10-year follow-up of patients with rheumatoid arthritis and secondary Sjögren's syndrome or sicca symptoms in daily clinical practice

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10-year follow-up of patients with rheumatoid
                  arthritis and secondary Sjögren’s syndrome or
                     sicca symptoms in daily clinical practice
       R.V. Moerman1, S. Arends1, E. Mossel1, F.G.M. Kroese1, A. Vissink2, H. Bootsma1

1
 Department of Rheumatology and             ABSTRACT                                    ca symptoms. These patients had lower
Clinical Immunology, and 2Department        Objective. To evaluate the presence         gland function and worse patient-re-
of Oral and Maxillofacial Surgery,          of sicca symptoms and secondary             ported outcomes.
University of Groningen, University
                                            Sjögren’s syndrome (SS) and the as-
Medical Centre Groningen,
the Netherlands.                            sociation with clinical characteristics,    Introduction
                                            functional tests and patient-reported       Sicca symptoms of eyes and mouth are
Rada V. Moerman, MD
Suzanne Arends, PhD                         outcomes in patients with rheumatoid        rather common in patients with rheu-
Esther Mossel, MD                           arthritis (RA) at baseline and after 10     matoid arthritis (RA) (1-6). These sicca
Frans G.M. Kroese, PhD                      years of follow-up.                         symptoms can be due to a variety of dis-
Arjan Vissink, DMD, MD, PhD                 Methods. A cohort of RA patients was        eases that are associated with RA and/
Hendrika Bootsma, MD, PhD                   evaluated in 2008 and re-evaluated in       or the use of xerogenic medication that
Please address correspondence to:           2018 with respect to sicca symptoms,        patients take because of these diseases
Hendrika Bootsma,                           presence of secondary SS according to       (7). More specifically, RA patients with
Department of Rheumatology                  AECG classification criteria, disease       sicca symptoms as main complaint can
and Clinical Immunology,
University Medical Centre Groningen,
                                            activity of RA and patient-reported         suffer from secondary Sjögren’s syn-
P-O. Box 30.001,                            outcomes. Patient characteristics were      drome (SS) (8-11).
9700 RB Groningen, the Netherlands.         compared between the RA-non-sicca,          SS is a chronic autoimmune inflamma-
E-mail: h.bootsma@umcg.nl                   RA-sicca and RA-SS groups.                  tory disease characterised by progres-
Received on March 21, 2020; accepted        Results. Of the original 2008 cohort        sive focal lymphocytic cell infiltration of
in revised form on July 13, 2020.           of 96 RA patients, 32 (33%) had sicca       the salivary and lacrimal glands giving
Clin Exp Rheumatol 2020; 38 (Suppl. 126):   symptoms and 6 (6.3%) secondary SS.         rise to focal sialoadenitis with, amongst
S64-S72.                                    Of the 36 patients who agreed to be re-     others, the sensation of a dry mouth (xe-
© Copyright Clinical and                    evaluated in 2018, 6 (17%) had sicca        rostomia) and dry eyes (keratoconjunc-
Experimental Rheumatology 2020.             symptoms and 2 (6%) developed sec-          tivitis) as a result. Moreover, extra glan-
                                            ondary SS. In the majority of patients,     dular manifestations can occur in the
Key words: secondary Sjögren’s              sicca symptoms were reversible while        course of SS (12). Sicca symptoms and
syndrome, rheumatoid arthritis,             the functional tests of salivary and lac-   rheumatic nodules are the most com-
sicca symptoms                              rimal glands significantly decreased.       mon extra-articular manifestations in
                                            67% of RA-sicca patients had no sicca       RA patients (2). Therefore, RA patients
                                            complaints at the second screening,         with sicca symptoms should be evaluat-
                                            while only two RA-sicca patients devel-     ed for secondary SS because of the risks
                                            oped secondary SS. RA-SS patients and,      of excessive fatigue, early dental loss,
                                            to a slightly lesser extent, RA-sicca pa-   damage of the cornea, desiccation of the
                                            tients had significantly higher RA dis-     oral mucosa, oral infections, increased
                                            ease activity (DAS-28), lower lacrimal      risk of developing mucosa associated
                                            (Schirmer’s test) and salivary gland        lymphoid tissue (MALT) lymphomas,
                                            function, more limitations in daily ac-     and increased mortality (13-16). Addi-
                                            tivities (HAQ), worse health-related        tionally, treatment choice of RA should
                                            quality of life (RAND-36), more fa-         be carefully evaluated if SS is present,
                                            tigue (MFI) and more patient symptoms       as some treatment modalities, like meth-
                                            (ESSPRI) compared to RA-non-sicca           otrexate, can predispose to lymphoma,
                                            patients.                                   in particular the development of MALT
                                            Conclusion. Secondary SS was found          lymphoma (17).
                                            in a minor subset of the RA patients.       Several clinical characteristics of RA
                                            Sicca symptoms of the eyes or mouth         have been reported to be associated with
                                            were more frequent, but their presence      SS: RA patients with longstanding dis-
                                            varied over time. Higher RA disease         ease, female gender, high disease activ-
Competing interests: none declared.         activity was associated with SS and sic-    ity, high titers of rheumatoid factor, ero-

