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Reumatologia/Rheumatology
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4/2021
vol. 59
 
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Case-based review

Sicca syndrome in the same family – the importance of anti-Ro60, anti-Ro52 and anti-La antibody profiling in Sjögren’s syndrome

Arkadiusz Koszarny
1
,
Maria Majdan
1

1.
Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, Poland
Reumatologia 2021; 59, 4: 260–264
Online publish date: 2021/08/20
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Introduction

Sjögren’s syndrome (SS) is one of the most common rheumatic autoimmune diseases. It is a chronic condition characterized by lymphocytic infiltration of exocrine glands and impairment of their function, which manifests with symptoms of ocular and oral dryness. Sjögren’s syndrome can lead to changes in internal organs and significantly increases the risk of developing lymphoma [1]. Sjögren’s syndrome is relatively often comorbid with other autoimmune disorders and diseases associated with the presence of organ-specific antibodies. It can also run in families, as the cause of SS has a genetic background.
Current classification criteria for the diagnosis of SS, developed by the American College of Rheumatology and the European League Against Rheumatism (EULAR), were published in 2016 [2]. They include five items: anti-SSA/Ro antibody posi­tivity, focal lymphocytic sialadenitis on minor salivary gland biopsy (focus score ≥ 1), an abnormal ocular staining score (lissamine green test), a Schirmer’s test result of ≤ 5 mm/5 min in at least one eye, and an unstimulated salivary flow rate of ≤ 0.1 ml/min. Until 2016, both anti-SSA/Ro and anti-SSB/La auto­antibodies had been considered to be marker antibodies for primary Sjögren’s syndrome (pSS). Anti-SSA/Ro auto­antibodies alone have been associated for years with the occurrence of SS and systemic lupus erythematosus (SLE) [3]. Importantly, there are two subtypes of SSA/Ro auto­antigen: Ro60 and Ro52. They are coded by different cDNAs. The Ro52 antibody works in the process of ubiquitination and regulates production of type-1 interferon. The Ro60 antibody works as quality control for misfolded RNA. In pSS, anti-SSA/Ro autoantibodies are found in 60–70% of patients, but the latest research indicates that they can be present in up to 90% of cases. In lupus erythematosus, the occurrence of anti-SSA/Ro autoantibodies is estimated at 36–64% [4].
Recently, the need for separate detection of anti-Ro60 and anti-Ro52 antibodies has been discussed, as researchers have noted that they may be associated with different phenotypes in systemic connective tissue diseases [5, 6].

Material and methods

In this paper the analysis of current literature and a description of a pSS patient case in the light of presence of anti-SSA types (anti-Ro52 and anti-Ro60) and anti-SSB/La antibodies are presented. We intend to review the potential significance of anti-Ro60, anti-Ro52 and anti-La antibody profiling in the management of connective tissue diseases. Analysis of the literature was performed using the PubMed database and the key words ‘primary Sjögren’s syndrome’, ‘anti-Ro60’, ‘anti-Ro52’. The case description concerns a 41-year-old female patient with diagnosis of pSS and with family history of autoimmune diseases, and her three daughters, who were under observation for rheumatic disease due to sicca symptoms.

Results

The literature search of the PubMed database revealed 19 articles, of which 13 were published in the last 10 years (2011–2021). Articles based on patients with SS that are clinically relevant and present patient groups depending on their serological profile, at least anti-Ro, are especially included [8–15]. Articles excluded from the analysis were: editorial (1) and older than 25 years (1), both focused on other matters (Fig. 1).

Case description

A 41-year-old woman presented with a four-year history of pSS with positivity of Ro60, Ro52 and La anti­bodies, with secondary vasculitis, and autoimmune thyroiditis (AT) as well as with persistent disease activity assessed using the EULAR Sjögren’s syndrome disease activity index (ESSDAI) > 5. The patient is under medical monitoring by a rheumatologist. The patient’s sister has been diagnosed with SLE, and another with granulomatosis with polyangiitis (GPA). All three of the patient’s daughters, 20, 18 and 15 years old, had been examined by an ophthalmologist as they had reported symptoms of eye dryness and conjunctival hyperemia. After the ophthalmological examination, which included Schirmer’s test, they were referred to a rheumatologist for further evaluation for a systemic connective tissue disease (with SS indication). Table I shows the patients’ serological antinuclear antibody (ANA) profiles, and Table II presents the SS classification criteria for all observed patients. The presented data were collected during hospitalization at the rheumatology department upon first contact with each patient.
The 20-year-old daughter reported pain in the small joints of the hands and knee joints accompanied by morning stiffness, and symptoms of dry eyes and mouth. With a Ro60+Ro52–La– antibody profile and a positive Schirmer’s test, she met the 2016 criteria for SS (score of 4) [2] – see Table II. Investigations showed the following: ANA indirect immunofluorescence (IIF) method (involving human epithelial cell line) was negative; result of extractable nuclear antigen (ENA) test semi-quantitative method: anti-Ro60 positive (+). The patient was also diagnosed with AT. At one-year follow-up, investigations still showed the ANA IIF test negative; results of ENA test: anti-Ro60 positive (++); and Schirmer’s test positive (1 mm/5 min in each eye). The patient was placed on long-term hydroxychloroquine (HCQ) therapy due to diagnosis of undifferentiated connective tissue disease in the rheumatologist’s opinion.
The 18-year-old daughter reported mild joint pain for the previous 3 years and symptoms of dryness of the eyes and mouth meeting the pSS criteria. Investigations showed the following: ANA IIF test and ENA test: both negative, Schirmer’s test positive. Laboratory findings revealed hyperchloremia and vita­min D3 deficiency. Biopsy of the minor salivary gland and unstimulated whole salivary flow were not performed due to labial herpes zoster infection. Autoantibody tests repeated at a one-year follow-up were negative for ANA and ENA. The patient was treated with eye drops and had supplementation of vitamin D3. The 15-year-old daughter reported dry eye symptoms for several previous years, frequent relapses of conjunctival hyperemia, and recurrent cheek erythema. On physical examination, the patient had livedo reticularis. In performed immunological testing the ANA IIF test was positive and the result of the ENA test showed high positivity of anti-Ro52 antibodies (+++).
The patient was diagnosed with pSS, and HCQ the­rapy was initiated. We presume that biopsy of the minor salivary gland was not performed due to the young age and final diagnosis of pSS. Because the patient is a teenager and is followed up at the place of residence, we do not have access to her current medical records. To sum up, all three daughters of the patient with pSS were placed under observation for rheumatic disease immediately after referral by an ophthalmologist. The eldest (20 years) and the youngest (15 years) daughters were diagnosed with an autoimmune disease – pSS. Both met the 2016 criteria for pSS. So far they are being treated with HCQ. All procedures leading to confirmation of the diagnosis of pSS should be performed (see Table II).
The limitations of the comparative analysis of cases may be the decision not to perform a biopsy due to the young age and coexisting infection in the area of the biopsy, but in some cases other results of the study allowed conclusions to be drawn according to current classification criteria.

