Concise report. Characteristics of Sjögren s syndrome in rheumatoid arthritis RHEUMATOLOGY

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1 RHEUMATOLOGY Rheumatology 2013;52: doi: /rheumatology/kes374 Advance Access publication 4 February 2013 Concise report Characteristics of Sjögren s syndrome in rheumatoid arthritis Jing He 1, *, Yan Ding 1, *, Min Feng 1, Jianping Guo 1, Xiaolin Sun 1, Jing Zhao 1, Di Yu 2 and Zhanguo Li 1 Abstract Objective. To compare features of SS in RA with primary SS and RA without SS. Methods. Patients hospitalized between January 2007 and December 2010 were retrospectively studied. Seventy-four cases of overlap RA and SS (RA/SS) among 509 cases of RA were identified. Cases of SS (n = 187) detected during the same period acted as controls. Results. Among those with RA/SS, there were 46 cases of RA-onset SS and 12 cases of SS-onset RA. Sixteen patients had simultaneous-onset RA and SS. Compared with RA without SS, RA/SS patients had more severe arthritis; a higher incidence of haematological abnormality, fever and rash; and a higher frequency of RF, ANAs and anti-ssa and anti-ssb antibodies (P < 0.05). Compared with primary SS, RA/SS patients were older, had more severe arthritis, anaemia and lung involvement; a lower incidence of fever, rash, leucopenia, thrombocytopenia and hyperthyroidism; and a higher frequency of RF, anti-keratin antibody, anti-perinuclear factor and anti-cyclic citrullinated antibodies (P < 0.05). Compared with RA and primary SS, RA/SS patients had higher disease activity scores of both RA and SS. Conclusion. RA/SS patients have distinctive features, with more complications and systemic involvement. In addition, disease activity is higher in RA/SS. Key words: rheumatoid arthritis, Sjögren s syndrome, disease activity. CLINICAL SCIENCE Introduction RA is a systemic autoimmune disease that causes joint damage as well as extra-articular complications. Sicca symptoms are common in patients with RA. SS is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. The features of SS are xerostomia and xerophthalmia, which are caused by impaired function of the salivary and lacrimal glands [1]. Earlier studies classified SS as primary or secondary according to whether or not it coexisted with other CTDs. 1 Department of Rheumatology and Immunology, Peking University People s Hospital, Beijing, China and 2 Department of Immunology (Clayton), School of Biomedical Sciences, Monash University, Victoria, Australia. Submitted 13 November 2011; revised version accepted 31 October Correspondence to: Zhanguo Li, Department of Rheumatology and Immunology, Peking University People s Hospital, 11 Xizhimen South Street, Beijing , China. zgli@yahoo.cn *Jing He and Yan Ding contributed equally to this study. Secondary SS can be associated with diseases such as SLE and RA [1, 2]. Previous studies [3] have revealed profiles of the clinical manifestations of sicca symptoms that are distinct from those of primary SS (pss). However, the percentage of RA patients who fulfil the SS classification criteria, and the prevalence of sicca symptoms in patients with RA, varies considerably among published studies [1, 4, 5]. There is controversy about whether secondary SS is related to disease activity and disease duration in RA [6]. In addition, the characteristics and pathogenesis of the SS in RA is unclear. Therefore research that focuses on the features of overlap RA and SS (RA/SS) is needed. In this study we systematically compared the clinical and serological characteristics of RA/SS with pss and RA to establish features of RA in patients who are prone to developing the sicca syndrome. We also compared complications in different groups, such as the incidence of coronary heart disease, hypertension and diabetes mellitus, in an attempt to explore the clinical spectrum of RA/ SS and to help physicians in the recognition of disease severity in patients with RA/SS.! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Characteristics of SS in RA Patients and methods Patients We retrospectively reviewed the medical records of 509 RA patients admitted between January 2007 and December 2010 to the Peking University People s Hospital. All RA patients were evaluated for evidence of secondary SS according to the 2002 revised international classification criteria for SS [7]. Seventy-four patients fulfilled the criteria for SS among 509 RA patients. Among the 74 patients who fulfilled the criteria for both RA and SS, there were 46 cases of RA-onset SS and 12 cases of SS-onset RA. Sixteen patients had simultaneous RA and SS. The control group consisted of 187 inpatients treated in the Peking University People s Hospital who fulfilled the criteria for SS during the same period. For all patients, the onset and duration of either RA or SS were