Clinical and laboratory features of primary Sjögren’s syndrome complicated with mild to severe thrombocytopenia

Introduction

Sjögren’s syndrome (SS; also known as Sicca syndrome) is a chronic systemic autoimmune disease characterized by xerophthalmia (dry eyes) and/or xerostomia (dry mouth). Glandular features such as dry eyes and dry mouth can also occur as a late complication in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other rheumatic disorders, called ‘secondary’ SS (1).

In addition to the impaired function of exocrine glands, other organs may be also involved, such as the skin, joints, lungs, liver, kidneys, and hematological system.

Hematologic abnormalities is common in primary SS (pSS) patients, a third of patients with SS have cytopenias such as leukopenia, anemia, and thrombocytopenia (2), because its degree is usually mild and asymptomatic, often have been disregarded in daily practice and only a few studies conducted on it. Leukopenia occur in about 20–60% of patients, associated with positive anti-SSA antibodies and a more severe glandular involvement (3-5). Anemia is also frequently seen in pSS, its reported that anemia occurs in 11.2–19% of pSS patients (6), but autoimmune hemolytic anemia (AIHA) is uncommon in pSS. In a study, the pSS patients with AIHA, fever, liver involvement, leukopenia and thrombocytopenia occurred significantly more frequently than those without AIHA (7). Although in pSS, leukopenia and anemia is the most common complications of the hematological system, a few cases are complicated with AIHA and thrombocytopenia (8). A previous study analyzed 99 pSS patients and reported that 61 (61.5%) developed lymphopenia and leukopenia, and 7 (7.1%) had thrombocytopenia (9).

Although thrombocytopenia is not common in pSS patients (10), severe thrombocytopenia can increase the occurrence of adverse events, which are sometimes fatal. Some patients are misdiagnosed because they lack the typical signs in their eyes and mouths (11). Thus, in 2015, the European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) that is aimed at developing consensual recommendations to provide a homogeneous approach to pSS patients presenting with systemic involvement. The guideline mentioned that patients with thrombocytopenia accompanied by positive Ro/SS-A and/or La/SS-B autoantibodies have a possible diagnosis of SS (12). Due to its low prevalence, large-sample controlled studies on thrombocytopenia in pSS are scarce. Thus, in this study, we aimed to investigate the clinical and laboratory characteristics of pSS complicated with mild to severe thrombocytopenia, and compared them with those of pSS patients without thrombocytopenia. We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-162/rc).

Methods

Design

In this medical records review study, we identified 841 pSS patients hospitalized in the Department of Rheumatology of The First Affiliated Hospital of Soochow University between March 2007 and March 2018. Of these pSS patients, 43 developed mild to severe thrombocytopenia (thrombocytopenia group), and 45 patients who did not develop thrombocytopenia were included in the analysis as the control group. The age and sex of the control group were matched to those of the thrombocytopenia group. The patients’ demographic data, clinical manifestations, laboratory examinations, and other results were analyzed retrospectively.

Patients

PSS diagnosis was confirmed either by pathological or clinical methods based on the 2002 American College of Rheumatology Classification Criteria (13). Patients with other diseases such as chronic hepatitis C, human immunodeficiency virus infection, previous lymphoproliferative processes, or other autoimmune diseases were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Ethics Board of The First Affiliated Hospital of Soochow University (No. 2020105). Individual consent for this retrospective analysis was waived.

Clinical features

The clinical characteristics of pSS are as follows: fever, axillary temperature >37.5 ℃; Raynaud phenomenon, cool skin and cutaneous color changes of the fingers and toes exposed to cold and/or stress; articular features, arthralgia or non-erosive arthritis involving two or more peripheral joints; pulmonary complications, chronic and persistent cough, dyspnea, or both, with alveolitis or fibrosis in computed tomography (CT) scans; nephropathy, permanent proteinuria (>0.5 g/day), continuously increasing serum creatinine (Cr) level (>111 µmol/L), renal tubular acidosis, or glomerular nephritis; liver damage, altered plasma liver function (aminotransferase, alkaline phosphatase, gamma glutamyl transferase, and bilirubin) and/or altered bile ducts in ultrasonography, CT, or magnetic resonance imaging; hemorrhagic manifestations, skin bleeding (skin purpura or bruises), oral bleeding (oral blood blister or gingival bleeding), nasal hemorrhage, gastrointestinal bleeding (visible bleeding or fecal occult blood), urinary bleeding (urinating blood or microscopic hematuria), vaginal bleeding (massive bleeding or prolonged menstrual period), conjunctival bleeding, and intracerebral hemorrhage. The seriousness of bleeding was assessed using the immune thrombocytopenic purpura (ITP) bleeding scoring system (14).

