|Year : 2016 | Volume
| Issue : 4 | Page : 202-206
Study on demography and outcome of extraglandular manifestations of primary sjögren's syndrome
Kavitha Mohanasundaram1, Madeshwaran Mani2, Saranaya Chinnadurai2, Bhuvanesh Mahendran2, Chilukuri Balaji2, Ashok Bhoorasamy3, M Saravanan2, Sankaralingam Rajeswari2
1 Institute of Rheumatology, Madras Medical College; Saveetha Medical College Hospital, Thandalam, Chennai, India
2 Institute of Rheumatology, Madras Medical College, Chennai, India
3 Department of Community Medicine, Melmaruvathur Adhiparasakthi Institute of Medical Sciences and Research, Melmaruvathur, Chennai, India
|Date of Web Publication||8-Nov-2016|
Dr. Kavitha Mohanasundaram
6 First Street, Shanthi Nagar, Adambakkam, Chennai - 600 088, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Primary Sjögren's syndrome (pSS) is a systemic disease with a wide array of life-threatening extraglandular manifestations. The main objective of this study was to assess glandular and extraglandular manifestations of pSS.
Methods: Eighty-two newly diagnosed pSS patients fulfilling revised American-European Consensus Group criteria of 2002 were included in the study. Twenty patients had predominantly glandular manifestations and 62 had predominant extra-glandular manifestations. Patients underwent baseline hematological, biochemical, immunological investigations, and imaging as needed. All patients underwent Schirmer's Test and lip biopsy irrespective of whether they had sicca symptoms or not.
Results: The extraglandular manifestations observed in our patient were arthritis, neurological, renal, respiratory, and vasculitis. Almost 50% of patients with extraglandular manifestations did not have sicca symptoms. Cervical dental caries was seen in 40% of our patients with extraglandular manifestations. Our study had a higher percentage of renal involvement. Age at presentation and duration of illness were lower in the extraglandular group, which were statistically significant. European Sjögren's syndrome disease activity index (ESSDAI) at onset and at 1 year was higher in extraglandular group.
Conclusion: The demography of patients with extraglandular manifestations in terms of age, duration of illness, and disease activity is different from those with only glandular manifestations.
Keywords: Cervical dental caries, European Sjogren′s syndrome disease activity index, extraglandular manifestations
|How to cite this article:|
Mohanasundaram K, Mani M, Chinnadurai S, Mahendran B, Balaji C, Bhoorasamy A, Saravanan M, Rajeswari S. Study on demography and outcome of extraglandular manifestations of primary sjögren's syndrome. Indian J Rheumatol 2016;11:202-6
|How to cite this URL:|
Mohanasundaram K, Mani M, Chinnadurai S, Mahendran B, Balaji C, Bhoorasamy A, Saravanan M, Rajeswari S. Study on demography and outcome of extraglandular manifestations of primary sjögren's syndrome. Indian J Rheumatol [serial online] 2016 [cited 2020 Aug 7];11:202-6. Available from: http://www.indianjrheumatol.com/text.asp?2016/11/4/202/192690
| Introduction|| |
Primary Sjögren's syndrome (pSS) is a rare autoimmune connective tissue disorder characterized by autoimmune destruction of exocrine glands predominantly lacrimal and salivary glands. The disease often manifests as sicca symptoms and is considered as a mild disease by many. The hallmark of the disease is lymphocytic infiltration of exocrine glands, tissue destruction, and glandular dysfunction., The wide array of extraglandular manifestations ranging from acute transverse myelitis, mononeuritis multiplex, and interstitial lung disease to hypokalemic paralysis due to renal tubular acidosis is a challenge – both in terms of diagnosis and treatment. We aimed at studying extraglandular manifestations in detail, to observe the changes in demographics and outcome of patients with glandular and extraglandular manifestations.
| Materials and Methods|| |
Time and place of the study
This was a prospective observational study conducted at the Institute of Rheumatology, Madras Medical College, Chennai, India, between March 2013 and August 2015.
Inclusion and exclusion criteria
All consecutive newly diagnosed pSS patients attending our rheumatology clinic were included in the study. Their diagnosis was based on 2002 revised American-European Consensus Group (AECG) classification criteria for pSS. Patients with secondary Sjögren's syndrome and overlap syndrome were excluded from the study. Patients with only sicca symptoms and glandular enlargement were included in the glandular manifestations group and with any other systemic symptoms were included in the extraglandular group.
pSS was diagnosed when patient satisfied four of the six criteria items in revised AECG criteria or any three out of the four objective criteria items (in our study Schirmer's test, lip biopsy with focus score >1, and autoantibody positivity), the latter was used mainly when patients presented only with extraglandular symptoms and no sicca symptoms.