defined from the time when the diagnosis of RA or SS could be ascertained using established classification criteria. This study was approved by the Medical Ethics Committee of Peking University People s Hospital. Patient consent was obtained according to the Declaration of Helsinki. Clinical features and complications The following features of disease were included in this study: arthritis, fever, rash, lymphadenopathy, RP, parotid gland enlargement, xerostomia, xerophthalmia, anaemia (Hb <12 g/dl), leucopenia (white blood cell count <4000/ml), thrombocytopenia (platelet count < /ml), pulmonary involvement, renal involvement, hepatic involvement (autoimmune hepatitis, primary biliary cirrhosis), nervous system involvement, autoimmune thyroiditis, coronary heart disease, hypertension and diabetes mellitus. Laboratory findings All patients underwent extensive serological evaluations, including ANA, anti-ssa and anti-ssb antibodies, RF, anti-keratin antibody (AKA), anti-perinuclear factor (APF) and anti-ccp. Sera IgG, IgA and IgM were also measured. Classification criteria All patients were Chinese and fulfilled the ACR 1987 criteria [8] for the diagnosis of RA and the 2002 revised international classification criteria for SS [7]. The EULAR SS disease activity index (ESSDAI) [9] and DAS28 [10] scores were used as indices of disease activity. Statistical analysis Data analyses were performed using SPSS for Windows, version Differences between groups were assessed using t-test and chi-square analyses for categorical variables. Logistic regression was used to adjust P-values by age, sex and duration of diseases. P < 0.05 were considered statistically significant. Results Among the 509 patients with RA, 74 (14.5%) fulfilled the criteria for both SS and RA. Forty-six patients (62.2%) had sicca symptoms after the diagnosis of RA (ranging from 6 months to 35 years). The diagnosis of SS preceded the diagnosis of RA by 9 months to 29 years in 12 patients (16.2%). Sixteen patients had RA and SS almost at the same time (Fig. 1). Demographic data in RA/SS compared with pss and RA The demographic and general characteristics of the three groups (RA/SS, RA and pss) are summarized in Table 1. The proportion of women in the RA/SS group was lower FIG. 1Onset of RA and SS in 74 patients with RA/SS. Of these 74 patients, 46 (62.2%) had secondary SS after the diagnosis of RA. The diagnosis of RA preceded SS by 6 months to 35 years. In 12 patients (16.2%), the diagnosis of SS preceded RA by 9 months to 29 years. Sixteen patients (21.6%) had almost simultaneous RA and SS

3 Jing He et al. TABLE 1 Comparison of features between groups Characterisitc RA/SS vs SS RA/SS vs RA RA/SS RA without SS Primary SS (n = 74) (n = 435) (n = 187) P P 4 P P 4 Female, % Age at RA onset, years 45.6 (1.77) 46.9 (0.721) NA NA 0.48 Age at SS onset, years 51.3 (1.42) NA 45.3 (0.99) NA Duration of RA, months (15.10) (5.14) NA NA <0.001 Duration of SS, months (18.51) NA 97.1 (7.01) <0.001 NA Family history, % <0.001 < Number of swollen joints (0.906) 12.9 (0.407) 4.17 (0.415) <0.001 < Number of tender joints (0.917) (0.396) 1.32 (0.254) <0.001 < Deformed joints, % <0.001 < Morning stiffness, % <0.001 < Fever, % RP, % Lymphadenopathy, % Rash, % Parotid gland enlargement, % <0.001 <0.001 Xerostomia, % <0.001 <0.001 Xerophthalmia, % <0.001 <0.001 RF-IgM (positive), % <0.001 <0.001 < RF-IgG (positive), % (15/119) a <0.001 < RF-IgA (positive), % (12/119) a <0.001 < AKA (positive), % (7/121) a <0.001 < APF (positive), % (7/121) a <0.001 < Anti-CCP (positive), % (7/108) a <0.001 < ANA (positive), % <0.001 <0.001 Anti-SSA (positive), % <0.001 <0.001 Anti-SSB (positive), % <0.001 <0.001 IgA " (positive), % IgG " (positive), % IgM " (positive), % 11, Hyperimmunoglobulinaemia (positive), % Leucopenia (positive), % <0.001 <0.001 Thrombocytopenia (positive), % <0.001 <0.001 Anaemia (positive), % <0.001 <0.001 Interstitial lung disease (positive), % < Autoimmune liver disease (positive), % <0.001 <0.001 Renal involvement (positive), % Thyroid involvement (positive), % Hyperthyroidism (positive), % Hypothyroidism (positive), % Nervous system involvement (positive), % Coronary heart disease (positive), % Hypertension (positive), % Diabetes mellitus (positive), % DAS28 (scores) 6.44 ± ± NA NA ESSDAI (scores) 6.38 ± NA 4.95 ± <0.001 <0.001 NA Mean (S.E.M.) for continuous variables or percentages for categorical variables. P < 0.05 are considered significant. P 4 was adjusted by sex, age and duration of disease. a Number varies due to missing data. NA: not applicable. than in the pss group (P = 0.041). Compared with patients with pss and RA only, the duration of disease was longer in patients with RA/SS (P < 0.001). Clinical manifestations and disease activity in RA/SS, RA and pss The prevalence of distinct clinical manifestations in RA/ SS, RA only and pss is presented in Table 1. When compared with RA and pss patients, those with RA/SS demonstrated higher disease activity [DAS28 score 6.44 (0.161) vs 5.96 (0.074), P = 0.023; ESSDAI 6.38 (0.251) vs 4.95 (0.150), P < 0.001]. Comparison of laboratory findings between the groups The laboratory findings of the three groups of patients are presented in Table 1. Compared with pss patients, RA/SS patients had a higher frequency of RF, AKA, APF and anti-ccp. Statistical differences in RF-IgM, RF-IgA,

