Introduction: Cryoglobulinemia is associated with extraglandular features in patients with Sjögren’s syndrome, while lymphocyte interstitial pneumonitis (LIP) is a type of interstitial lung disease relatively specific for this syndrome.
Case presentation: A 61-year-old male was admitted for further workup of suspected pneumonia, presenting with a history of persistent cough and fever as well as a finding of a unilateral infiltrate on his chest X-ray. His chest CT was consistent with LIP. Due to decreased serum C3 and C4 levels and the presence of cryoglobulinemia type 3, he underwent further workup that finally confirmed the diagnosis of Sjögren’s syndrome and LIP as its extraglandular feature. In addition to appropriate antibiotic treatment of his acute respiratory infection, he was initially treated with hydroxychloroquine and prednisone with improvement in symptoms and normalization of his erythrocyte sedimentation rate as well as complement levels. However, due to a slight aggravation of his dyspnea and decline in C3 and C4 levels in the further course, azathioprine was added with a beneficial therapeutic and glucocorticoid-sparing effect.
Conclusion: Although cryoglobulinemia does not seem to be a direct cause of LIP, it may serve as a clue towards recognizing extraglandular features of undiagnosed Sjögren’s syndrome.
Keywords: Sjögren’s syndrome, lymphocytic interstitial pneumonitis, cryoglobulinemia, diagnosis
INTRODUCTION
Sjögren’s syndrome is a systemic autoimmune disease that generally affects the exocrine glands, primarily salivary and lacrimal, resulting in oral and ocular dryness. One-third of patients present with extraglandular manifestations. (1) One of the typical lung manifestations is lymphocytic interstitial pneumonitis (LIP), a rare form of interstitial lung disease characterized by cellular expansion and infiltration of the lung interstitium with reactive B and T lymphocytes, plasma cells, and histiocytes. (2, 3)
Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below the core body temperature (37 °C) and dissolve when reheated. (4) Cryoglobulinemia may be associated with cryoglobulinemic vasculitis, however, cryoglobulinemia without clinically apparent vasculitis seems to be even more common. It has been documented in various systemic autoimmune diseases, most frequently in patients with primary Sjögren’s syndrome, where cryoglobulinemia also has prognostic implications. (5)
We present the case of a patient diagnosed with LIP in which the presence of cryoglobulinemia and decreased serum complement levels served as clues towards the diagnosis of Sjögren’s syndrome.
CASE REPORT
A 61-year-old male patient with no history of smoking initially presented to the emergency room with dry cough, dyspnea on exertion, fever lasting for two weeks, as well as diaphoresis.
His past medical history revealed an episode of sunlight “allergy” in his youth as well as a spontaneous ablation of his left retina, without a clear provoking cause. Over the preceding decades, he experienced a few episodes of thrombophlebitis of the varicose veins in his legs.
Over the course of two weeks prior to admission, he suffered from non-spiking fevers up to 39 0C. He also reported symptoms of dyspnea on exertion as well as occasional productive cough with white sputum. No improvement was observed despite a three-day course of azithromycin. A chest X-ray in the outpatient family medicine setting revealed a suspected left-sided perichilar infiltrate.
Given that the symptoms did not improve, he was admitted for further inpatient workup due to suspected pneumonia. His physical findings revealed minimal bilateral lung crackles. He complained of shortness of breath on minimal exertion. Physical examination revealed a small palpable, soft, mobile and painless lymph node (1 cm in diameter) in the left axilla, as well as a mild systolic heart murmur over the mitral valve. There was no enlargement of the salivary glands. His abdomen and extremities were unremarkable, as were his musculoskeletal and skin examination results.