S-64                                                                                     Clinical and Experimental Rheumatology 2020
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

sions and extra-articular manifestations      Table I. Patient questionnaire for the assessment of xerostomia and ocular dryness based on
are at risk of developing sicca symp-         sicca questionnaire from the AECG 2002 classification criteria (27).
toms and SS (10, 11, 18-22). Most stud-
                                              1.       Did you have daily, persistent, troublesome dry eyes for more than 3 months?
ies evaluated either sicca complaints
                                              2.       Do you have a recurrent sensation of sand or gravel in the eyes?
among the RA patients or secondary SS
                                              3.       Do you use tear substitutes more than 3 times a day?
in RA patients. We are not aware of the
studies that compared sicca complaints        4.       Did you have daily feeling of dry mouth for more than 3 months?
and secondary SS simultaneously and           5.       Did you have recurrently or persistently swollen salivary glands as an adult?
prospectively. Furthermore, little is         6.       Do you frequently drink liquids to aid in swallowing dry food?
known whether sicca symptoms change
over time and if RA patients with sicca       antibodies (anti-CCP), antinuclear anti-           posal and concluded that formal approv-
symptoms will develop secondary SS            bodies (ANA), anti-SSA/SSB antibod-                al was not required as we looked to the
over time. In the present study, we as-       ies, and immunoglobulin’s (IgG, IgA,               patients from the standard of care point.
sessed the prevalence and progression         IgM) were measured.
of sicca symptoms and secondary SS            To assess sicca symptoms, a sicca-ques-            Statistical analysis
over time and the association with clini-     tionnaire was applied (Table I). Patients          Results are presented as number of
cal characteristics, functional tests and     reporting at least one sicca symptom of            patients (%) for categorical data and
patient-reported outcomes in a cohort         the eyes or mouth were classified into             mean±SD (median) for continuous data.
of RA outpatients.                            the RA-sicca group. All patients from              Three groups were distinguished: RA-
                                              the sicca group underwent a diagnostic             non-sicca group, RA-sicca group and
Methods                                       work-up for the presence of secondary              RA-SS group. Because the sample
In 2008, established RA patients were         SS according to the American-Euro-                 size of RA-SS group was small, non-
randomly selected from eligible RA            pean Consensus Group (AECG) clas-                  parametric statistics were used to com-
patients attending our outpatient clinic.     sification criteria as applied in daily            pare clinical characteristics, functional
Patients were selected by appointment         clinical practice (25, 26). In addition            tests and patient-reported outcomes.
time: RA patients who had an appoint-         to whole saliva, submandibular/sublin-             Continuous parameters were overall
ment at 9.00, 10.00 and 11.00 o’clock         gual (SM/SL) and parotid (PAR) saliva              compared between these three groups
were asked to participate. Patients           were collected to assess salivary gland            with Kruskal-Wallis test. Only param-
were included if they were 18 years           function. Glandular saliva was collect-            eters with a p value ≤0.05 were further
or older and have been diagnosed with         ed in pre-weighed plastic tubes from               tested between each two groups with
RA according to American College of           each parotid gland and simultaneously              Mann-Whitney test. For categorical
Rheumatology 1987 criteria (23). All          from the submandibular/sublingual                  parameters, Chi-Square test was used,
patients were on a routine six month re-      (SM/SL) glands by syringe aspiration.              followed by Chi-Square or Fisher’s ex-
call schedule by their rheumatologist or      The first five minutes unstimulated sali-          act test. Additionally, univariable and
had, due to their disease activity, more      vary secretions was collected, followed            multivariable logistic regression analy-
frequent visits. As the development of        by citric acid stimulated secretions               ses were used to assess the associations
sicca complaints made RA patients sus-        over 10 minutes (27, 28). Schirmer’s               between sicca symptoms or secondary
pect to have developed secondary SS,          test was performed to assess lacrimal              SS and disease activity parameters cor-
these RA patients with sicca complaints       function (29). Patients were asked to              rected for potential confounders (age,
were subjected to a routine diagnostic        complete the Health Assessment Ques-               sex, and RA duration) at baseline.
Sjögren’s work-up according to normal         tionnaire (HAQ) to assess functional               To explore if there was potential bias in
clinical practice. Patients with a his-       status, RAND-36 questionnaire to asses             the selection of patients, Independent
tory of HIV, hepatitis C, head and neck       health-related quality of life and Mul-            Samples t-test or Mann Whitney U-test
radiotherapy, pre-existing lymphoma,          tidimensional Fatigue Inventory (MFI)              and Chi-Square or Fisher’s Exact test
sarcoidosis, graft versus host disease        to assess fatigue (30-32).                         were used as appropriate to compare
and diabetes mellitus were excluded           In 2018, all RA patients who partici-              baseline characteristics of the patients
from the study. Disease activity of RA        pated in the screening in 2008 were                from 2008 who did and did not take
was measured by a rheumatologist us-          asked to participate again. The identi-            part in the screening in 2018.
ing Disease Activity Score of 28 joints       cal screening protocol as in 2008 was              Clinical characteristics, functional tests
(DAS-28 score) (24). Age of onset of          applied in 2018. In addition, patients             and patient-reported outcome of RA pa-
RA, duration of RA, presence of ero-          were asked to complete the EULAR                   tients who participated in the screening
sions and extra-articular manifestations,     Sjögren’s Syndrome Patient Reported                in 2018 were compared over time (2008
and current medication were record-           Index (ESSPRI) to assess patient symp-             vs. 2018) with Paired Samples t-test or
ed. Laboratory parameters, including          toms of dryness, fatigue and pain (33).            Wilcoxon Signed Rank test for continu-
erythrocyte sedimentation rate (ESR),         The Medical Ethical Committee of the               ous parameters and McNemar test for
C-reactive protein (CRP), rheumatoid          University Medical Centre Groningen,               categorical parameters.
factor (RF), anti-citrullinated protein       the Netherlands, assessed the study pro-           Finally, clinical characteristics, func-