Laboratory features

The laboratory features were as follows: mild to severe thrombocytopenia manifested by platelet (PLT) count <50×10⁹/L, leukopenia as leucocyte count <4.0×10⁹/L, anemia as hemoglobin (HGB) <120 g/L, and hypocomplementemia with complement 3 (C3) <0.79 g/L and/or complement 4 (C4) <0.16 g/L. Rheumatoid factor (RF) (latex test positive at a value >20 IU/mL) was analyzed by enzyme-linked immunosorbent assay. Antinuclear antibodies (ANAs; positive at a titer 1:100 by indirect immunofluorescence) and 60- and 52-kDa forms of anti-Ro/SSA and anti-La/SSB antibodies were tested independently.

Statistical analysis

SPSS software version 21.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Continuous variables were compared using the Wilcoxon test, and proportions were analyzed using chi-square and Fisher’s exact test. P<0.05 was considered to indicate statistical significance.

Results

Patient characteristics

In this study, the total incidence rate of mild to severe thrombocytopenia in pSS patients was 5.1%. Among the 43 patients with mild to severe thrombocytopenia, only 3 (6.9%) were men. PSS patients with mild to severe thrombocytopenia were 17–70 years old, with a mean age of 51.69±12.43 years, while control patients were 41.46±14.89 years old. The median disease duration in the thrombocytopenia group was 18 vs. 44 months in the control group (Table 1).

Clinical features in pSS patients with mild to severe thrombocytopenia

Table 2 presents the clinical features of patients in the thrombocytopenia group. The classic manifestations of SS, such as dryness of the mouth and eyes, rampant caries, and other clinical features like fatigue, fever, and weight loss were observed. The incidence rates of xerostomia and xerophthalmia were significantly lower in the thrombocytopenia group than in the control group (P=0.0028, and P=0.0024, respectively). Of the 43 patients in the thrombocytopenia group, 17 sought admission because of thrombocytopenia and/or hemorrhagic manifestations, without exocrine gland features. Meanwhile, pulmonary interstitial disorders were more common in the control group (P=0.0088). There were no statistically significant differences in the frequency of fever, rashes, arthritis, and Raynaud phenomenon between the two groups. As expected, the thrombocytopenia group had a significantly higher EULAR Sjögren’s syndrome disease activity index (ESSDAI scores) than the control group (P<0.001).

Differences in serologic features

Not surprisingly, the PLT count in the thrombocytopenia group was markedly lower than that in the control group (P<0.001). The thrombocytopenia group had significant hypocomplementemia (C4 level) compared to the control group (P=0.0024). However, the existence of ANA, anti-SSA 60- and 52-kDa, anti-SSB, M2, anti-double-stranded DNA (anti-dsDNA), and anti-centromere antibodies (ACAs) was not obviously different between the two groups (Table 3). The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, and RF were not markedly different between the two groups. The levels of immunoglobulin A (IgA) were significantly lower in the thrombocytopenia group than in the control group (P=0.0019); however, no difference was observed between the levels of IgG and IgM in the two groups. Among the regular chemical parameters, the glutamic-pyruvic transaminase (alanine transaminase) level was significantly increased in the thrombocytopenia group (P=0.043) (Table 4).

Disease and prognosis in pSS patients with mild to severe thrombocytopenia

In the thrombocytopenia group, the most common hemorrhagic manifestations were skin bleeding, such as purpura/bruises (21 of 43, 48.8%), and gingival bleeding (17 of 43, 39.5%). There were no hemorrhagic manifestations in 14 of 43 patients (32.6%) (Table 4). At baseline, the ITP bleeding score was 1.32±1.17, and no correlation was found between hemorrhagic manifestations and treatment effect (Table 5). No patient died during the study period. Mild to severe thrombocytopenia was treated with high-dose corticosteroids and/or intravenous gamma-immunoglobulin, and hydroxychloroquine and cyclosporine were also used. During hospitalization, 35 of the 43 patients were responsive to treatment, while the remaining eight patients were not. One patient underwent splenectomy because of refractory thrombocytopenia.

