenic anti-Ro (SSA) and anti-La (SSB) autoantibodies directed to the small cytoplasmic RNP-bound peptides SSA-60kD, SSA-52kD, and SSB-48kD.
      • Cornec D
      • Devauchelle-Pensec V
      • Tobón GJ
      • et al.
      B cells in Sjögren's syndrome: from pathophysiology to diagnosis and treatment.
      The role of T-cells in Sjögren's syndrome is more controversial, but it is thought that there is an abnormal T-cell activation with secondary cytotoxicity and altered function of regulatory T-cells and T-helper 17 cells.
      • Alunno A
      • Carubbi F
      • Bistoni O
      • et al.
      T regulatory and T helper 17 cells in primary Sjögren's syndrome: facts and perspectives.
      In addition, the innate immunity in SS is also altered: several studies have shown that epithelial cells are capable of constitutively or inducibly expressing various molecules implicated in promoting chronic innate responses
      • Kyriakidis NC
      • Kapsogeorgou EK
      • Gourzi VC
      • et al.
      Toll-like receptor 3 stimulation promotes Ro52/trim21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type i interferon pathway.
      ,
      • Aqrawi LA
      • Kvarnstrom M
      • Brokstad KA
      • et al.
      Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren’s síndrome.
      and also alterations in the interferon pathway.
      • Nezos A
      • Gravani F
      • Tassidou A
      • et al.
      Type I and II interferon signatures in Sjögren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjögren's related lymphomagenesis.
      However, there is extra-glandular involvement in up to 33% of patients with Sjögren's syndrome, affecting most of the systems of the body and making it a true multisystemic disease.
      • Mavragani CP
      • Moutsopoulos HM.
      Sjögren syndrome.
      Eye involvement,
      • Mathews PM
      • Hahn S
      • Hessen M
      • et al.
      Ocular complications of primary Sjögren syndrome in men.
      neurological involvement,
      • Berkowitz AL
      • Samuels MA.
      The neurology of Sjögren's syndrome and the rheumatology of peripheral neuropathy and myelitis.
      digestive involvement,
      • Ebert EC.
      Gastrointestinal and hepatic manifestations of Sjögren's syndrome.
      renal and urological involvement,
      • Duffles Amarante GB
      • Zotin MC
      • Rocha E
      • et al.
      Renal tubular dysfunction in patients with primary Sjögren syndrome.
      hematological complications,
      • Baimpa E
      • Dahabreh IJ
      • Voulgarelis M
      • et al.
      Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects.
      musculoskeletal manifestations,
      • Mavragani CP
      • Moutsopoulos HM.
      Sjögren syndrome.
      and psychological manifestations
      • Ramos-Casals M
      • Font J
      • Garcia-Carrasco M
      • et al.
      Primary Sjögren syndrome: hematologic patterns of disease expression.
      have all been described.
      A major system commonly affected in Sjögren's syndrome is the respiratory system, which typically appears late in the course of the disease: the prevalence varies from 10-20%, with an estimated incidence of 10% (±3%) 1 year after diagnosis of Sjögren's syndrome and increases to 20% (±4%) by 5 years.
      • Palm O
      • Garen T
      • Berge Enger T
      • et al.
      Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
      • Nannini C
      • Jebakumar AJ
      • Crowson CS
      • et al.
      Primary Sjögren's syndrome 1976–2005 and associated interstitial lung disease: a population-based study of incidence and mortality.
      • Kreider M
      • Highland K.
      Pulmonary involvement in Sjögren syndrome.
      Respiratory manifestations include airway abnormalities, interstitial lung disease, and lymphoproliferative disorders.
      • Stojan G
      • Baer AN
      • Danoff SK.
      Pulmonary manifestations of Sjögren's syndrome.
      • Flament T
      • Bigot A
      • Chaigne B
      • et al.
      Pulmonary manifestations of Sjögren’s syndrome.
      • Gupta S
      • Ferrada MA
      • Hasni SA.
      Pulmonary Manifestations of primary sjögren's syndrome: underlying immunological mechanisms, clinical presentation, and management.
      Airway abnormalities are the most frequent finding in Sjögren's syndrome and are believed to be the result of exocrine glandular destruction and T cell infiltration occurring in the whole airway; however, a morphometric study of the respiratory airway in SS patients did not show bronchial gland atrophy, raising the possibility of a functional, instead of a structural, glandular defect. Airway manifestations include bronchial hyperresponsiveness (observed in 42–60% of patients)
      • Papiris SA
      • Saetta M
      • Turato G
      • et al.
      CD4-positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren's syndrome.
      ,
      • Papiris SA
      • Maniati M
      • Constantopoulos SH
      • et al.
      Lung involvement in primary Sjögren's syndrome is mainly related to the small airway disease.
      ; interestingly, the bronchial hyperresponsiveness observed in Sjögren's syndrome does not respond very well to inhaled corticosteroids in a high proportion of patients (40–60%).
      • Gudbjörnsson B
      • Hedenström H
      • Stålenheim G
      • et al.
      Bronchial hyperresponsiveness to methacholine in patients with primary Sjögren's syndrome.
      Bronchiolitis is the most common airway disease observed in SS patients, with the frequency ranging between 12 to 24% depending on whether the diagnosis was done based on biopsies or radiological criteria.
      • Ito I
      • Nagai S
      • Kitaichi M
      • et al.
      Pulmonary manifestations of primary Sjögren's syndrome: a clinical, radiologic, and pathologic study.
      Different types of bronchiolitis have been found on biopsies, including follicular bronchiolitis, chronic bronchiolitis, obliterative bronchiolitis,
      • Shi J-H
      • Liu H-R
      • Xu W-B
      • et al.
      Pulmonary manifestations of Sjögren's syndrome.
      lymphocytic bronchiolitis,
      • Wells AU
      • du Bois RM.
      Bronchiolitis in association with connective tissue disorders.
      constrictive bronchiolitis associated with bronchiolar destruction,
      • White ES
      • Tazelaar HD
      • Lynch JP.
      Bronchiolar complications of connective tissue diseases.
      and panbronchiolitis.
      • Okano A
      • Sato A
      • Suda T
      • et al.
      [A case of diffuse panbronchiolitis complicated by malignant thymoma and Sjögren's syndrome].
      Bronchiectasis has also been observed in SS patients.
      • Mandl T
      • Diaz S
      • Ekberg O
      • et al.
      Frequent development of chronic obstructive pulmonary disease in primary SS – results of a longitudinal follow-up.