Clinical and Experimental Rheumatology 2020                                                                                            S-65
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

Table II. Clinical characteristics of RA patients with SS, with sicca symptoms but no SS, and without sicca symptoms in 2008.

                                                     RA-Non-Sicca                RA-Sicca                           RA-SS                     p-value
                                                        (n=58)                    (n=32)                             (n=6)                   (overall)

Demographics
 Female gender 42 (72%)                                                          28 (88%)                           5 (83%)                   0.241
 Age (years)   54 ± 12 (56)                                                      54 ± 8 (55)                       58 ± 7 (60)                0.655
Disease variables
 Time since RA diagnosis (years)   10 ± 8 (10)                                    14   ± 9 (11)                     15   ± 9 (13)             0.175
 RF positive                       48 (83%)                                       28    (88%)                        6   (100%)               0.481
 Anti-CCP positive                 48 (83%)                                       27    (84%)                        5   (83%)                0.584
 Anti-SSA positive                  4 (7%)                                         2    (6%)                         1   (17%)                0.661
 ANA positive                      40 (53%)                                       21    (66%)                        5   (83%)                0.461
 IgG level                       12.9 ± 2.8 (12.7)                              12.7   ± 2.7 (12.7)               14.9   ± 2.6 (15.2)         0.191
 Xerogenic drug use                29 (50%)                                       26   (81%)*                        4   (67%)                0.014
 Presence of erosions              39 (67%)                                       27   (84%)                         6   (100%)               0.068
 Presence of EAMs                  25 (43%)                                       17   (53%)                         4   (67%)                0.421
 DAS-28(ESR)                      2.7 ± 1.1 (2.6)                                3,2   ± 1.1 (3.1)*                5.1   ± 1.4 (5.9)*†        0.001
 DAS-28(CRP)                      2.4 ± 0.8 (2.2)                                2.9   ± 0.9 (3.0)*                4.1   ± 1.5 (4.2)*         0.001
Dryness
 Schirmer’s test (mm/5min)  16.7 ± 10.5 (14.0)                                  15.4   ±   11.4 (13.8)             3.9   ±   1.8 (3.0)*†      0.001
 Whole rest saliva (ml/min) 0.35 ± 0.27 (0.23)                                  0.18   ±   0.12 (0.15)            0.05   ±   0.04 0.06)*†     0.001
 SM/SL, at rest (ml/min)    0.27 ± 0.24 (0.18)                                  0.15   ±   0.10 (0.11)*           0.05   ±   0.04 (0.05)*†    0.001
 SM/SL, stimulated (ml/min) 0.55 ± 0.32 (0.50)                                  0.38   ±   0.33 (0.34)*           0.11   ±   0.11 (0.07)*†    0.000
 PAR, at rest (ml/min)      0.07 ± 0.06 (0.07)                                  0.04   ±   0.04 (0.03)*           0.01   ±   0.02 (0.01)*     0.000
 PAR, stimulated (ml/min)   0.18 ± 0.12 (0.16)                                  0.14   ±   0.11 (0.10)            0.06   ±   0.04 (0.05)*     0.013
Patient-related outcomes
 HAQ                                                   0.5 ± 0.6 (0.4)           1.0 ± 0.6 (1.0)*                  1.4 ± 1.0 (1.4)*           0.001
 RAND-36
  Physical functioning                                  69   ±   25 (75)         48    ±   24 (50)*                38    ±   29 (40)*         0.000
  Role physical                                         64   ±   42 (100)        35    ±   41 (25)*                17    ±   41 (0)*          0.002
  Bodily pain                                           70   ±   19 (67)         57    ±   21 (57)*                37    ±   24 (38)*         0.001
  General health                                        54   ±   22 (55)         42    ±   21 (35)*                33    ±   14 (35)*         0.012
  Vitality                                              66   ±   18 (70)         54    ±   22 (50)*                31    ±   12 (33)*†        0.000
  Social functioning                                    81   ±   19 (88)         67    ±   25 (63)*                50    ±   18 (44)*         0.001
  Role emotional                                        81   ±   35 (100)        73    ±   42 (100)                56    ±   50 (67)          0.434
  Mental health                                         80   ±   15 (84)         76    ±   20 (80)                 56    ±   18 (52)*†        0.020
 MFI
  General fatigue    9 ± 4 (10)                                                  12    ±   4 (12)*                 14    ±   2 (14)*          0.001
  Physical fatigue   9 ± 4 (10)                                                  12    ±   4 (13)*                 15    ±   3 (16)*          0.000
  Reduced activity   9 ± 4 (8)                                                   11    ±   5 (12)*                 14    ±   4 (16)*          0.004
  Reduced motivation 9 ± 4 (8)                                                   10    ±   4 (10)                  15    ±   4 (16)*†         0.003
  Mental fatigue     7 ± 3 (6)                                                    9    ±   5 (9)*                  12    ±   3 (12)*          0.006