Laboratory workup revealed increased acute phase reactants, mild anemia of chronic disease, slight leukopenia and decreased C3 and C4 complement levels. His serum protein electrophoresis revealed polyclonal hypergammaglobulinemia (21.2 g/L) predominantly due to increased IgG (24.16 g/L, NR 7-16) and IgA (4.39 g/L, NR 0.7-4). Interestingly, the presence of type III cryoglobulinemia was detected. (Table 1)
His chest computed tomography (CT) revealed bilateral thin-walled cystic lesions, interlobular septal thickening and several nodular consolidations with ground-glass opacities, corresponding to lymphocytic interstitial pneumonitis (LIP). No enlarged lymph nodes were revealed. (Figure 1)
Viral antibody tests for HIV, Epstein-Barr virus, cytomegalovirus, as well as hepatitis B and C came out negative. Blood cultures came out negative as well, while his sputum tested positive (105 CFU/ml) for Pseudomonas monteilii, Streptococcus species (viridans) and Candida albicans.
Updated medical history revealed subjective mouth dryness, which was present for several years, but the patient reported no symptoms of ocular dryness. He also recalled episodes of spontaneous painful enlargement of each of his parotid glands over the preceding decades, as well as the fact that, on several occasions over the preceding years, his laboratory findings revealed an unexplained increase in his erythrocyte sedimentation rates as well as slightly decreased white blood cell counts. He had no other signs or symptoms of connective tissue disease. Up until admission, he received no chronic therapy. He followed a gluten-free diet because his son suffered from coeliac disease.
Further workup revealed a decreased tear break-up time (4/5 seconds), and a positive Schirmer’s test (3/5 mm). A salivary flow test revealed a decreased saliva production (0.0 ml/5 minutes; 0.5 ml/15 minutes).
He was started on moxifloxacin, leading to a decline in his fever and CRP levels. In addition to a 10-day course of moxifloxacin, he was also treated with fluconazole over the course of 10 days. He was scheduled for elective pulmonary workup 14 days after completing his antibiotic treatment.
Lung function tests came out unremarkable including his forced expiratory volume (FEV1) of 108%, forced vital capacity (FVC) of 110%, FEV1/FVC of 0.77. His CO diffusing capacity (DLCO) was 69% and his transfer coefficient (KCO) was 70%. Bronchoalveolar lavage (BAL) revealed a CD4/CD8 ratio of 2.2, while cytology revealed a lymphocytic type of BAL with a slightly elevated neutrophil count (numerous lymphocytes (21.5%), alveolar macrophages (72.5%) and neutrophils (6%)). The angiotensin-converting enzyme level in the serum was unremarkable and his bronchoalveolar fluid tested negative for Pneumocystis jirovecii. Given the diagnosis of LIP, he was started on prednisone at a dose of 30 mg qd.
Two weeks after, at the patient’s follow-up visit at the Division of Rheumatology, the patient’s antinuclear antibodies came out positive (indirect immunofluorescence titer of 1:6400), with a positive Luminex test for dsDNA (807 IU/L, NR 0-40), histone (180 IU/L, NR 0-40), SS-A 52 (158 IU/L, NR 0-40), SS-A 60 (122 IU/L, NR 0-40), SS-B (64 IU/L, NR 0-40), U1-RNP (51 IU/L, 0-40) and ribosomal (77 IU/L, NR 0-40) antibodies. Anti-leukocyte antibodies also came out positive. Anti-phospholipid antibodies came out negative, while IgG4 antibodies were unremarkable. The biopsy of the lower-lip minor salivary glands revealed several lymphocytic foci. The patient was finally diagnosed with Sjögren’s syndrome with LIP as the presenting symptom.
