Objectives Guidelines advise to test for anti–Sjögren's-syndrome-related antigen A (anti-SSA) and anti–Sjögren's-syndrome-related antigen B (anti-SSB) antibodies in all patients with rheumatoid arthritis (RA) who wish to conceive. Our objective was to determine the prevalence and titres of anti-SSA and anti-SSB autoantibodies in patients with RA with a wish to conceive or pregnant.
Methods Patients were derived from two large cohorts on RA and pregnancy (PARA cohort and PreCARA cohort). In addition, to determine the clinical relevance of searching for anti-SSA and anti-SSB in patients with RA, we studied the prevalence of the maternal diagnosis of RA in the French national registry of neonatal lupus syndrome (NLS) and congenital heart block (CHB).
Results 26 out of 647 patients with RA had detectable anti-SSA and/or anti-SSB. Anti-SSA was detected in 25 out of 647 patients (3.9%) (Ro-52, n=17; Ro-60, n=19), anti-SSB in 7 out of 647 (1.1%). Thirteen women had a titre of >240 units/mL of anti-SSA antibodies. The prevalence of anti-SSA and/or anti-SSB was higher in rheumatoid factor (RF)-positive patients compared with RF-negative patients (5.1% vs 1.6%, p=0.04). No cases of CHB and/or NLS in the offspring were observed. In the French national register, the prevalence of RA in mothers with SSA related CHB was 1.5%.
Conclusion Anti-SSA and anti-SSB have a low prevalence in patients with RA who wish to conceive. Especially for RF-negative patients, the current advise to test for anti-SSA and anti-SSB should be reconsidered.
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What is already known about this subject?
The presence of maternal anti–Sjögren's-syndrome-related antigen A (anti-SSA) and anti–Sjögren's-syndrome-related antigen B (anti-SSB) autoantibodies is associated with congenital heart block and neonatal lupus syndrome.
Current American College of Rheumatology(ACR) guidelines on the management of rheumatic diseases during the reproductive period recommend to test for anti-SSA and anti-SSB antibodies in all patients with rheumatoid arthritis with a wish to conceive.
What does this study add?
Women with rheumatoid arthritis in their reproductive age have a low prevalence and low titres of anti-SSA and anti-SSB antibodies. In particular in rheumatoid factor-negative patients, anti-SSA and anti-SSB autoantibodies are uncommon.
The prevalence of rheumatoid arthritis in mothers with anti-SSA-related congenital heart block is 1.5%.
How might this impact on clinical practice or future developments?
If our findings can be replicated in other cohorts, it is justified to critically review the current guidelines on testing for anti-SSA and anti-SSB autoantibodies in women with rheumatoid arthritis. Especially for rheumatoid factor-negative patients with a wish to conceive, the current advise to test for anti-SSA and anti-SSB could be reconsidered.
Anti–Sjögren's-syndrome-related antigen A (anti-SSA oranti-Ro, including Ro-52 kDa and Ro-60 kDa subunits) and anti–Sjögren's-syndrome-related antigen B (anti-SSB oranti-La) autoantibodies are frequently reported in patients with systemic lupus erythematosus (SLE) and Sjögren syndrome (SS).1
The association between maternal levels of anti-SSA autoantibodies and complete congenital heart block (CHB) and neonatal Lupus syndrome (NLS) is well established, with CHB occurring in 1%–2% of fetuses exposed to anti-SSA.1 Moreover, the level of maternal antibodies is associated with fetal complications; higher levels of anti-SSA correlate with a higher risk of cardiac complications whereas pre-natal exposure to high titres of anti-SSB is associated with non-cardiac features of NLS.2 Intensive preventive echocardiographic screening strategies have been developed for high-risk women to detect conversion to a CHB in early stage, however, their usefulness is currently questioned.3
Nevertheless, the ‘2020-ACR-Guideline-for-the-Management-of-Reproductive-Health-in-Rheumatic-and-Musculoskeletal-Diseases’ recommends to screen for anti-SSA and anti-SSB in all patients with rheumatoid arthritis (RA) who are planning pregnancy or who are pregnant.4 Hence, highlighting the importance of knowledge on the prevalence of anti-SSA and anti-SSB in this patient group. Until now, no studies on the presence of these autoantibodies in patients with RA in the reproductive age have been published.
The objective of this study is to determine the prevalence and titres of anti-SSA and anti-SSB autoantibodies in patients with RA and a wish to conceive and to determine the clinical relevance of searching for anti-SSA and anti-SSB in patients with RA by analysing the prevalence of the maternal diagnosis of RA in the French national registry of NLS and CHB.
Participants were derived from two cohort studies on RA and pregnancy: PARA-cohort5 and the ongoing PreCARA-cohort.6 These studies were approved by the Erasmus MC ethics review board in compliance with the Helsinki declaration. All patients with RA were over 18 years of age and gave informed consent.