Values are presented as number of patients (percentage) or mean ±SD (median).
*p
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

Fig. 1. Flowchart of inclusion screening in 2008 and follow-up in 2018.

RA-sicca and RA-non-sicca patients.                lower saliva production of submandib-         fatigue (MFI) than RA-non-sicca pa-
RA-sicca patients had also higher dis-             ular and sublingual glands both at rest       tients (Table II).
ease activity than RA-non-sicca pa-                and after stimulation and also lower pa-
tients (Table II).                                 rotid gland secretion at rest compared        Follow-up 2018
Functional tests of lacrimal (Schirmer’s           to RA-non-sicca patients.                     From the 96 RA patients included in
test) and salivary glands (whole and               Both groups of RA patients with sicca         the study in 2008, 36 (38%) were able
glandular saliva) were significantly im-           complaints and SS had more limita-            and willing to participate in the follow-
paired in RA-SS patients compared to               tions in daily activities (HAQ), expe-        up screening in 2018 (Fig. 1). From the
RA-non-sicca and RA-sicca patients                 rienced worse health-related quality          60 patients without follow-up data, 5
(Table II). RA-sicca patients showed               of life (RAND-36), and reported more          patients were deceased (one patient be-

Clinical and Experimental Rheumatology 2020                                                                                          S-67
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