      Interstitial lung disease

      Patients with interstitial lung disease (ILD) present mainly with dyspnea and cough and have a higher frequency of rheumatoid factor and antinuclear antibodies with higher levels of gammaglobulins.
      • Parambil JG
      • Myers JL
      • Lindell RM
      • et al.
      Interstitial lung disease in primary Sjögren syndrome.
      ,
      • Li X
      • Xu B
      • Ma Y
      • et al.
      Clinical and laboratory profiles of primary Sjögren’s syndrome in a Chinese population: a retrospective analysis of 315 patients.
      The presence of anti-SSA has been noted as a predisposing factor.
      • Li X
      • Xu B
      • Ma Y
      • et al.
      Clinical and laboratory profiles of primary Sjögren’s syndrome in a Chinese population: a retrospective analysis of 315 patients.
      In bronchoalveolar lavage (BAL) studies, these patients are found to have lymphocytic alveolitis, mainly with T cell infiltrates, and biopsies show infiltrates in all components of the lung interstitium (alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues).
      • Fox RI.
      Sjögren's syndrome.
      Several types of ILD have been described by lung biopsy in patients with SS, including nonspecific interstitial pneumonitis (NSIP) (45%), usual interstitial pneumonitis (UIP) (16%), organizing pneumonia (7%), lymphocytic interstitial pneumonitis (LIP) (15%).
      • Ramos-Casals M
      • Brito-Zerón P
      • Seror R
      • et al.
      Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements.

