Академический Документы
Профессиональный Документы
Культура Документы
Sjgren syndrome
S
jgren syndrome is a chronic, systemic known. The current hypothesis is that an inter- Competing interests: None
disorder of an autoimmune nature. It is play between environmental contributors (e.g., declared.
characterized by lymphocytic infiltration viruses, stress, hormones) and the patients This article has been peer
of the exocrine (mainly salivary and lacrimal) genetic background can lead to inflammatory reviewed.
glands and by remarkable B-cell hyperactivity. responses against epithelial tissues. In this Correspondence to:
The latter is manifested by hypergammaglobu- review, we summarize the current evidence, Haralampos Moutsopoulos,
hmoutsop@med.uoa.gr
linemia and the presence of serum autoantibod- mostly from observational, open-label and ran-
ies, including antinuclear antibodies, rheumatoid domized clinical trials, for the clinical manifesta- CMAJ 2014. DOI:10.1503
factor, cryoprecipitable immunoglobulins and tions, diagnosis and management of Sjgren /cmaj.122037
antibodies against two ribonucleoproteinic com- syndrome (Box 1).
plexes named Ro/SSA and La/SSB; these anti-
bodies are considered hallmarks of the disease.1,2 What are the clinical features
Although their exact role is not known, recent
data suggest that antibodies against the Ro52
of Sjgren syndrome?
component of the Ro/SSA antigen (a 52kD pro-
tein that inhibits proinflammatory responses) The clinical features of Sjgren syndrome can be
might inhibit its regulatory function.3 The condi- largely divided into those related to exocrine dys-
tion is nine times more common among women function (glandular) and those that affect organs
than among men, with peak onset during meno- other than the exocrine glands (extraglandular or
pause.1 A recent review suggests that the preva- systemic). The latter can be further divided into
lence ranges from 0.1% to 4.8%,1 with rates in- nonspecific features, those characterized by peri-
creasing with advanced age.4,5 Heterogeneity in epithelial infiltrates in parenchymal organs and
inclusion criteria, ethnic origin, sample size and those that result from immunocomplex deposi-
sex distribution between studies contributed to tion as a result of B-cell hyperactivity.7,8 Most pa-
the observed variability. tients with Sjgren syndrome (about 90%) have
Although Sjgren syndrome is classically con- an indolent benign course; however, a small but
sidered to be localized disease of the exocrine important number of cases (5%10%) are com-
glands, mainly manifested with oral and ocular plicated by immunocomplex pathology and lym-
dryness, it also has a wide range of systemic clin- phoid neoplasia, both of which are associated
ical manifestations that affect essentially any with high mortality (a 3.25-fold increase com-
organ system, and a small number of cases are pared with the general population).6,7,9
complicated by the development of non-Hodgkin
lymphoma.1,6 Secondary Sjgren syndrome is
associated with an established connective-tissue Key points
disease. Sjgren syndrome is a chronic autoimmune disease that mainly affects
As is the case for many autoimmune diseases, middle-aged women.
the primary etiopathogenetic events are not Clinical manifestations are mainly classified as glandular (manifested
mainly by dry eyes and mouth) or extraglandular (systemic).
About 5%10% of cases are complicated by the development of
Box 1: Evidence used in this review
lymphoma.
Using the MeSH term Sjgren syndrome, we Diagnosis is made by observing ocular and oral dryness, by measuring
searched MEDLINE for randomized controlled serum autoantibody levels and by observing periductual lymphocyte
trials, systematic reviews and observational infiltration in salivary gland biopsy samples.
studies involving adult humans. We included
studies published in English between Jan. 1, Local measures and cholinergic agents are the main therapeutic
1975, and Nov. 25, 2012. We also manually methods used to alleviate oral and ocular dryness. B-cell targeted
searched the reference lists of relevant articles therapies are reserved for the systemic manifestations of the
retrieved. syndrome.