Study procedures for both PARA and PreCARA cohorts are extensively described previously.6 7 Blood was collected at every visit, serum samples were stored at −80°C.
The presence and titres of anti-SSA (both Ro-52 kDa and Ro-60 kDa subunits) and anti-SSB were quantitatively determined by fluorescence-enzyme immunoassay (FEIA) using EliA technology on the Phadia-250 system according to manufacturer’s instructions (Thermo Fisher Scientific, Freiburg, Germany). The upper limit of quantification for this test is >240 units/mL for anti-SSA and >340 units/mL for anti-SSB. Normal range for both antibodies is <7 units/mL.
In a previous study on maternal anti-SSA antibodies as a prognostic marker, ELISA was used to determine these antibodies.2 To allow quantitative comparison of our anti-SSA FEIA results with the anti-SSA ELISA results, we determined a conversion factor between both assays.
Descriptive statistics are shown as numbers (n) and percentages (%). Values are presented as mean±SD or median±IQR. Categorical data were tested using Fisher’s-exact or χ2 tests, continuous data were tested using Student’s t-test or Wilcoxon-rank. A two-sided p value of <0.05 was considered significant. All statistical analyses were performed using Stata V.16 (StataCorp-LP).
Maternal diagnosis of auto-immune disease in fetuses with CHB
To determine the clinical relevance of anti-SSA and anti-SSB in patients with RA, data of the French national registry of NLS and CHB were obtained. The data include fetuses or children born to mothers with anti-SSA and/or anti-SSB antibodies and were previously published by Levesque et al.8 In this cohort, we studied the prevalence of a maternal diagnosis of RA among all maternal diagnoses of an autoimmune disease.
Twenty-six out of six hundred and forty-seven patients with RA with a wish to conceive had detectable anti-SSA and/or anti-SSB antibodies: anti-SSA was detected in 25 (3.9%) (Ro-52 n=17, Ro-60 n=19), anti-SSB in 7 patients (1.1%). Table 1 shows a detailed description of the study population stratified for the presence of anti-SSA and/or anti-SSB. The prevalence anti-SSA and/or anti-SSB was higher in rheumatoid factor (RF)-positive patients compared with RF-negative patients (5.1% vs 1.6%, p=0.04). This observation was not seen for anti–citrullinated protein antibody(ACPA) (p=0.99).
Titres of anti-SSA and anti-SSB antibodies
Thirteen (52% of the anti-SSA positive patients, 2.0% of the total population) patients had a titre of >240 units/mL of anti-SSA antibodies (table 2). Three (42.9% of the anti-SSB positive patients, 0.46% of the total population) patients had titres >340 units/mL, two of these patients had combined anti-SSA titres of >240 units/mL, the titre of anti-SSA in the remaining patient was 159 units/mL. One patient only had anti-SSB antibodies, and no anti-SSA. The titre of anti-SSB in this patient was 8.5 units/mL.
CHB and NLS
No cases of CHB or NLS were observed in the PARA and PreCARA cohort.
Maternal diagnosis of RA in fetuses with congenital atrioventricular block in the French national registry of NLS and CHB
Fifty-one out of one hundred and ninety-five mothers (26.3%, 1 missing data) with CHB in the French national registry of NLS and CHB had a diagnosis of autoimmune disease. Three (1.5% of the total population, 5.9% of the patients with an autoimmune disease) of these women had RA. One patient with RA (unknown RF and/or ACPA status) had an overlap-syndrome with SLE. The other two had an isolated diagnosis of RA (one patient: unknown RF and/or ACPA status, the other patient RF positive, ACPA status unknown). None of the cases of NLS within this cohort were born to mothers with RA.
Conversion factor between current FEIA and previous ELISA to determine anti-SSA antibodies
A conservative conversion factor of 3.2 between both anti-SSA assays was determined (online supplemental figure 1).
In this first article on the presence of anti-SSA and anti-SSB in women with RA in their reproductive age, we showed that the prevalence of these antibodies in this patient population is low. The prevalence of these antibodies was higher in RF-positive patients compared with RF-negative patients.
We observed a lower prevalence of anti-SSA in patients with RA compared with previous studies. A study by Cavazzana et al (n=195) observed a prevalence of anti-SSA of 6%9 in patients with RA, differences in patients characteristics like, higher age and increased coexisting SS/SLE are most likely attributing to this observation. Although anti-SSA is probably the most prevalent autoantibody found in the general population, data are scarce10: in a Japanese study, 58/2181 (2.7%) healthy residents had detectable anti-SSA antibodies.11 Their observed prevalence of anti-SSA is only slightly lower to that we observed in the total RA population in the current study (3.9%), and comparable to what we observed in RF-negative patients (1.6%).