Discussion

The current classification criteria for pSS developed in 2016 [2] include only anti-SSA/Ro antibody, while the latest literature postulates separate detection of anti-Ro60 antibodies and anti-Ro52 in the diagnosis of systemic diseases due to the different clinical associations of those autoantibodies and their different correlations with the findings of additional laboratory tests. Given the above and the already demonstrated differences in clinical utility of anti-SSA/Ro and anti-SSB/La autoantibodies in the analysis of systemic autoimmune diseases [7], it seems reasonable that anti-Ro60 and anti-Ro52 antibodies should be determined separately. In a study by Robbins et al. [8], the Ro60+Ro52– profile was common in patients with SLE, in whom a possible association with antiphospholipid antibodies was also demonstrated. This profile was also found in our patient’s two daughters (20 and 15 years old), both of whom were positive for ENA (Ro60 and Ro52). Although pSS most closely corresponds to the Ro60+Ro52+La+ profile (at risk of lymphoma [9]) and – when anti-La is not taken into account – the Ro60+Ro52+ profile, the results of previous studies on pSS are not unequivocal. In Sjögren’s syndrome patients, a strong association with the presence of antibodies against Ro52 has been demonstrated [10, 11]; on the other hand, anti-Ro52 did not co-occur with anti-Ro60 equally frequently in those patients [16].
Gkoutzourelas et al. [12] made the same observation for systemic sclerosis (SSc): reactivity against Ro52-1 was significantly more frequent in the Ro52+Ro60+ than in the Ro52+Ro60– profile. In this context, it seems sound, from the point of view of diagnosis, to detect anti-Ro60 and anti-Ro52 separately in patients with suspected systemic autoimmune disease. Anti-Ro52 alone is no longer treated as a marker of pSS due to its lack of specificity in the absence of other autoantibodies [8]. Isolated anti-Ro52 is more commonly associated with idiopathic inflammatory myositis (IMM), primary biliary cholangitis (PBC), rheumatoid arthritis (RA) and pSS patients [9]. Also Dugar et al. [6] associated anti-Ro52 presence with IMM, and confirmed that anti-Ro52 was signifi­cantly more frequent than anti-Ro60 in patients with IMM, SSc, PBC, mixed essential cryoglobulinemia and pSS. Separately, anti-Ro60 reactivity correlated with oral ulcers and co-existed with anti-Sm and anti-nRNP/Sm antibodies [9]. Thus, determination of anti-Ro60 may prove to be sufficient in the diagnosis of systemic diseases, in particular SLE beside SS. It was reported in 2002 that Ro60+52– and Ro60+52+ and even Ro60+52+La+ profiles predispose to SLE [14].
According to the current literature, anti-SSA/Ro antibody positive patients may differ from patients without those marker antibodies in clinical symptoms, findings of other laboratory tests, and prognosis [17]. This observation may have practical implications for the follow-up of the patients described in this case study and their further evaluation, in particular in relation to salivary gland biopsy.
La Paglia et al. [15], in a study concerning ultrasound salivary gland examination, found that Ro60+ and Ro52+60+ profiles were associated with the severity of parotid involvement in pSS patients. In a study by Park et al. [17], patients with pSS who were negative for anti-SSA autoantibodies were less likely to show rheumatoid factor positivity, leukopenia, hypergammaglobulinemia, and lower 2-microglobulin levels, and were more likely to show anti-centromere antibody positivity, dryness symptoms, tooth loss, and involvement of the peripheral nervous system. Meek et al. [13] found that both Ro-60 and Ro-52 epitopes were strongly associated with pSS recognition but not with RA with keratoconjunctivitis sicca.

Conclusions

Due to the increased familial incidence of systemic connective tissue diseases, young age, female gender, early onset of characteristic clinical symptoms, and the diagnosis of AT, the patients described in our study should be subjected to further careful rheumatological monitoring, including evaluation for a possible diagnosis of SLE.
In the light of the current investigations into ANA profiling, further research is needed to find new marker antibodies and methods of their quantification as well as new diagnostic methods for pSS and other autoimmune systemic diseases. The authors declare no conflict of interest.

References

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Copyright: © 2021 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.






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