      Lymphoproliferative disorders

      The lungs have mucosa-associated lymphoid tissue in the bronchi that is analogous to gut-associated lymphoid tissue, and chronic inflammation of the lungs might lead to lymphoproliferative disorders. Patients with Sjögren's syndrome have a 16 to 44-fold increased risk of non-Hodgkin lymphoma; the most common subtypes are Marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue.
      • Kauppi M
      • Pukkala E
      • Isomäki H.
      Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland).
      The estimated prevalence of primary pulmonary lymphoma is 1–2%.
      • Hansen LA
      • Prakash UB
      • Colby TV.
      Pulmonary lymphoma in Sjögren's syndrome.
      Other, less commonly described pulmonary diseases found in patients with Sjögren's syndrome include pulmonary hypertension and pulmonary embolism.
      • Launay D
      • Hachulla E
      • Hatron P-Y
      • et al.
      Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome: report of 9 new cases and review of the literature.
      ,
      • Chung W-S
      • Lin C-L
      • Sung F-C
      • et al.
      Increased risks of deep vein thrombosis and pulmonary embolism in Sjögren syndrome: a nationwide cohort study.
      But even rarer is the occurrence of pulmonary nodules: most described cases of pulmonary nodules correspond to pulmonary amyloidosis, with fewer than 200 cases described in the literature, most of them in women (98%) and involving multiple nodules in both lungs,
      • Rajagopala S
      • Singh N
      • Gupta K
      • et al.
      Pulmonary amyloidosis in Sjögren's syndrome: a case report and systematic review of the literature.
      ,
      • Xian JZ
      • Cherian SV
      • Idowu M
      • et al.
      A 45-year-old woman with multiple pulmonary nodules and sjögren syndrome.
      and only one case reported a solitary nodule.
      • Reuss-Borst MA
      • Hartmann U.
      Pulmonary nodules as initial manifestation of primary Sjögren's syndrome.
      Primary pulmonary amyloidosis is classified based on the patterns of distribution and in three subtypes nodular: tracheobronchial, and diffuse interstitial. In the nodular type, nodules may present with a ground-glass appearance, suggesting an involvement of the adjacent peribronchiolar spaces or can be surrounded by bullae. Pulmonary amyloidosis can be associated with LIP and cystic lesions.
      • Milani P
      • Basset M
      • Russo F
      • et al.
      The lung in amyloidosis.
      Diffuse pulmonary nodules as seen in our patient appear in multiple conditions, including tumors, infections, autoimmune diseases, pneumoconiosis,
      • Boitsios G
      • Bankier AA
      • Eisenberg RL.
      Diffuse pulmonary nodules.
      and may pose a challenge for the clinician because of the wide range of possible differential diagnoses (Table 1); however, the predominant location of the nodules sometimes can help to distinguish between these conditions. For example, the nodules seen in sarcoidosis are predominantly in the pleural surfaces or bronchocentric, nodules in silicosis and pneumoconiosis are predominantly in the upper lobes, the nodules observed in asbestosis and metastases are usually located in the lower lobes and the nodules in Kaposi sarcoma are bronchocentric. Other clues in the diagnosis of pulmonary nodules include miliary distribution as seen in tuberculosis and cavitations or calcification as seen in infectious causes and septic emboli.
      • Boitsios G
      • Bankier AA
      • Eisenberg RL.
      Diffuse pulmonary nodules.
      However, a surgical lung biopsy is generally required to establish the diagnosis and rule out lymphoma, given the association between Sjögren's and low-grade B-cell lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma of the lung.
      • Rajagopala S
      • Singh N
      • Gupta K
      • et al.
      Pulmonary amyloidosis in Sjögren's syndrome: a case report and systematic review of the literature.
      Table 1Differential Diagnosis of Pulmonary Nodules
      ConditionsTumorsInfectionsAutoimmunePneumoconiosisRare
      DiseasesMalignant