Three months thereafter, the patient was feeling well on prednisone at a dose of 15 mg qd, and he reported less episodes of dyspnea on exertion – he was able to hike and to be physically active. His ESR was 16 mm/h, CRP was undetectably low, whilst his gamma globulin level was 15.6 g/L. Hydroxychloroquine was introduced at a dose of 200 mg qd. He was feeling well for the next several months, allowing a prednisone taper to a dose of 10 mg qd. However, at a follow-up visit one year following his first admission, he complained again of increased dyspnea and diaphoresis. His salivary ultrasound revealed a diffuse heterogeneous pattern with hypoechogenic foci and fibrotic areas. (Figure 2) His ESR and CRP levels were unremarkable, however his previously normal complement levels became slightly decreased again, with C3 values of 0.7 g/L and C4 values of 0.09 g/L. Once again, his SS-A 52 148 IU/L, SS-A 60 99 IU/L, and SS-B 91 IU/L values were positive, however, dsDNA became only slightly detectable, with a value of 40 IU/L. All of the aforementioned symptoms, in addition to a slight decline in the patient’s complement levels, were crucial for the decision to introduce azathioprine at a dose of 2 mg/kg body weight (150 mg daily divided into two doses). This led to the alleviation of his dyspnea with persistently normal levels of ESR and CRP and stabilization of lung function tests over the next months. Two years after his first admission, his lung function tests came out unremarkable: FVC of 101%, FEV1 of 102%, FEV1/FVC of 0.78; DLCO of 88% and KCO of 84%. A follow-up chest CT revealed no changes in the bilateral cysts with a diameter of up to 3 cm. This allowed a further prednisone taper to a dose of 5 mg qd. Over the further follow-up during the course of 4.5 years in total, the patient was stable on the same treatment regimen. His SS-A, SS-B and SS-B were persistently positive, while his ds-DNA antibodies became negative.
DISCUSSION
The association between LIP and Sjögren’s syndrome was first elaborated in 1973. (6) Although LIP has been described as a feature specific to Sjögren’s syndrome, it is not its most common pulmonary manifestation. According to a systematic review of 273 studies on systemic features associated with primary Sjögren’s syndrome, pulmonary involvement has been described in 16% of patients: Moreover, 45% of patients had non-specific interstitial pneumonia (NSIP), making it the most frequent pulmonary feature, whereas 15% of patients exhibited symptoms of LIP. (7)
LIP is usually linked to an underlying systemic disease, mostly Sjögren’s syndrome (53.3%). (8) Besides Sjögren’s syndrome, it has less frequently been reported in cases of other autoimmune disorders, such as systemic lupus erythematosus (SLE) (8-10), rheumatoid arthritis (RA) (8, 11), polymyositis (PM) (8), and Hashimoto’s disease (11). LIP has also been associated with immunodeficiencies (8) and chronic viral infections, including human immunodeficiency virus (HIV) infection (12) and Epstein-Barr virus (EBV) infection. (9) Despite the fact that the patient initially had anti-dsDNA antibodies, we believe that the patient had primary Sjögren’s syndrome rather than SLE (and secondary Sjögren’s syndrome), due to the lack of other clinical and laboratory items typically seen in the context of SLE (except for leukopenia). Moreover, LIP seems to be more strongly associated with Sjögren’s syndrome than with SLE.
The most common presenting symptoms of LIP include cough and dyspnea on exertion, sometimes with pleuritic chest pain and systemic symptoms such as fever, fatigue, arthralgias, and weight loss. Inspiratory crackles can be heard on auscultation. (8, 13) Pulmonary function tests usually reveal a restrictive pattern with decreased diffusing capacity for carbon monoxide. (13, 14) It can be expected that, in the case of predominantly cystic disease, a normal FVC and FEV1 with a decreased DLCO may be observed, similar to emphysema. HRCT findings associated with LIP include ground-glass opacities, poorly defined centrilobular and subpleural nodules, interlobular septal thickening, and enlargement of the mediastinal lymph nodes. Thin-walled cysts are characteristically seen in patients with LIP associated with Sjögren’s syndrome. (15-18) CT findings that may help differentiate LIP from lymphoma include cysts, which are more common in patients with LIP, while large nodules (11 – 30 mm in diameter) and pleural effusions have been more commonly described in patients with lymphoma. (19) Bronchoalveolar lavage (BAL) is non-specific and usually shows increased white blood cell counts and lymphocytosis with a normal CD4/CD8 ratio. (8) In selected cases, BAL may be used to detect lymphocyte clonality suggestive of lymphoma. In rare cases, surgical lung biopsy may be required to confirm the diagnosis.
