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 202010-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-6510-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).
*p10-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 202010-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-6910-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
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