      Bronchial carcinoma

      Metastases

      Pulmonary lymphoma

      Sarcoma de Kaposi



      Benign

      Hamartoma

      Chondroma
      Bacterial

      Tuberculosis

      Haemophilus influenzae

      Mycoplasma pneumoniae



      Fungal

      Aspergillosis

      Histoplasmosis
      Sarcoidosis

      Rheumatoid arthritis

      Wegener's granulomatosis

      Churg‐Strauss syndrome

      Goodpasture syndrome

      Sjogren's Syndrome

      Systemic Lupus Erythematosus

      Polymyositis

      Dermatomyositis
      Silicosis

      Asbestosis
      Amyloidosis
      Surprisingly in our case, histological analysis of the nodules did not show deposits of fibrinoid necrosis surrounded by histiocytes, which are compatible with rheumatoid nodules and have been reported in one case of Sjögren's.
      • Reuss-Borst MA
      • Hartmann U.
      Pulmonary nodules as initial manifestation of primary Sjögren's syndrome.
      The histology reported the presence of fibrinoid nodules with an inflammatory reaction (Fig. 2A), congo red staining did not show amyloid fibrils ruling out amyloidosis (Fig. 2B). To our knowledge, this is the first case in which pulmonary fibrinoid nodules have been reported in a patient with primary Sjögren's syndrome (SS). Their occurrence can be secondary to the chronic inflammation and immune response observed in patients with Sjögren's. Since nodules are not very commonly observed in Sjögren's and they can mimic metastatic malignant lesions,
      • Raad RA
      • Suh J
      • Harari S
      • et al.
      Nodule characterization subsolid nodules.
      their occurrence should lead to a thorough exploration of the patient's history, imaging, and histological studies to rule out malignancy.
      Fig 2
      Fig. 2Histology of the nodules. A. Shows interstitial fibrosis and chronic inflammation (hematoxylin and eosin staining, magnification × 2.5), B. Does not show amyloid fibrils (congo red staining, magnification x10).
      The characteristics of lung nodules can help distinguish autoimmune-related causes from malignancy in some cases. As in rheumatoid arthritis where certain features like nodule multiplicity, smooth border, cavitation, satellite nodules, pleural contact, and subpleural rind of tissue have been associated with benign nodules, Sjögren's does not have a similar scoring system. But subpleural and pleural location,
      • Koslow M
      • Bennji SM
      • Griffith-Richards S
      • Ahmad K
      • Johnson GB
      • Ryu JH
      • Nathan SD
      • Allwood BW
      A 48-year-old south african woman with rheumatoid arthritis and lung nodules.
      number >4, and cavitation were all seen in our patient too, demonstrating a similar pattern of benign nodules associated with autoimmune conditions. Further research in this area is needed to come up with specific monitoring guidelines for autoimmunity-associated lung nodules to avoid aggressive interventions and formulate management ideas.

      Conclusions

      The case that we present here is aimed to bring forward a rare association of fibrotic and inflammatory lung nodules with Sjögren's syndrome and the clinical dilemma that it presents in terms of suspicion of malignancy. We propose to highlight the importance of recognizing autoimmunity as an important cause of lung nodules and that managing these lung nodules requires consistent follow-up imaging, treatment of underlying infections and autoimmunity, biopsying lesions which have a high suspicion of malignancy in terms of characteristics or are increasing in size disproportionate to the underlying disease activity. In these cases, early immunosuppressive therapy and rheumatology involvement will show a fast and good response to treatment.

      Author Contributions

      The case was conceived by Alexander Carvajal-González with Suma Sri Chennapragada, histopathology was done by Ekin Ozluk. The first draft of the manuscript was written by Alexander Carvajal-Gonzalez, revised by Phani Morisseti and all authors had the opportunity to comment on the manuscript and approve the final version.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Source of funding

      None.