The occurrence of CHB in the presence of anti-SSA is depended on the titre of these antibodies. Jaeggi et al showed that women with low anti-SSA antibody titres have almost no risk of CHB and only antibody titres of >100 units/mL are clinically relevant.2 Our observed titres cannot be compared with the titres observed by Jeaggi et al directly, since we used a different quantification method. We compared both quantification methods (online supplemental figure 1), the proposed ‘high titres’ of 100 units/mL as measured by ELISA probably best correspond with the upper detection limit of >240 units/mL in FEIA. Therefore, the prevalence of patients with clinically relevant titres of anti-SSA is probably around 2%.
To determine the clinical relevance of anti-SSA and/or anti-SSB in patients with RA, we showed that in the French CHB register, only 1.5% of all cases were observed in women diagnosed with RA. This observation was in line with previous literature, in which no maternal diagnosis of RA in children born with congenital cardiac manifestations related to anti-SSA were observed.12
Almost all patients that have anti-SSB antibodies have concomitant anti-SSA antibodies,1 an observation which is confirmed in our study. The role of anti-SSB-antibodies in the development of CHB is uncertain, most literature suggests that the development of immune mediated CHB is associated to fetal exposure to high titres of anti-SSA, whereas the presence of anti-SSB may not be required.2 Taking into account both this insight and the low observed prevalence of anti-SSB in patients with RA with a wish to conceive, testing for anti-SSB antibodies in patients, as advised by current guidelines, might not be appropriate.
Intensive surveillance in patients with anti-SSA antibodies has been the dogma for decades. However, CHB is rarely discovered and if so, there is no known effective therapy for CHB, especially since fluorinated steroids failed to demonstrate their efficacy.3 13 Consequently, the 2016 EULAR recommendations on pregnancy and SLE/APS stated that the cost-effectiveness of intensive surveillance with fetal echocardiography in patients with anti-SSA and anti-SSB and no previous child with CHB remains to be established.14 They also recommended against performing systematic fetal echocardiography but only to do so in cases of suspected fetal dysrhythmia or myocarditis.14 We showed a low prevalence of anti-SSA in patients with RA with a wish to conceive. Therefore, even if these antibodies were to be detected the consequences are more than uncertain.
Some limitations need to be considered, due to the low number of patients with detectable anti-SSA and/or anti-SSB, we were unable to test associated factors with these antibodies in a multivariate analysis. And, total anti-nuclear antibody titres and titres of ACPA and RF were not available. Furthermore, due to the absence of CHB in our cohort of patients with RA we were unable to determine valuable clinical cut-off points for anti-SSA titres in patients with RA. Based on the nature of this condition, scientific consensus on testing can only be achieved by replicating our results in other study populations.
In conclusion, anti-SSA and anti-SSB have a low prevalence in patients with RA with a wish to conceive. Moreover, in the French national registry of NLS and CHB maternal diagnosis of RA was infrequent. If our findings could be replicated in other studies, it is justified to critically review the current guidelines. Especially since the practical consequences of finding these antibodies is currently questioned. In particular for RF-negative patients the current advise to test for both anti-SSA and anti-SSB can be reconsidered.
Approval obtained (MEC-214.320/2002/117 and MEC-2011-032).
We thank all participants of the PreCARA and PARA studies. Additionally, we extend our gratitude to the laboratory workers, in particular Nadine Davelaar and Priyanka Bangoer, and research assistants for their contribution to the data collection. We thank ReumaNederland (LLP project number: LLP-26) for their financial support. The kits for measurement of anti-SSA and anti-SSB were a kind gift from Thermo Fischer Scientific. We also thank Thermo Fischer Scientific for providing the original results of the anti-SSA FEIA versus ELISA comparison.
Presented at This work was previously presented at the EULAR 2021 virtual congress (POS0541).
Contributors All authors met the authorship criteria, they had a substantial contribution to the conception or design of the work (HS, MWJS, JMJC, RJEMD) or the acquisition (MWJS, RJEMD, NC-C), analysis (HS, RJEMD) or interpretation of data for the work (all authors) and were involved in revising a draft of this work, gave final approval of this version to be published and are accountable for all aspects of the work in ensuring accuracy and integrity.
Funding This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26). The kits for measurement of anti-SSA and anti-SSB were a kind gift from Thermo Fischer Scientific.
Competing interests None declared.
Patient and public involvement statement Patients were involved in the design of the PARA and PreCARA cohorts. We obtained input from patients in the design of the questionnaires, materials and management. We carefully assessed the burden on participating patients and intend to share the results to participating patients.
Provenance and peer review Not commissioned; externally peer reviewed.