Our decision to assess the patient for the presence of cryoglobulinemia despite the absence of overt small vessel vasculitis was driven by the presence of LIP in a patient with decreased complement levels and high suspicion of Sjögren’s syndrome, that is, a case in which cryoglobulinemia (with or without vasculitis) has significant prognostic implications. Such a diagnostic approach may be of use, especially in the setting where results of ANA testing may not be promptly available. Cryoglobulinemia has been described in 16 – 47% of patients with Sjögren’s syndrome: type 2 has been more commonly associated with Sjögren’s syndrome than type 3. (20) Patients with cryoglobulinemia associated with Sjögren’s syndrome exhibit higher RF values, lower values of C4 in the serum, as well as Ro (SS-A) antibody positivity more commonly compared to their cryoglobulin-negative counterparts. Extraglandular manifestations are more commonly observed in patients with cryoglobulinemia (in 82% of patients with cryoglobulinemia compared to 47% of patients without cryoglobulinemia). (21) The presence of cryoglobulins at diagnosis of Sjögren’s syndrome has been associated with a higher mortality rate (HR=5,09, p=0,001). (22) Moreover, there is a higher risk of developing B-cell lymphoma, usually MALT lymphoma, in patients with Sjögren’s syndrome with cryoglobulinemia (HR=2,56). The risk is even higher in patients with cryoglobulinemic vasculitis (HR=7,47). The time to diagnosis of lymphoma is also shorter in patients with cryoglobulinemia. (23, 24)
The exact association of LIP and cryoglobulinemia is not clear. Our search of the Pubmed database, which was conducted on May 30, 2024, revealed only 11 publications, and it involved the search query: “lymphocytic interstitial pneumonia” AND “cryoglobulinemia”. Interestingly enough, only one report was noted in the context of Sjögren’s syndrome. In their work, Abou Ziki et al. described a 78-year-old patient with LIP, pleural effusions and cryoglobulinemia with vasculitis. (25) The only additional case of LIP and cryoglobulinemic vasculitis was described in the context of HIV infection. (26) It is interesting to note that, despite the fact that hepatitis C virus (HCV) infection is a frequent cause of cryoglobulinemia worldwide, our literature search revealed no description of LIP in an HCV patient.
Although cryoglobulinemic vasculitis can affect the lungs irrespective of the context of Sjögren’s syndrome, it is highly unlikely that pulmonary vasculitis will be the sole manifestation of cryoglobulinemic vasculitis in a given patient. Furthermore, LIP has not been described as a feature of cryoglobulinemic vasculitis. Our opinion is that the association of LIP and cryoglobulinemic vasculitis is probably indirect, with cryoglobulinemia serving as a predictor of extraglandular disease including LIP.