      References

        • Gougerot H.
        Insuffisance progressive et atrophie des glandes salivaires et muqueuses de la bouche, des conjonctives (et parfois des muqueuses nasale, laryngée, vulvaire) sécheresse de la bouche, des conjonctives, etc).
        Bull Méd. 1926; 40: 360-368
        • Fox RI.
        Sjögren's syndrome.
        Lancet. 2005 Jul 23; 366: 321-331
        • Palm O
        • Garen T
        • Berge Enger T
        • et al.
        Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
        Rheumatology (Oxford). 2013; 52: 173-179
        • Nannini C
        • Jebakumar AJ
        • Crowson CS
        • et al.
        Primary Sjögren's syndrome 1976–2005 and associated interstitial lung disease: a population-based study of incidence and mortality.
        BMJ Open. 2013; 3e003569
        • Kreider M
        • Highland K.
        Pulmonary involvement in Sjögren syndrome.
        Semin Respir Crit Care Med. 2014; 35: 255-264
        • Helmick CG
        • Felson DT
        • Lawrence RC
        • et al.
        Estimates of the prevalence of arthritis and other rheumatic conditions in the United States.
        Part I. Arthritis Rheum. 2008; 58: 15-25
        • Martel C
        • Jauberteau M-O
        • Vidal E
        • et al.
        Pathophysiology of primary Sjögren's syndrome.
        Rev Med Interne. 2014; 35: 524-530
        • Lessard CJ
        • Li H
        • Adrianto I
        • et al.
        Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome.
        Nat Genet. 2013; 45: 1284-1292
        • Tapinos NI
        • Polihronis M
        • Tzioufas AG
        • et al.
        Sjögren's syndrome. Autoimmune epithelitis.
        Adv Exp Med Biol. 1999; 455: 127-134
        • Cornec D
        • Devauchelle-Pensec V
        • Tobón GJ
        • et al.
        B cells in Sjögren's syndrome: from pathophysiology to diagnosis and treatment.
        J Autoimmun. 2012; 39: 161-167
        • Alunno A
        • Carubbi F
        • Bistoni O
        • et al.
        T regulatory and T helper 17 cells in primary Sjögren's syndrome: facts and perspectives.
        Mediators Inflamm. 2015; 2015243723
        • Kyriakidis NC
        • Kapsogeorgou EK
        • Gourzi VC
        • et al.
        Toll-like receptor 3 stimulation promotes Ro52/trim21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type i interferon pathway.
        Clin Exp Immunol. 2014; 178: 548-560
        • Aqrawi LA
        • Kvarnstrom M
        • Brokstad KA
        • et al.
        Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren’s síndrome.
        Clin Exp Immunol. 2014; 177: 244-252
        • Nezos A
        • Gravani F
        • Tassidou A
        • et al.
        Type I and II interferon signatures in Sjögren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjögren's related lymphomagenesis.
        J Autoimmun. 2015; 63: 47-58
        • Mavragani CP
        • Moutsopoulos HM.
        Sjögren syndrome.
        CMAJ. 2014 Oct 21; 186 (Epub 2014 Feb 24): E579-E586https://doi.org/10.1503/cmaj.122037
        • Mathews PM
        • Hahn S
        • Hessen M
        • et al.
        Ocular complications of primary Sjögren syndrome in men.
        Am J Ophthalmol. 2015; 160: 447-452
        • Berkowitz AL
        • Samuels MA.
        The neurology of Sjögren's syndrome and the rheumatology of peripheral neuropathy and myelitis.
        Pract Neurol. 2014 Feb; 14: 14-22
        • Ebert EC.
        Gastrointestinal and hepatic manifestations of Sjögren's syndrome.
        J Clin Gastroenterol. 2012; 46: 25-30
        • Duffles Amarante GB
        • Zotin MC
        • Rocha E
        • et al.
        Renal tubular dysfunction in patients with primary Sjögren syndrome.
        Clin Nephrol. 2014; 81: 185-191
        • Baimpa E
        • Dahabreh IJ
        • Voulgarelis M
        • et al.
        Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects.
        Medicine (Baltimore). 2009; 88: 284-293
        • Ramos-Casals M
        • Font J
        • Garcia-Carrasco M
        • et al.
        Primary Sjögren syndrome: hematologic patterns of disease expression.
        Medicine (Baltimore). 2002; 81: 281-292
        • Stojan G
        • Baer AN
        • Danoff SK.
        Pulmonary manifestations of Sjögren's syndrome.
        Curr Allergy Asthma Rep. 2013 Aug; 13: 354-360
        • Flament T
        • Bigot A
        • Chaigne B
        • et al.
        Pulmonary manifestations of Sjögren’s syndrome.
        Eur Respir Rev. 2016; 25: 110-123
        • Gupta S
        • Ferrada MA
        • Hasni SA.
        Pulmonary Manifestations of primary sjögren's syndrome: underlying immunological mechanisms, clinical presentation, and management.