All patients who satisfied the inclusion criteria underwent detailed clinical examination with special emphasis on extraglandular manifestations. Complete blood count, liver function tests, renal function tests, erythrocyte sedimentation rate, and C-reactive protein were done. Rheumatoid factor (RF), antinuclear antibodies (ANA) by indirect Immunofluorescence using Hep2 cells, ANA Profile 3 by Euroimmun line immunoblot, cryoglobulin assay, and complements C3 and C4 as measured by single radial immunodiffusion were done.
High resolution computerized tomography of chest, pulmonary function tests were done at onset, at 6 months, and 1 year, nerve conduction study, sural nerve biopsy, ulcer biopsy, complete urine analysis including pH, bicarbonate values, and arterial blood gas analysis were done in appropriate setting. All patients underwent Schirmer's test and lip biopsy irrespective of whether they had sicca symptoms or not. Lip biopsy was done in Government Dental Hospital, affiliated to our hospital by dental surgeons and results were interpreted by oral pathologist. Lip biopsy was considered as positive if more than/equal to one focus (50 cells or more) of lymphocytic infiltration was observed in a 4 mm 2 of normally appearing minor salivary gland tissue. Salivary scintigraphy or unstimulated salivary flow was not done in any of our patients. Viral markers (hepatitis B surface antigen, antihepatitis C virus, and HIV) were done on all patients.
Disease activity was assessed using European Sjögren's syndrome disease activity index (ESSDAI) at the onset and at 1 year. ESSDAI score of ≥1 was considered to be active disease.
Anaxslyses were done using SPSS software version 20 (IBM). Analysis for categorical variables was done using Chi-square/Fisher's exact t-test and for comparison of two groups (glandular vs. extraglandular) – independent t-test was used.
| Results|| |
A total of 82 newly diagnosed pSS were included in our study, out of which twenty had predominantly glandular and 62 had extraglandular manifestations.
Demographic characteristics of two groups
Age at presentation
The mean age at presentation in the glandular group was 45 ± 5.86, whereas in extraglandular group, it was 34 ± 9.21 years. Patients with extraglandular manifestations present much earlier, and the difference was statistically significant (P < 0.001) [Figure 1].
|Figure 1: Box plot depicting age at onset, duration of illness, European Sjögren's syndrome disease activity index at onset and at 1 year of two groups|
Click here to view
In the recruited study group, 5 were males and remaining 77 were females. Female:male ratio in our series was 13.4:1. Extraglandular manifestations were dominant in 59 females and in 3 males. The sex difference was not statistically significant between two groups.
Duration of illness
The mean duration of illness in two groups was statistically significant with a shorter duration of illness noted in the extraglandular manifestations (1.91 ± 0.91 years) when compared to the other group (5.65 ± 1.64 years) [Figure 1].
The dominant extraglandular manifestations observed in our patients were arthritis (18/82), renal (13/82), respiratory (15/82), neurological (7/82), and cutaneous (9/82). We did not observe either lymphoma or thyroiditis, the two common associations with pSS in any of our patients.
In a total of 82 patients, 50 had sicca symptoms and the rest 32 did not have any. All the 32 had extraglandular manifestations. Sicca symptoms which are by rule, the hallmark of pSS, were absent in almost 40% of our total study group and in 50% of patients with extraglandular manifestations; however, they had objective signs of glandular dysfunction in terms of positive Schirmer's and lip biopsy. [Figure 2] illustrates the presence of sicca symptoms in the study group. Dental caries was one of the major clinical signs we found in our patients even without sicca symptoms [Figure 3]. Out of 82 patients, 51 had dental caries, amounting to 62%. This was almost equally distributed among glandular and extraglandular patients.