cause of a pulmonary embolism after        Table III. Comparison of clinical characteristics of RA patients from 2008 who took part
surgery, 4 other patients because of a     in the follow-up screening in 2018 vs. those who did not take part in the follow-up in 2018.
malignancy (lung, oesophagus, breast       		                              RA-follow-up 2018+           RA-follow-up 2018-          p-value
and cholangiocarcinoma)), 38 patients      		                                    (n=36)                       (n=60)
were lost to follow-up and 17 patients
                                           Demographics
were not willing to participate.            Female gender 27 (75%)                                           48 (80%)               0.615
To check for a potential selection bias     Age (years)   54 ± 10 (55)                                       55 ± 11(56)            0.628
on inclusion in 2018, we compared          Disease variables
baseline parameters of patients who         Time since RA diagnosis (years)  13 ± 9 (10)                      11 ± 8 (10)           0.542
took part in the screening in 2018          RF positive                      27 (75%)                         54 (90%)              0.136
                                            Anti-CCP positive                30 (83%)                         50 (83%)                  1
(N=36) to those of patients who did not     Anti-SSA positive                 3 (8%)                           4 (7%)                   1
participate in 2018 (N=60, Table III).      ANA positive                     21 (58%)                         39 (65%)              0.523
We did not find any significant differ-     IgG level                        13 ± 3 (12.5)                    13 ± 3 (12.9)         0.851
ences in clinical characteristics, func-    Xerogenic drug use               21 (58%)                         38 (63%)              0.669
                                            Presence of erosions             24 (67%)                         48 (80%)              0.154
tional tests and patient-reported out-      Presence of EAMs                 19 (53%)                         27 (45%)              0.529
come between these two groups.              DAS-28(ESR)                     3.0 ± 1.2 (3.0)                  2.9 ± 1.1 (2.6)        0.696
In most patients, sicca symptoms were       DAS-28(CRP)                     2.8 ± 1.0 (2.6)                  2.6 ± 1.0 (2.4)        0.403
not constantly present over time. We       Dryness
screened 21 patients in 2018 who were       Schirmer’s test (mm/5min)  16.3 ± 11 (14.5)                     14.5   ± 10.7 (12.50)   0.552
                                            Whole saliva (ml/min)      0.27 ± 0.21 (0.20)                   0.28   ± 0.26 (0.20)    0.994
originally in RA-non-sicca group in         SM/SL, at rest (ml/min)    0.22 ± 0.17 (0.16)                   0.22   ± 0.23 (0.14)    0.881
2008. Of these 21 patients, 17 patients     SM/SL, stimulated (ml/min) 0.49 ± 0.36 (0.45)                   0.46   ± 0.31 (0.38)    0.984
had still no sicca complaints and 4 pa-     PAR, at rest (ml/min)      0.05 ± 0.05 (0.04)                   0.06   ± 0.06 (0.04)    0.584
tients reported to have developed at       Patient-related outcomes
least one sicca symptom of the eyes         HAQ                                  0.8 ± 0.7 (0.7)             0.7 ± 0.6 (0.6)        0.287
or mouth. Furthermore, we screened           RAND-36
                                              Physical functioning 57 ±                28 (0.60)             61    ± 26 (0.61)      0.613
12 patients in 2018 from the RA-sicca         Role physical        49 ±                42 (0.50)             52    ± 45 (0.50)      0.634
group in 2008. Of these 12 patients, 2        Bodily pain          61 ±                21 (0.67)             64    ± 22 (0.67)      0.338
patients had developed secondary SS,          General health       49 ±                19 (0.47)             48    ± 25 (0.45)      0.674
2 patients still had sicca symptoms           Vitality             59 ±                21 (0.60)             60    ± 21 (0.60)      0.994
                                              Social functioning   73 ±                21 (0.75)             75    ± 24 (0.75)      0.371
and 8 patients did not experience sicca       Role emotional       76 ±                37 (100)              77    ± 40 (100)       0.640
complaints anymore after 10 years of          Mental health        80 ±                14 (0.84)             76    ± 19 (82)        0.560
follow-up.                                   MFI
Furthermore, we compared the clinical         General fatigue    11 ±                  4 (12)                11    ± 5 (10)         0.693
characteristics of the 36 RA-patients         Physical fatigue   10 ±                  4 (11)                11    ± 5 (10)         0.923
                                              Reduced activity   10 ±                  4 (10)                10    ± 5 (11)         0.936
who participated in the screening in          Reduced motivation  9±                   4 (9)                 10    ± 4 (9)          0.571
2018 with their clinical characteristics      Mental fatigue      8±                   4 (6)                  8    ± 4 (8)          0.557
from 2008. We found that except for
IgG levels, all serological parameters     and these patients also reported more            and more fatigue. Furthermore, they
like RF, anti-CCP, anti-SSA and ANA        fatigue. In addition, patient-reported           had more SS-related symptoms meas-
positivity did not change over time. RA    symptoms assessed with total ESSPRI              ured by the ESSPRI total score and the
disease activity did not change signifi-   score and the subscales dryness and pain         subscales dryness and pain.
cantly over time, whereas lacrimal flow,   were significantly higher compared to            The prevalence of SS in RA in our study
whole rest saliva and submandibular/       RA-non-sicca patients (Table V).                 was 6.3% and the prevalence of sicca
sublingual saliva both at rest and after                                                    symptoms was 33%. These findings are
stimulation were significantly lower in    Discussion                                       in line with reported prevalence’s in the
2018. Furthermore, RA patients expe-       To our knowledge, this is the first study        literature (10, 11, 20, 34-36). A Danish
rienced more limitations in daily ac-      evaluating as well sicca symptoms as             study reported a prevalence of 3.8%
tivities, lower general health and more    SS in patient with RA over a period of           of SS in patients with RA, whereas a
mental fatigue in 2018 (Table IV).         10 years. In this study we showed that           Brazilian study reported a prevalence
RA-sicca and RA-SS patients showed         RA patients with higher disease activ-           of 24.3% in a similar group. These dif-
in 2018 significant impairment in the      ity more often have sicca symptoms               ferences in the prevalence of SS in RA
secretion of whole rest salivary flow      and more often are diagnosed with sec-           can be possibly explained by the defi-
and submandibular/sublingual salivary      ondary SS than RA patients with lower            nition of SS and application of differ-
flow both at rest and after stimulation.   disease activity. Furthermore, RA pa-            ent classification criteria, geographical
The domains Role Emotional and Men-        tients with sicca complaints and SS ex-          differences and perhaps differences in
tal Health of RAND-36 were impaired        perienced more limitations in daily ac-          the treatment modalities of RA, assum-
in both RA-sicca and RA-SS patients        tivities, had lower general health status        ing that the disease activity may be a