        Front Immunol. 2019. Jun 12; 10: 1327
        • Papiris SA
        • Saetta M
        • Turato G
        • et al.
        CD4-positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren's syndrome.
        Am J Respir Crit Care Med. 1997; 156: 637-641
        • Papiris SA
        • Maniati M
        • Constantopoulos SH
        • et al.
        Lung involvement in primary Sjögren's syndrome is mainly related to the small airway disease.
        Ann Rheum Dis. 1999; 58: 61-64
        • Gudbjörnsson B
        • Hedenström H
        • Stålenheim G
        • et al.
        Bronchial hyperresponsiveness to methacholine in patients with primary Sjögren's syndrome.
        Ann Rheum Dis. 1991; 50: 36-40
        • Ito I
        • Nagai S
        • Kitaichi M
        • et al.
        Pulmonary manifestations of primary Sjögren's syndrome: a clinical, radiologic, and pathologic study.
        Am J Respir Crit Care Med. 2005; 171: 632-638
        • Shi J-H
        • Liu H-R
        • Xu W-B
        • et al.
        Pulmonary manifestations of Sjögren's syndrome.
        Respir Int Rev Thorac Dis. 2009; 78: 377-386
        • Wells AU
        • du Bois RM.
        Bronchiolitis in association with connective tissue disorders.
        Clin Chest Med. 1993; 14: 655-666
        • White ES
        • Tazelaar HD
        • Lynch JP.
        Bronchiolar complications of connective tissue diseases.
        Semin Respir Crit Care Med. 2003; 24: 543-566
        • Okano A
        • Sato A
        • Suda T
        • et al.
        [A case of diffuse panbronchiolitis complicated by malignant thymoma and Sjögren's syndrome].
        Nihon Kyōbu Shikkan Gakkai Zasshi. 1991; 29: 263-268
        • Mandl T
        • Diaz S
        • Ekberg O
        • et al.
        Frequent development of chronic obstructive pulmonary disease in primary SS – results of a longitudinal follow-up.
        Rheumatol Oxf Engl. 2012; 51: 941-946
        • Parambil JG
        • Myers JL
        • Lindell RM
        • et al.
        Interstitial lung disease in primary Sjögren syndrome.
        Chest. 2006; 130: 1489-1495
        • Li X
        • Xu B
        • Ma Y
        • et al.
        Clinical and laboratory profiles of primary Sjögren’s syndrome in a Chinese population: a retrospective analysis of 315 patients.
        Int J Rheum Dis. 2015; 18: 439-446
        • Ramos-Casals M
        • Brito-Zerón P
        • Seror R
        • et al.
        Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements.
        Rheumatology (Oxford). 2015; 54: 2230-2238
        • Kauppi M
        • Pukkala E
        • Isomäki H.
        Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland).
        Cancer Causes Control. 1997; 8: 201-204
        • Hansen LA
        • Prakash UB
        • Colby TV.
        Pulmonary lymphoma in Sjögren's syndrome.
        Mayo Clin Proc. 1989 Aug; 64: 920-931
        • Launay D
        • Hachulla E
        • Hatron P-Y
        • et al.
        Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome: report of 9 new cases and review of the literature.
        Medicine (Baltimore). 2007; 86: 299-315
        • Chung W-S
        • Lin C-L
        • Sung F-C
        • et al.
        Increased risks of deep vein thrombosis and pulmonary embolism in Sjögren syndrome: a nationwide cohort study.
        J Rheumatol. 2014; 41: 909-915
        • Rajagopala S
        • Singh N
        • Gupta K
        • et al.
        Pulmonary amyloidosis in Sjögren's syndrome: a case report and systematic review of the literature.
        Respirol Carlton Vic. 2010; 15: 860-866
        • Xian JZ
        • Cherian SV
        • Idowu M
        • et al.
        A 45-year-old woman with multiple pulmonary nodules and sjögren syndrome.
        Chest. 2019; 155: e51-e54
        • Reuss-Borst MA
        • Hartmann U.
        Pulmonary nodules as initial manifestation of primary Sjögren's syndrome.
        Ann Rheum Dis. 2006 May; 65: 685-687
        • Milani P
        • Basset M
        • Russo F
        • et al.
        The lung in amyloidosis.
        Eur Resp Rev. 2017; 26170046
        • Boitsios G
        • Bankier AA
        • Eisenberg RL.
        Diffuse pulmonary nodules.
        AJR. 2010; 194: W354-W366
        • Raad RA
        • Suh J
        • Harari S
        • et al.
        Nodule characterization subsolid nodules.
        Radiol Clin N Am. 2014; 52: 47-67
        • Koslow M
        • Bennji SM
        • Griffith-Richards S
        • Ahmad K
        • Johnson GB
        • Ryu JH
        • Nathan SD
        • Allwood BW
        A 48-year-old south african woman with rheumatoid arthritis and lung nodules.
        Chest. 2020 May; 157: e151-e155