Out of 13 patients with renal presentation, 1 had membranoproliferative glomerulonephritis with cryoglobulin positivity and the remaining had distal renal tubular acidosis. Interstitial lung disease was present in 15 of our patients, the patterns observed were nonspecific interstitial pneumonia (n = 9), usual interstitial pneumonia (n = 4), and bronchiolitis obliterans organizing pneumonia (n = 2). Transverse myelitis (n = 2), multiple sclerosis (n = 1), and mononeuritis multiplex (n = 4) were the neurological manifestations observed in our study group. Cutaneous manifestations such as purpura (n = 3), recalcitrant skin ulcers (n = 3), and peripheral gangrene (n = 3) were present in 9 of our patients. All patients with arthritis presented with symmetrical polyarthritis. Raynaud's phenomenon was observed in 41% of our patients.
The difference in the laboratory parameters between the two groups is enlisted in [Table 1].
Disease activity measurement
ESSDAI at onset was 2 ± 0.79 in the glandular group and 5.1 ± 1.35 in the extraglandular group (P < 0.001) and at 1 year ESSDAI of 1.25 ± 0.64 and 1.69 ± 0.68 were observed, respectively (Chi-square 7.67, P < 0.05) [Figure 1].
Three deaths were observed in the extraglandular group during the study period, one patient had distal renal tubular acidosis, recurrent attacks of flaccid paralysis-succumbed to sepsis, one with recurrent attacks of multiple sclerosis succumbed to respiratory failure, and the third had mononeuritis multiplex, skin ulcers, and succumbed to sepsis. All the three patients had high ESSDAI >6 at onset.
| Discussion|| |
pSS is a systemic disease with a wide array of organ involvement though many a times it is quiescent only with sicca symptoms, fatigue, and arthralgia. Our study had more patients with extraglandular manifestations which could be explained by the referral bias that happens often in tertiary care centers.
The mean age of presentation was significantly lower in the group with extraglandular manifestations (34 vs. 45 years) which was statistically significant. Misra et al. had observed that Sjögren's syndrome in India occurs earlier by 10 years when compared to the West (mean age = 45 years), similar to our glandular group. No definitive data exist on the age of presentation of extraglandular manifestations of pSS. To the best of our knowledge, ours is a first of its kind study to say extraglandular manifestations appear 10 years earlier in pSS cohort.
The sex ratio of 13:1 (female:male) observed in our study is much higher than lupus which has a ratio of 9:1. The sex ratio was also similar to many studies which places them anywhere between 9:1 and 20:1.,, The mean duration of illness was 5.65 years (range 8–84 months) in those with glandular manifestation which is similar to many studies where it is 5–6.5 years depending on the population studied., The significant part of this observation is that in our study those with extraglandular manifestations had a duration of illness which was much lower (1.91 years).
Sicca symptoms surprisingly were present in only 60% of our study group, but objective signs were noted in > 90% of patients. The Spanish cohort places xerostomia and dry eyes at 95.8% and 93%, respectively, and the SICCA cohort with 886 pSS patients had dry eyes in 87% and dry mouth in 93% of the study group., We noted that 62% of our study group and 59% of patients with extraglandular manifestations had dental caries though most of them did not have sicca symptoms. Increase in dental caries has been made as inclusion criteria in the recent American College of Rheumatology (ACR) SICCA Sjögren's 2012 classification criteria proposed by Shiboski et al. We reinforce that dental caries should be looked for in all patients with suspected pSS; they are an important clinical clue.
The Spanish registry which has 921 patients with pSS has noted the following frequency of systemic manifestations: Arthritis in 40%, cutaneous in 10%, pulmonary in 15%, renal in 2%, and neurological at 7%, whereas it is 28%, 10%, 18%, 16%, and 8%, respectively, in our study group. Our cohort had a very high proportion with renal involvement.
RF and ANA positivity was observed in approximately 84% and 85% of our patients, respectively. A study by Ramos-Casals et al. had RF positivity in 56.5%, but ANA positivity was seen in 90% of the analyzed 921 patients. The same study had anti-Sjögren's syndrome type A (SSA) positivity and anti-Sjögren's syndrome type B (SSB) positivity at 72.6% and 45.8%, respectively. Anti-SSA positivity was observed in 87.5% of our study group and anti-SSB positivity in 25% of the study group. The high positivity rate of anti-SSA in the extraglandular group can be explained by the selection bias of pSS patients, who were included only if they satisfy the AECG 2002 criteria, where 3 of the 4 objective criteria need to be satisfied in the absence of sicca symptoms. Since unstimulated whole sialometry and sialography were not performed in any of the patients, all patients who were included had to have a positive Schirmer's, lip biopsy suggestive of pSS, and anti-SSA and/or anti-SSB.