Discussion

To the best of our knowledge, this is the first study to demonstrate a negative correlation between mild to severe thrombocytopenia and lung involvement in pSS. PSS is one of the major chronic inflammatory autoimmune diseases associated with B lymphocyte hyper-reactivity. Recently, the prevalence of pSS has been reported to range from 0.05% to 0.23% (15,16), and in China, the prevalence of pSS is approximately 0.33–0.77% (17). Although most patients have exocrine gland involvement, such as labial gland and lacrimal gland involvement (18), their clinical manifestation is usually quite non-specific and varied, resulting in delayed diagnosis for 3–8 years from the onset of first symptoms (19,20). In our study, all 88 patients received pathological examination of lower lip biopsy. Among the pSS patients with mild to severe thrombocytopenia, four had no lymphocytic foci; however, in pSS patients without thrombocytopenia, one had no lymphocytic foci.

The mechanisms of SS with thrombocytopenia is not clear. A few studies have shown that may be a complex immune pathology relating multiple factors，such as P-selectin (21), TLR7 signaling pathway (22) and FcγRIIb on B cells (23).

A multicentre study reported a 3.7% incidence of thrombocytopenia in patients with SS (4). In our study, 5.1% of pSS patients developed mild to severe thrombocytopenia, and among these patients, 95.3% were female. Moreover, our participants were in-patients, making our cohort similar to those in other studies. Previous studies have reported that 5–16% of pSS patients develop thrombocytopenia (17,24,25). Although there was no real distinction in the median time for diagnosis confirmation between patients with or without mild to severe thrombocytopenia, pSS patients with mild to severe thrombocytopenia had obviously higher ESSDAI scores than those without, and required longer hospitalization.

Leukopenia is the most frequent hematologic abnormality noted in pSS, and 30–40% of pSS patients may have leukopenia (8). In our study, 29.5% of patients had leukopenia, but among patients with mild to severe thrombocytopenia, the prevalence of leukopenia was significantly lower than in those without thrombocytopenia. All patients responded remarkably well to corticosteroids. Anti-neutrophil antibody may be responsible for autoimmune neutropenia (26), but the low frequency of neutropenia in pSS patients with mild to severe thrombocytopenia was not reported in previous studies; thus, further research is required. In our study, decreased levels of C4 and IgA were more common in the thrombocytopenia group, indicating a possible important complex immune mechanism in the pathogenesis of thrombocytopenia in pSS patients.

A large proportion of patients in both groups were positive for ANA. The prevalence of all autoantibodies such as anti-SSA and anti-SSB, AIM-M2, CENPB, ACA, anti-dsDNA, and U1RNP showed no remarkable differences between the two groups. For some antibodies, the absence of a significant difference may have resulted from a relatively small sample size.

Lung involvement is present in 10–20% of pSS patients (27). Among 88 patients, 21.6% had lung involvement, which fairly accorded with the results in previous study (28). The prevalence of pSS-ILD is around 20% in pSS patients (29). PSS-ILD can occur at any stage in the course, and the severity of pSS-ILD do not correlate with the manifestations of pSS. The common ILD pattern is nonspecific interstitial pneumonia, usual interstitial pneumonia and organising pneumonia, lymphocytic interstitial pneumonia in SS patients. However, in pSS patients with mild to severe thrombocytopenia, the incidence of lung involvement reduced markedly in our study. PLT-derived growth factor was reported to contribute directly to the migration of fibrocytes to the injured lungs (30). The current understanding of the pathophysiology of lung disease in pSS suggests a similar process as those in the salivary glands, with epithelial cells playing a critical role in the initiation (28). It can be assumed that pSS with lung involvement and pSS with hematological involvement have different pathological and clinical manifestations. This study has limitations that hindered the generalization of the results, including the small sample size, retrospective design, and single-center setting, etc. Thus, more research is needed on the relationship between thrombocytopenia and lung involvement in pSS.