S-68                                                                                            Clinical and Experimental Rheumatology 2020
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

Table IV. Comparison of clinical characteristics of 36 RA patients from screening in 2008               erature concerning the association be-
and the same 36 RA patients from follow-up in 2018.                                                     tween disease activity and the presence
		                                 RA-screening 2008             RA-follow-up 2018            p-value
                                                                                                        of sicca symptoms and SS.
		                                      (n=36)                        (n=36)                            Some studies did not report an associa-
                                                                                                        tion between disease activity, sicca and
Disease variables			                                                                                    SS, while other studies found this asso-
 RF positive           27 (75%)                                        27   (79%)                  1
 Anti-CCP positive     30 (83%)                                        27   (75%)              0.375
                                                                                                        ciation as well (10, 11, 20, 36, 37). It is
 Anti-SSA positive      3 (8%)                                          3   (8%)                   1    still not clear if secondary SS should be
 ANA positive          21 (58%)                                        21   (46%)              0.727    considered as an extra-articular mani-
 IgG level             13 ± 3 (12.5)                                   11   ± 3 (11)           0.000‫٭‬   festation of RA or as a concomitant au-
 Xerogenic drug use    21 (58%)                                        25   (69%)              0.289
 Presence of erosions  24 (67%)                                        30   (83%)              0.109
                                                                                                        to-immune disease. It is known that pa-
 Presence of EAMs      19 (53%)                                        19   (53%)                  1    tients with RA have more extra-articular
 DAS-28(ESR)          3.0 ± 1.2 (3.0)                                 2.8   ± 1.1 (2.6)        0.251    manifestations if their disease activity
 DAS-28(CRP)          2.8 ± 1.0 (2.6)                                 2.2   ± 1.0 (2.0)        0.499    is high (18). Therefore, RA treatment
Dryness			                                                                                              should be aggressive, especially at the
 Schirmer’s test (mm/5min)  16.3 ± 11 (14.5)                           10   ±   9 (6.7)        0.000‫٭‬   start of the disease, using the window
 Whole rest saliva (ml/min) 0.27 ± 0.21 (0.20)                       0.17   ±   0.21 (0.8)     0.003‫٭‬
 SM/SL, at rest (ml/min)    0.22 ± 0.17 (0.16)                       0.12   ±   0.15 (0.06)    0.001‫٭‬   of opportunity. In 2008, our RA popula-
 SM/SL, stimulated (ml/min) 0.49 ± 0.36 (0.45)                       0.19   ±   0.20 (0.09)    0.000‫٭‬   tion already had a long disease duration
 PAR, at rest (ml/min)      0.05 ± 0.05 (0.04)                      0.05ì   ±   0.07 (0.02)    0.742    of at least 10 years. It will be interest-
 PAR, stimulated (ml/min)   0.17 ± 0.11 (0.16)                       0.12   ±   0.12 (0.08)    0.056    ing to investigate the prevalence of SS
Patient-related outcomes                                                                                in early RA patients in the new era of
 HAQ                                   0.8 ± 0.7 (0.7)               1.08 ± 0.9 (1.0)          0.006‫٭‬
 RAND-36
                                                                                                        biological therapies. Treatment modali-
    Physical functioning                57    ±   28 (0.60)           56    ±   29 (52)        0.828    ties of RA can possibly be of influence
    Role physical                       49    ±   42 (0.50)           47    ±   44 (50)        0.652    on the development of SS in RA as we
    Bodily pain                         61    ±   21 (0.67)           63    ±   24 (66)        0.858    observed that patients with high disease
    General health                      49    ±   19 (0.47)           56    ±   22 (55)        0.031‫٭‬