4 Characteristics of SS in RA ANA, anti-ssa, anti-ssb and IgG were observed between the RA/SS group and the RA group. Comparisons of systemic involvement and clinical complications between the groups As shown in Table 1, differences in the incidence of leucopenia, thrombocytopenia, anaemia, interstitial lung disease, autoimmune liver disease and hyperthyroidism between the RA/SS and pss groups were statistically significant. RA/SS patients had a higher frequency of leucopenia, thrombocytopenia, anaemia, interstitial lung disease, autoimmune liver disease, renal involvement, nervous system involvement and coronary heart disease than RA patients. Discussion SS often coexists with other systemic autoimmune diseases, including RA and SLE. Since 1965, there have been several studies that have focused on RA associated with SS [11]. Subsequent studies demonstrated significant differences in the clinical features of SS patients with and without RA [4 6]. To our knowledge, this is the first study to describe the demographic, clinical, serological features, systemic involvement and complications of RA/SS, RA and SS patients systematically. Studies have shown that the percentage of RA patients who fulfil the SS criteria ranges from 4% to 31% [4 6]. In this study we demonstrated that 14.5% of the 509 RA patients fulfilled the SS criteria. During the study, all RA patients were asked about sicca symptoms identified with SS. One hundred and thirty-six of RA without SS patients have xerostomia syndrome and 98 have xerophthalmia. Overall, 159 of the patients who underwent SS-related examination had sicca symptoms. RA patients who have no complaint of sicca symptoms may not be included in the protocol of SS patients diagnosis. Hence, a portion of early SS patients might be missed. To reduce the rate of misdiagnosis, every RA patient was checked for ANA and anti-ssa/ssb antibodies, but some ANA-positive patients did not fulfil the SS criteria. Those patients may develop SS with disease duration and progression. Of these RA patients, only 16 underwent salivary gland biopsy because of lack of SS-related antibodies, but they had clear and definite sicca symptoms. All 16 patients were diagnosed as secondary SS. Others were not obliged to undergo the biopsies. Drug therapy is very important for the progression of disease, so we analysed the treatment of these patients. Sixty per cent of RA patients lacked standard treatment for 1 month before being enrolled in the study, stopped taking medicine prescribed by doctors or used Chinese medicine irregularly. Forty per cent (n = 174) of the RA patients underwent standard treatment, such as MTX, SSZ, HCQ, LEF, prednisone or so on. Sixty-five per cent (n = 48) of the RA/SS patients lacked standard treatment, and 35% of the patients used MTX, SSZ, HCQ, LEF or prednisone regularly. There was no significant difference between these two groups. Ninety per cent (n = 163) of the SS patients lacked standard treatment. These drugs might influence the development of disease, but that cannot be calculated accurately. Our data suggest that patients with RA/SS are older than patients with pss. RA/SS patients had a longer duration of disease than those with RA only or pss. Patients with RA/SS have a more severe form of arthritis. Sicca syndrome (xerostomia and xerophthalmia) appears to present a similar profile in patients with RA/SS and those with pss. In addition, the statistically significant association of family history is of particular note. RA/SS patients had a more obvious family aggregation autoimmune disease tendency. As has been established, SS and RA are influenced by genetic factors. Previous studies have proved that pss and secondary SS are associated with different genetic factors [12]. This phenomenon deserves further study in patients with RA/SS, RA only and pss. Significant differences in RF, AKA, APF and anti-ccp between RA/SS and pss patients are of note, suggesting that these parameters could be a useful tool in distinguishing pss, RA and sss. Primary SS patients and RA without SS patients can present with a variety of haematologic abnormalities, including anaemia, leucopenia and thrombocytopenia. Anaemia in RA patients is associated with DAS28 [13] and RA patients with anaemia represent