There’s no report on the recurrence rate of thrombocytopenia in patients with pSS. The same thing happened in primary immune thrombocytopenia (ITP). Antibodies against PLT glycoproteins and inflammation has been shown to be closely related to the pathogenesis and prognosis of ITP (31). Therefore, close follow-up and avoidance of infection may be an effective way to prevent recurrence.

In conclusion, our study explored the clinical features of pSS accompanied by mild to severe thrombocytopenia. PSS patients with mild to severe thrombocytopenia could have higher ESSDAI scores than those without thrombocytopenia, but the incidence of some complications such as leukopenia and lung involvement was low. In pSS patients with mild to severe thrombocytopenia, the incidence of xerostomia, xerophthalmia, and lung involvement was markedly reduced. Thrombocytopenia could be present upon the onset of pSS development, without any involvement of the exocrine glands. Thus, there is an urgent need for more detailed classification of pSS based on its clinical manifestations and pathology. Knowledge about the features of pSS associated with thrombocytopenia will lead to earlier and better diagnosis and treatment.

Acknowledgments

We would like to thank Editage (https://www.editage.cn/) for English language editing.

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81771782, No. 81801595, and No. 81873876).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-162/rc

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-162/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-162/coif). JW, XC and CL report this work was supported by grants from the National Natural Science Foundation of China (No. 81771782, No. 81801595, and No. 81873876). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Ethics Board of The First Affiliated Hospital of Soochow University (No. 2020105). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Brito-Zerón P, Baldini C, Bootsma H, et al. Sjögren syndrome. Nat Rev Dis Primers 2016;2:16047. [Crossref] [PubMed]
2. Ramos-Casals M, Daniels TE, Fox RI, et al. Sjögren’s syndrome. In: Stone JH. editor. A clinician’s pearls and myths in rheumatology. New York: Editorial Springer, 2009.
3. Brito-Zerón P, Acar-Denizli N, Ng WF, et al. How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project). Clin Exp Rheumatol 2018;36:102-12. [PubMed]
4. Thorlacius GE, Hultin-Rosenberg L, Sandling JK, et al. Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. Rheumatology (Oxford) 2021;60:837-48. [PubMed]
5. Cafaro G, Gerli R, Bartoloni E. Association Between Glandular Infiltrate and Leukopenia in Sjögren Syndrome (SS): Data From the Italian Research Group on SS (GRISS). J Rheumatol 2020;47:1840-1. [Crossref] [PubMed]
6. Kikawada M, Watanabe D, Kimura A, et al. Autoimmune hemolytic anemia in an elderly patient with primary Sjögren's syndrome. Intern Med 2005;44:1312-5. [Crossref] [PubMed]
7. Wen W, Liu Y, Zhao C, et al. Clinical and serologic features of primary Sjögren's syndrome concomitant with autoimmune hemolytic anemia: a large-scale cross-sectional study. Clin Rheumatol 2015;34:1877-84. [Crossref] [PubMed]
8. Schattner A, Friedman J, Klepfish A, et al. Immune cytopenias as the presenting finding in primary Sjögren's syndrome. QJM 2000;93:825-9. [Crossref] [PubMed]
9. Aoki A, Ohno S, Ueda A, et al. Hematological abnormalities of primary Sjogren's syndrome. Nihon Rinsho Meneki Gakkai Kaishi 2000;23:124-8. [Crossref] [PubMed]
10. Ramakrishna R, Chaudhuri K, Sturgess A, et al. Haematological manifestations of primary Sjögren's syndrome: a clinicopathological study. Q J Med 1992;83:547-54. [Crossref] [PubMed]
11. Khattri S, Barland P. Primary Sjogren's syndrome and autoimmune cytopenias: a relation often overlooked. Bull NYU Hosp Jt Dis 2012;70:130-2. [PubMed]