                                                                                                        activity of RA more often suffered from
    Vitality                            59    ±   21 (0.60)           60    ±   21 (60)        0.770
    Social functioning                  73    ±   21 (0.75)           74    ±   25 (81)        0.705    sicca complaints and/or SS.
    Role emotional                      76    ±   37 (100)            79    ±   38 (100)       0.752    We consider SS not as an extra-articular
    Mental health                       80    ±   14 (0.84)           80    ±   16 (84)        0.748    manifestation of RA, but as a distinct
 MFI			                                                                                                 disease entity. SS occurs concomitantly
  General fatigue    11 ±                         4 (12)              15    ±   5 (12)         0.135    in other diseases like SLE, scleroderma
  Physical fatigue   10 ±                         4 (11)              12    ±   5 (12)         0.059
  Reduced activity   10 ±                         4 (10)              10    ±   4 (9)          0.772    or myositis etc. Furthermore, SS can
  Reduced motivation  9±                          4 (9)                9    ±   3 (9)          0.097    be the first auto-immune disease de-
  Mental fatigue      8±                          4 (6)                9    ±   4 (8)          0.008‫٭‬   tected in a patient, while RA or SLE
                                                                                                        or scleroderma can be diagnosed in the
predicting factor for developing of SS.              sicca symptoms (2), whereas in a Bra-              same patient thereafter. Salivary gland
The prevalence of SS in our study                    zilian study 57.3% of RA patients had              biopsies in patients with secondary
might be underestimated due to lack                  sicca symptoms (36). In a population of            SS showed comparable abnormalities
of a full diagnostic work-out in all in-             RA patients from Egypt with high dis-              between primary SS patients, SS-RA,
cluded RA patients, i.e. salivary gland              ease activity (mean DAS-28 of 5.3±1.2)             SS-SLE and SS-scleroderma patients,
biopsy and full ophthalmologic investi-              and duration of RA of 4.7±4.2 years,               as reported by Hérnandez-Molina et
gation was not done in all patients. We              71% of the patients had sicca symp-                al. (26). Important shortcoming of the
did not add a salivary gland biopsy or               toms, but no patients were diagnosed               term ‘secondary’ SS is that this disease
a full ophthalmologic examination to                 with SS (22). This scattered prevalence            always comes to the second place and
the RA patients suspected for having                 may be caused by various concomitant               too little research is provided on this
developed secondary SS when adding                   diseases and/or xerogenic medication               field. Moreover, probably most patients
these examinations would not result                  use (7, 13). Age-related alterations of            with secondary SS are not well recog-
in a patient to be classified as second-             salivary and lacrimal glands, irradia-             nised by clinicians as their attention
ary SS according to the AECG criteria.               tion and infections, such as hepatitis C           goes to the primary disease, like RA
Furthermore, three anti-SSA positive                 and HIV, amyloidosis, diabetes mellitus            or SLE or scleroderma (38, 39). In our
patients from the RA-non-sicca (n=2)                 (DM) IgG4 disease and sarcoidosis are              study, we found that 2 patients (6%)
and RA-sicca (n=1) groups in 2008                    all associated with sicca syndrome.                had developed SS during the 10 years
were lost to follow-up.                              Associations between sicca symptoms                of follow-up. Both patients had sicca
The reported prevalence of sicca symp-               and/or the presence of SS in RA pa-                complaints in 2008. This indicates that
toms in RA is higher than the prevalence             tients, and poorer health status meas-             the minority of established RA-sicca
of SS, but is very variable as well. In a            ures are frequently reported. However,             patients will develop SS in the later
Turkish study 11.4% of RA patients had               there are conflicting results in the lit-          course of RA. Both patients were anti-