In the study by Ramos-Casals et al. comparing the ESSDAI scores in a Spanish cohort, the mean ESSDAI at diagnosis was 5.81. In our study group, it was 2 ± 0.79 versus 5.10 ± 1.35 at the onset, and at the end of 1 year, it was 1.24 ± 0.64 and 1.69 ± 0.69 in the glandular and extraglandular groups, respectively. The total follow-up of their cohort was for 75 months, a higher cumulative ESSDAI of 3.34 was observed. ESSDAI as a valid tool for disease activity in pSS has been quoted in many other studies too.,,
Limitations of the study
We have not performed two tests; namely unstimulated salivary flow and salivary scintigraphy, which form a part of AECG criteria. Hence, the presence of high antibody positivity (ANA, anti-SSA) in our patients may not be appropriate since unavailability of these two tests act as a selection bias. We also did not compare AECG and the current ACR 2012 classification criteria, due to the nonavailability of ocular staining score at our center. Duration of study was only 2 years; hence, we were not able to follow-up for the presence of lymphoma in our cohort, which is usually a long-term complication. This cohort gives us an opportunity to follow them up and study their progression.
| Conclusion|| |
pSS affects major organ systems and can result in serious morbidities and mortality. In the present study patients with predominantly extraglandular manifestations had a younger age at onset, lower mean duration of illness, high disease activity at onset, and at 1 year as assessed by ESSDAI. Dental caries is an important clinical clue in the diagnosis of pSS even in the absence of sicca symptoms.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X. Primary Sjogren syndrome. BMJ 2012;344:e3821.
Katsifis GE, Moutsopoulos NM, Wahl SM. T lymphocytes in Sjögren's syndrome: Contributors to and regulators of pathophysiology. Clin Rev Allergy Immunol 2007;32:252-64.
Manoussakis MN, Boiu S, Korkolopoulou P, Kapsogeorgou EK, Kavantzas N, Ziakas P, et al.
Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: Correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum 2007;56:3977-88.
Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med 2004;164:1275-84.
Malladi AS, Sack KE, Shiboski SC, Shiboski CH, Baer AN, Banushree R, et al.
Primary Sjögren's syndrome as a systemic disease: A study of participants enrolled in an international Sjögren's syndrome registry. Arthritis Care Res (Hoboken) 2012;64:911-8.
Misra R, Pandya S, Danda D. Sjögren syndrome. In: Stone JH, editor. Primary Sjögren's Syndrome: Report from India. London: Springer; 2009. p. 425-7.
Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI, Siozos C, Drosos AA. Epidemiology of primary Sjögren's syndrome in north-west Greece, 1982-2003. Rheumatology (Oxford) 2006;45:187-91.
Kabasakal Y, Kitapcioglu G, Turk T, Oder G, Durusoy R, Mete N, et al.
The prevalence of Sjögren's syndrome in adult women. Scand J Rheumatol 2006;35:379-83.
Anagnostopoulos I, Zinzaras E, Alexiou I, Papathanasiou AA, Davas E, Koutroumpas A, et al.
The prevalence of rheumatic diseases in central Greece: A population survey. BMC Musculoskelet Disord 2010;11:98.
Ramos-Casals M, Brito-Zerón P, Solans R, Camps MT, Casanovas A, Sopeña B, et al.
Systemic involvement in primary Sjögren's syndrome evaluated by the EULAR-SS disease activity index: Analysis of 921 Spanish patients (GEAS-SS Registry). Rheumatology (Oxford) 2014;53:321-31.
Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, et al.
American College of rheumatology classification criteria for Sjögren's syndrome: A data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475-87.
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al.
Classification criteria for Sjögren's syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8.
Risselada AP, Kruize AA, Bijlsma JW. Clinical applicability of the EULAR Sjögren's syndrome disease activity index: A cumulative ESSDAI score adds in describing disease severity. Ann Rheum Dis 2012;71:631.
Pertovaara M, Korpela M. Serum ß2 microglobulin correlates with the new ESSDAI in patients with Sjögren's syndrome. Ann Rheum Dis 2011;70:2236-7.
Meiners PM, Arends S, Brouwer E, Spijkervet FK, Vissink A, Bootsma H. Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjögren's syndrome treated with rituximab. Ann Rheum Dis 2012;71:1297-302.
[Figure 1], [Figure 2], [Figure 3]