Despite the lack of clinical trial data focusing on the treatment of LIP, a relatively comprehensive therapeutic approach to the treatment of ILD in patients with Sjögren’s syndrome has been provided within the EULAR recommendations for the treatment of Sjögren’s syndrome and the American College of Rheumatology (ACR) guidelines for the treatment of ILD in patients with rheumatic diseases. (27, 28)
In both sets of recommendations, glucocorticoids represent the first line of treatment. In the EULAR recommendations, oral immunosuppressant drugs are positioned as the second line of treatment, with azathioprine being the most frequently used drug. Mycophenolate mofetil (MMF) and cyclosporine A have been mentioned as other options, although some authorities might have a preference towards MMF. Rituximab and cyclophosphamide can be considered as rescue options, yet rituximab may be preferred especially in the context of cryoglobulinemic vasculitis. (27) On the other hand, the recently published ACR guidelines conditionally recommended MMF over the other listed immunosuppressant options for the treatment of ILD in Sjögren’s syndrome, which include azathioprine, rituximab and cyclophosphamide. They also included MMF as the first line of treatment, indicating that glucocorticoids may be used as a short-term option along with the immunosuppressive agent. Unlike azathioprine, MMF remains a therapeutic option according to ACR even in cases of progressive ILD despite the failure of the initial immunosuppressant. (28) It should be noted that none of these two recommendations are specific for LIP, although the EULAR recommendations specified that glucocorticoids as the first treatment line may be especially recommended for LIP and organizing pneumonia, and less so for non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). Unlike the EULAR recommendations, the ACR guidelines did not recognize glucocorticoid monotherapy as the first line of treatment. (27, 28)
Our decision to start glucocorticoid monotherapy was based on a beneficial treatment effect at disease onset and was backed by the EULAR guidelines. Azathioprine was added for the purpose of disease control and glucocorticoid sparing. The reason for the difference between the preferred immunosuppressive agent between the EULAR and ACR recommendations/guidelines (azathioprine vs. MMF) is not clear, especially given the lack of comparative clinical trials. A possible preference towards MMF in the ACR guidelines may be due to caution, which was somewhat erroneously raised by the 2012 trial on patients with idiopathic pulmonary fibrosis (IPF) in which the mortality of patients treated with combined glucocorticoids and azathioprine exceeded the mortality of the control group. (29) Extrapolation of the result of this trial to CTD-ILD population is not biologically plausible due to its pathogenetic differences from IPF. Furthermore, in the original IPF trial, it was not possible to identify whether excess mortality was driven by glucocorticoids or azathioprine.
CONCLUSION
Cryoglobulinemia can be perceived as a feature of excessive lymphocyte activation in Sjögren’s syndrome, associated with a higher risk of extraglandular disease and lymphoma (30). Except for the general association of cryoglobulinemia and extraglandular disease, LIP and cryoglobulinemia do not seem to be directly causally associated. In patients presenting with a potential extraglandular manifestation of non-recognized Sjögren’s syndrome, cryoglobulinemia may serve as a clue that is crucial for disease diagnosis.
Authors’ Contributions: Conception and design of the work: M. T. and I. P.; Acquisition, analysis and interpretation of data: M. T., I. P. and A. H.; Drafting the work: M. T., I. P., A. H. and M. B.; Critical revision for important intellectual content: I. P., M. T., A. H., B. A.
Acknowledgments: The authors report no acknowledgments.
Declaration of funding: This work received no funding.
Declaration of Conflict of Interest: The authors declare that they have no conflict of interest relevant to this manuscript. This manuscript is an extension of the MD thesis of Ms. Margareta Topolovec, MD (University of Zagreb, School of Medicine, 2023; mentor: Assistant Professor Ivan Padjen, MD, PhD).
REFERENCES / LITERATURA
<jrn>29. The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. N Engl J Med. 2012;366:1968–77.PubMedhttps://doi.org/10.1056/NEJMoa1113354</jrn>
<jrn>30. Mayer M, Martinic M, Reihl Crnogaj M, Anic B. The risk of developing non-Hodgkin lymphoma and the mortality rate in primary Sjoegren’s syndrome: a single-centre, retrospective cohort study. Rheumatol Int. 2023;43:2031–6.PubMedhttps://doi.org/10.1007/s00296-023-05386-3</jrn>
Table 1. Laboratory workup at first hospital admission
NR – normal range / normalni raspon; RF – rheumatoid factor / reumatoidni faktor; WBC – white blood count / leukociti; PLT - platelets / trombociti ; MCV – mean corpuscular volume / prosječni obujam eritrocita; C3 – complement component C3 / C3 komponenta komplementa; C4 – complement component C4 / C4 komponenta komplementa.
Figure 1. Chest CT in a patient with Sjögren’s syndrome revealing cysts consistent with lymphocyte interstitial pneumonitis
Figure 2. Parotid gland ultrasound revealing hypoechogenic focal changes as well as hyperechogenic areas consistent with the diagnosis of Sjögren’s syndrome.