Clinical and Experimental Rheumatology 2020                                                                                                   S-69
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

Table V. Clinical characteristics of RA patients with SS, with sicca symptoms but no SS, and without sicca symptoms in 2018.

		                                      RA-Non-sicca                       RA-sicca                          RA-SS                   p-value
		                                        (n=25)                            (n=6)                             (n=5)                 (overall)

Disease variables
 RF positive           19 (76%)                                              5 (83%)                          3 (60%)                0.843
 Anti-CCP positive     18 (72%)                                              5 (83%)                          4 (80%)                0.482
 Anti-SSA positive      2 (8%)                                               1 (17%)                          1 (20%)                0.841
 ANA positive          15 (60%)                                            4 ( 67%)                           4 (80%                 0.502)
 IgG titer             12 ± 3 (12)                                           9 ± 2 (9)                      8.8 ± 1.6 (9.2)          0.168
 Xerogenic drug use    16 (64%)                                              4 (67%)                          5 (100%)               0.358
 Presence of erosions  21 (84%)                                              5 (83%)                          4 (80%)                0.710
 Presence of EAMs      10 (40%)                                              4 (67%)                          5 (100%)               0.097
 DAS-28(ESR)          2.8 ± 1.2 (2.6)                                      3.1 ± 0.8 (2.7)                  2.0 ± 0.8 (1.7)          0.461
 DAS-28(CRP)          2.2 ± 1.1 (2.0)                                      2.8 ± 0.6 (2.7)                  1.8 ± 0.3 (1.7)          0.579
Dryness
 Schirmer’s test (mm/5min)  10.6 ± 9.5 (7)                                  18   ±   11 (22)               1.4 ± 2.3 (0.5)           0.051
 Whole rest saliva (ml/min) 0.21 ± 0.22 (0.10)                            0.17   ±   0.15 (0.13)*         0.01 ± 0.01 (0.00)†        0.010
 SM/SL, at rest (ml/min)    0.15 ± 0.17 (0.09)                            0.10   ±   0.11 (0.04)*         0.01±0.01 (0.00)†          0.005
 SM/SL, stimulated (ml/min) 0.23 ± 0.22 (0.11)                            0.25   ±   0.19 (0.24)*         0.01±0.01 (0.01)†          0.019
 PAR, at rest (ml/min)      0.05 ± 0.07 (0.04)                            0.08   ±   0.05 (0.09)             0			                    0.092
 PAR, stimulated (ml/min)   0.14 ± 0.12 (0.09)                            0.14   ±   0.11 (0.16)          0.01 ± 0.01 (0.00)         0.054
Patient-related outcomes
 HAQ                                      0.8 ± 0.7 (0.6)                  1.6 ± 0.9 (1.4)                  1.9 ± 0.9 (1.9)          0.274
 RAND-36
  Physical functioning                    65    ±   26 (65)                43    ±   26 (45)                28    ±   29 (25)        0.136
  Role physical                           62    ±   43 (75)                 8    ±   20 (0)                 15    ±   22 (0)         0.224
  Bodily pain                             71    ±   23 (67)                45    ±   14 (45)                47    ±   20 (47)        0.648
  General health                          59    ±   23 (60)                48    ±   17 (52)                49    ±   17 (50)        0.391
  Vitality                                68    ±   18 (70)                45    ±   21 (52)                40    ±   13 (50)        0.084
  Social functioning                      82    ±   21 (88)                65    ±   28 (69)                48    ±   42 (50)        0.125
  Role emotional                          88    ±   30 (100)               67    ±   52 (100)*              47    ±   45 (67)†‡      0.013
  Mental health                           84    ±   16 (88)                77    ±   9 (76)*                30    ±   11 (25)†‡      0.021
 MFI
  General fatigue    10 ± 4 (9)                                            15    ±   3 (14)*                16    ±   4 (16)†‡       0.044
  Physical fatigue   11 ± 5 (10)                                           15    ±   4 (15)                 13    ±   4 (13)         0.232
  Reduced activity    9 ± 4 (8)                                            11    ±   2 (12)*                14    ±   4 (15)†‡       0.040
  Reduced motivation  9 ± 3 (9)                                            11    ±   1 (11)                 12    ±   4 (11)         0.398
  Mental fatigue      8±4 (8)                                               9    ±   3 (9)*                 13    ±   4 (16)†‡       0.033
 ESSPRI
  Dryness                                 0.3   ±   0.7 (0)                4.0   ±   2.7 (4.5)*             8.7   ±   1.5 (9)†‡      0.037
  Fatigue                                 3.1   ±   2.0 (3.0)              6.3   ±   1.6 (6.5)              8.0   ±   1.7 (7)        0.079
  Pain                                    3.2   ±   2.5 (2.5)              5.7   ±   1.9 (5.5)*             7.0   ±   2.6 (6)†       0.024
  Total ESSPRI                            2.2   ±   1.3 (1.8)              5.3   ±   1.2 (5.2)*             7.8   ±   1.9 (7.3)†‡    0.021

*p
10-year follow-up of patients with RA and secondary SS / R.V. Moerman et al.

ing sicca complaints, patients will stay      complaints are not constantly present                 9. TOMIAK C, DÖRNER T: Diagnosis and thera-
                                                                                                       py of secondary Sjögren’s syndrome accom-
in sicca group for the next years and         and vary over time within patients,
                                                                                                       panying rheumatoid arthritis. J fur Miner
that the number of patients in the sicca      while functional tests significantly de-                 2009; 16: 24-31.
group will constantly increase. In con-       crease over time in all patients. During             10. HAGA HJ, NADERI Y, MORENO AM, PEEN
trary, we found that 8 out of 12 exam-        10 years of follow-up, 2 out of 36 pa-                   E: A study of the prevalence of sicca symp-
                                                                                                       toms and secondary Sjögren’s syndrome in
ined patients had no sicca complaints         tients developed SS. Based on these re-                  patients with rheumatoid arthritis, and its
after 10 years of follow-up. These            sults we suggest that RA patients with                   association to disease activity and treatment
results could be a result of the use of       high disease activity should be moni-                    profile. Int J Rheum Dis 2012; 15: 284-8.
xerogenic drugs, but we found no dif-         tored for development of sicca symp-                 11. HE J, DING Y, FENG M et al.: Characteristics
                                                                                                       of Sjögren’s syndrome in rheumatoid arthri-
ferences in xerogenic drug use between        toms and SS.                                             tis. Rheumatology 2013; 52: 1084-9.
screening in 2008 and follow-up in                                                                 12. FOX RI: Sjögren’s syndrome. Lancet 2005;
2018. In contrast, the objective meas-        Take home messages                                       366: 321-31.
urements of functional tests decreased        • In rheumatoid arthritis, high disease              13. DELLI K, SPIJKERVET FKL, KROESE FGM,
                                                                                                       BOOTSMA H, VISSINK A: Xerostomia. Mon-
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flow, as well at rest as stimulated. These      ary Sjögren’s syndrome.                                O, MANDL T, MANTHORPE R, JACOBSSON
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                                                                                                       primary Sjögren’s syndrome: a cohort study
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