12. Brito-Zerón P, Theander E, Baldini C, et al. Early diagnosis of primary Sjögren's syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol 2016;12:137-56. [Crossref] [PubMed]
13. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8. [Crossref] [PubMed]
14. Thrombosis and Hemostasis Group, Hematology Society, Chinese Medical Association. Consensus of Chinese experts on diagnosis and treatment of adult primary immune thrombocytopenia (version 2016). Zhonghua Xue Ye Xue Za Zhi 2016;37:89-93. [PubMed]
15. Birlik M, Akar S, Gurler O, et al. Prevalence of primary Sjogren's syndrome in Turkey: a population-based epidemiological study. Int J Clin Pract 2009;63:954-61. [Crossref] [PubMed]
16. Anagnostopoulos I, Zinzaras E, Alexiou I, et al. The prevalence of rheumatic diseases in central Greece: a population survey. BMC Musculoskelet Disord 2010;11:98. [Crossref] [PubMed]
17. Zhang NZ, Shi CS, Yao QP, et al. Prevalence of primary Sjögren's syndrome in China. J Rheumatol 1995;22:659-61. [PubMed]
18. Asmussen K, Andersen V, Bendixen G, et al. Quantitative assessment of clinical disease status in primary Sjögren's syndrome. A cross-sectional study using a new classification model. Scand J Rheumatol 1997;26:197-205. [Crossref] [PubMed]
19. Pavlidis NA, Karsh J, Moutsopoulos HM. The clinical picture of primary Sjögren's syndrome: a retrospective study. J Rheumatol 1982;9:685-90. [PubMed]
20. Markusse HM, Oudkerk M, Vroom TM, et al. Primary Sjögren's syndrome: clinical spectrum and mode of presentation based on an analysis of 50 patients selected from a department of rheumatology. Neth J Med 1992;40:125-34. [PubMed]
21. Hu YH, Zhou PF, Long GF, et al. Elevated Plasma P-Selectin Autoantibodies in Primary Sjögren Syndrome Patients with Thrombocytopenia. Med Sci Monit 2015;21:3690-5. [Crossref] [PubMed]
22. Zhang S, Qu J, Wang L, et al. Activation of Toll-Like Receptor 7 Signaling Pathway in Primary Sjögren's Syndrome-Associated Thrombocytopenia. Front Immunol 2021;12:637659. [Crossref] [PubMed]
23. Chen H, Zhou S, Su D, et al. High-dose methylprednisolone pulse therapy upregulated FcγRIIb expression on B cells in primary Sjögren's syndrome patients with thrombocytopenia. Clin Rheumatol 2013;32:1783-90. [Crossref] [PubMed]
24. Asmussen K, Andersen V, Bendixen G, et al. A new model for classification of disease manifestations in primary Sjögren's syndrome: evaluation in a retrospective long-term study. J Intern Med 1996;239:475-82. [Crossref] [PubMed]
25. Alexander EL, Arnett FC, Provost TT, et al. Sjögren's syndrome: association of anti-Ro(SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity. Ann Intern Med 1983;98:155-9. [Crossref] [PubMed]
26. Hartman KR, Mallet MK, Nath J, et al. Antibodies to actin in autoimmune neutropenia. Blood 1990;75:736-43. [Crossref] [PubMed]
27. Kokosi M, Riemer EC, Highland KB. Pulmonary involvement in Sjögren syndrome. Clin Chest Med 2010;31:489-500. [Crossref] [PubMed]
28. Gupta S, Ferrada MA, Hasni SA. Pulmonary Manifestations of Primary Sjögren's Syndrome: Underlying Immunological Mechanisms, Clinical Presentation, and Management. Front Immunol 2019;10:1327. [Crossref] [PubMed]
29. Sambataro G, Ferro F, Orlandi M, et al. Clinical, morphological features and prognostic factors associated with interstitial lung disease in primary Sjӧgren's syndrome: A systematic review from the Italian Society of Rheumatology. Autoimmun Rev 2020;19:102447. [Crossref] [PubMed]
30. Aono Y, Kishi M, Yokota Y, et al. Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis. Am J Respir Cell Mol Biol 2014;51:793-801. [Crossref] [PubMed]
31. Li J, Ma S, Shao L, et al. Inflammation-Related Gene Polymorphisms Associated With Primary Immune Thrombocytopenia. Front Immunol 2017;8:744. [Crossref] [PubMed]

(English Language Editor: A. Kassem)