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ReplyLetter

Drs. Rasmussen and Scofield reply

Astrid Rasmussen and R. Hal Scofield
The Journal of Rheumatology December 2020, 47 (12) 1839; DOI: https://doi.org/10.3899/jrheum.200400
Astrid Rasmussen
1Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA;
2Dirección de Investigación, Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
MD, PhD
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R. Hal Scofield
3Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation;
4Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center;
5Oklahoma City Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.
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To the Editor:

The cardinal laboratory/pathological features of Sjögren syndrome (SS) are autoantibodies (anti-Ro/SSA and anti-La/SSB) and lymphocytic infiltrate of the salivary glands. The lymphocytic infiltrate is graded by the focus score (FS)1, 2, which is the number of foci with ≥ 50 lymphocytes per 4 mm2. Much has been published about the clinical and laboratory differences found among Sjögren patients with and without autoantibodies, with the presence of anti-Ro generally associated with more severe disease2,3. However, comparatively few studies have been directed at subjects without a salivary gland lymphocytic infiltrate.

Both we4 and Carubbi, et al5 have compared primary SS patients with an FS of zero (FS = 0) to those patients with a FS ≥ 1. As noted by Carubbi and Alunno6, these 2 studies have fundamental differences. Ours is a cross-sectional study at the time of minor salivary gland biopsy4, while the other is a retrospective, longitudinal study of patients who had undergone such a biopsy in the past and an average follow-up of almost 6 years5. Thus, the results are likely to be different but complementary. This is, in fact, what we find when reviewing the results of these studies.

However, there is major difference in the analyses. Because of the many clinical associations of anti-Ro with disease features3, we controlled for the role of anti-Ro by comparing FS = 0 subjects (who must be anti-Ro+ to meet pSS classification) to FS ≥ 1/anti-Ro+ subjects. Nonetheless, the comparisons made by Carubbi, et al both in their original publication5 and in the current letter6, are also of interest. These investigators compared FS = 0 subjects to all subjects with FS ≥ 1, regardless of antibody status. Thus, we have reanalyzed our subjects in a similar manner to the Carubbi, et al study5. First, we compared FS ≥ 1/anti-Ro+ to FS ≥ 1/anti-Ro–, and found that the anti-Ro+ subjects had worse ocular staining (70.2% vs 60.4%, P = 0.0005 by chi-square analysis, OR 2.19 (95% CI 1.4–3.4), a higher mean FS (4.55 vs 2.65, P < 0.0001 by unpaired t test), but less subjective dryness by the European League Against Rheumatism (EULAR) SS Patient Reported Index (5.85 vs 7.01, P = 0.0075 by unpaired t test). Examining the EULAR SS Disease Activity Index (ESSDAI), the biological domain was more likely to be positive in anti-Ro+ subjects (63.9% vs 43.8%, P = 0.001, OR 2.1, 95% CI 1.4−3.2) and this was driven by hypergammaglobulinemia (25.3% vs 3.74%, P < 0.0001, OR 8.73, 95% CI 2.8−24.3).

When we compared all FS = 0 to all FS ≥ 1 subjects, irrespective of their anti-Ro status, we continued to find more abnormal ocular staining among those with a positive FS (65.2% vs 49.3%, P = 0.012, OR 1.9, 95% CI 1.2−3.2), as well as a higher incidence of an abnormal Schirmer test (50.1% vs 41.3%, P < 0.0001, OR 5.15, 95% CI 2.4−10.4). Thus, objective ocular dryness was less common among those without a lymphocytic infiltrate in the minor salivary glands independent of the presence of anti-Ro. Meanwhile, there was no difference in the ESSDAI biological domain (P = 0.74), supporting previous findings that hypergammaglobulinemia is strongly linked to anti-Ro positivity2,3.

These 2 studies support the notion that there are various subgroups of patients with SS; those that have mainly an autoantibody-driven disease, a second group with active cellular infiltration of target tissues, and a third subset with both lymphocytic glandular infiltration and autoantibodies. Likely, some of the underlying disease mechanisms differ as well — a consideration that may prove relevant for therapeutic choices as well as studies.

The challenges of studying SS are demonstrated in these 2 studies4,5. SS is one of few, if not the only, inflammatory rheumatic disease in which there is easy access to the affected organ; therefore, studies with full sets of data including biopsies are critically important but also difficult to assemble. A prospective inception cohort study has not been reported. So, for now cross-sectional and retrospective studies remain the standard.

Footnotes

  • This work was supported in part by VA Merit Review 5I01BX001451 as well as National Institutes of Health grants AR053734, AR053483, AI082714, and GM104938.

REFERENCES

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    1. Fisher BA,
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    3. Daniels T,
    4. Bombardieri M,
    5. Brown RM,
    6. Morgan P,
    7. et al.
    Standardisation of labial salivary gland histopathology in clinical trials in primary Sjogren’s syndrome. Ann Rheum Dis 2017;76:1161–8.
    OpenUrlAbstract/FREE Full Text
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    1. Fayyaz A,
    2. Kurien BT,
    3. Scofield RH
    . Autoantibodies in Sjogren’s syndrome. Rheum Dis Clin North Am 2016 Aug;42:419–34.
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    1. Brito-Zeron P,
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    How immunological profile drives clinical phenotype of primary Sjogren’s syndrome at diagnosis: analysis of 10,500 patients (Sjogren Big Data Project). Clin Exp Rheumatol 2018;36 Suppl 112:102–12.
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    3. Kurien BT,
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    7. et al.
    Sjogren syndrome without focal lymphocytic infiltration of the salivary glands. J Rheumatol 2020;47:394–9.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Carubbi F,
    2. Alunno A,
    3. Cipriani P,
    4. Bartoloni E,
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    6. Quartuccio L,
    7. et al.
    A retrospective, multicenter study evaluating the prognostic value of minor salivary gland histology in a large cohort of patients with primary Sjogren’s syndrome. Lupus 2015;24:315–20.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Carubbi F,
    2. Alunno A
    . The serological status affects the prognostic role of salivary gland histology in primary Sjögren syndrome. J Rheumatol 2020;47:1838–9.
    OpenUrlFREE Full Text
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