a greater cost burden to hospitals [14]. The incidence of anaemia was higher in RA/SS patients than in RA and pss patients. Therefore patients with RA/SS require more therapy during treatment and higher hospitalization costs. Through analysis we found that the incidence of haematological system abnormality is much higher in RA/SS patients than in those without. Previous research reported that the frequency of anaemia in pss patients was 16% [15]. In this study, the frequency of anaemia in pss was 57.2%, which is higher than in previous studies and in RA patients. This may be associated with racial differences. Anaemia is defined as haemoglobin 411 g/ dl in females and 412 g/dl in males in Chinese people. The deviation might come from the pilot samples. If the number of patients is large enough, the results will be more reliable. From previous reports, the incidence of anaemia in RA ranges from 33% to 60%, whereas in our study it is 21%. A study by Al-Ghamdia and Suzan [4] showed that the prevalence of anaemia in RA is 61%, which might relate with disease duration and food imbalance. Da Mota et al. [5] showed that anaemia in RA is related to disease activity and associated with inflammatory activity [13]. From this study, the RA/SS patients had significantly longer disease duration and higher disease activity, which might be associated with the higher incidence of anaemia [5]. Leucopenia and thrombocytopenia in RA without SS is often associated with drug toxicity. Leucopenia and thrombocytopenia are frequently seen in RA/SS and pss, but seldom in RA only. The haematologic features of RA/SS have the similar characteristics in both RA and pss patients. Interstitial lung disease in patients with RA/SS is more common than in either pss or RA. The incidence of autoimmune liver disease in RA/SS was higher than in RA, but lower than in pss. The incidence of renal involvement in

5 Jing He et al. RA/SS is higher than in RA. Autoimmune thyroid diseases in pss are very common. Perez et al. [16] found that the percentage of thyroid dysfunction in SS patients was 45%. Autoimmune thyroiditis and autoimmune hyperthyroidism was 24 and 6%, respectively. The occurrence of clinically manifest hypothyroidism and subclinical hypothyroidism in RA patients was 6.8 and 2.5% in the Dutch population [17]. In this study, hypothyroidism is more common than hyperthyroidism in patients of the three groups. Hyperthyroidism is more frequently seen in patients with RA/SS and RA without SS than in those with pss. The features of systemic involvement may help to distinguish the three groups. More systemic involvement was found in RA/SS patients, which is an important observation for clinicians to be aware of. Cardiovascular events in rheumatic diseases such as RA, SLE and SS have been previously reported [18, 19]. Patients with RA often experience cardiovascular events, which are potentiated by high disease activity [18]. A 2-fold higher prevalence of diabetes mellitus has been demonstrated in patients with pss [19]. To our knowledge, no previous studies have identified the complications of coronary heart disease, hypertension and diabetes mellitus in well-defined RA/SS patients and compared them with those with RA without SS or with pss. The incidence of coronary heart disease in RA/SS patients was higher than in patients with RA. RA/SS patients were at higher risk of cardiovascular events. As to whether the sicca syndrome is associated with disease activity in RA, the answer varies between studies. Uhlig et al. [20] concluded that high RA disease activity was a predictor of reduced saliva production. In the current study, we found that in patients with RA/SS, the scores of both DAS28 and ESSDAI were higher than other two groups, pointing to the greater disease activity in RA/SS patients. In this group, therefore, attention needs to focus on early intervention and treatment to prevent disease progression and complications. Although the current study is a retrospective one, it suggests that patients with RA/SS have distinctive demographic, clinical and serological features. In addition, the profile of systemic involvement and complications appears to be different in those with RA/SS. Larger prospective studies are needed to confirm these preliminary results. Rheumatology key messages. RA/SS patients have distinctive features, with more complications and systemic involvement.. DAS28 and ESSDAI scores are higher in RA/SS patients. Acknowledgements J.H. and Y.D. performed the study. Z.L. conceived the study and participated in the design. All authors read and approved the final manuscript. Funding: This work was supported by the Beijing Natural Science Foundation (no ) and National Natural Science Foundation of China (nos and ). 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