2014 Canadian Medical Association or its licensors CMAJ, October 21, 2014, 186(15) E579
Review
The main features of glandular and extraglan- syndrome; these patients typically report func-
dular manifestations in Sjgren syndrome are tional disability and an increased need for
shown in Table 1.6,7,940 Besides sicca features, easy rest.13,26,41 Patients with primary Sjgren syndrome
fatigability is one of the most frequent symptoms, may show several psychopathologic features
occurring in 70% of patients with primary Sjgren depending on premorbid personality traits and in
continued
association with antibodies against neuropep- vasculitis or purpuric lesions, low C4 levels,
tides.42 Increased rates of neuroticism, psychoti- cryoglobulinemia and the presence of germinal
cism, obsessiveness, hypochondriasis, paranoid centres in salivary gland biopsy samples are
ideation, somatization, obsessivecompulsive well-recognized adverse predictors of lympho-
symptoms, sleep disturbances and defective cop- ma.7,9,39,40 In a comparative analysis involving
ing strategies have been reported.7,4347 patients with mucosa-associated lymphoid tissue
Non-Hodgkin lymphoma is a well-recognized lymphoma with or without underlying autoim-
complication of Sjgren syndrome.6,39 Peripheral mune disease, there were no differences in the
neuropathy, glomerulonephritis, lymphopenia, rate of relapse, time to relapse or survival.48
tion of selective serotonin reuptake inhibitors, steroidal anti-inflammatory drugs after bacterial
especially escitalopram and fluoxetine) and anti- infection and lymphoma have been ruled out.
histamines should be avoided because they exac- Ocular dryness should initially be treated with
erbate mucosal dryness; air conditioning should preservative-free teardrops or eye lubricants con-
also be avoided. Mouth hygiene, thorough dental taining either sodium hyaluronate or hydroxy-
follow-up, stimulation of salivary flow (sugar-free propyl methylcellulose, which improve both sub-
gum or citrus juice) and administration of saliva jective symptoms and objective signs of ocular
substitutes are generally advised for the manage- dryness (e.g., Schirmer test, rose bengal staining,
ment of oral dryness.59 Salivary substitutes have impression cytology scores).6164 In cases of mod-
been shown to improve subjective symptoms of erate to severe dry eye disease, cyclosporine
oral dryness (e.g., burning mouth, difficulties with drops (0.05%) for six months were shown to
mastication and swallowing) without affecting the lead to remarkable improvement in Schirmer test
rate of salivary output.60 Painful enlargement of and corneal staining scores and subjective ocular
salivary glands can be alleviated by local applica- symptoms (e.g., reduced blurred vision, use of
tion of moist heat and administration of non- artificial tears).65
Among patients with residual gland function, What therapies are effective
the beneficial use of two cholinergic agents was for the management of systemic
shown in controlled studies. Patients who used
pilocarpine (1030 mg once daily) showed statis- features in Sjgren syndrome?
tically significant improvements in dryness (oral,
ocular, nasal, vaginal, skin) and salivary flow Systemic therapy should be considered for
rates. Cevimeline use (30 mg three times daily) patients showing systemic features and should be
has been also associated with improved subjective tailored to the organs affected and to the severity.
oral and ocular symptoms, increased salivary flow Because of a lack of robust data from controlled
rates and objective ocular signs. 66 Although studies, the management of extraglandular mani-
steroid-containing ophthalmic solutions have festations is mainly based on case-series reports,
shown short-term benefits, caution should be open-label studies and expert opinion based on
taken with prolonged use because serious adverse biological rationale and experience with other
effects (e.g., raised intraocular pressure, worsen- autoimmune diseases. Therapeutic options for the
ing or development of cataracts, impaired corneal systemic manifestations of Sjgren syndrome are
wound healing, increased risk of infection risk) shown in Table 2.59,66,72,73
may occur.6669 Women with vaginal dryness and In patients for whom arthralgia or myalgia is the
dyspareunia may benefit from vaginal lubricants, predominant symptom, hydroxychloroquine ther-
as suggested by studies not focused on Sjgren apy has been shown to improve arthralgia, myalgia
syndrome.70 In patients with earlier disease onset and joint inflammation; methotrexate can be used
and preserved salivary function, improvements in cases of inflammatory arthritis.72,74 For cases of
have been shown using both subjective (visual persistent arthritis, rituximab has been shown to
analog scale [VAS] scores for sicca symptoms) significantly improve the tender and swollen joint
and objective measures after treatment with ritux- count.75 A pilot open-label study reported that
imab (monoclonal antibody against CD20).71 weekly administration of methotrexate to patients
Feature Therapy
Nonspecific symptoms
with Sjgren syndrome reduced the frequency of 8. Malladi AS, Sack KE, Shiboski S, et al. Primary Sjgrens syn-
drome as a systemic disease: a study of participants enrolled in
parotid gland enlargement, dry cough and pur- an international Sjgrens syndrome registry. Arthritis Care Res
pura.76 In patients with primary Sjgren syndrome, (Hoboken). 2012; 64:911-8.
9. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk
blockade of tumor necrosis factor (infliximab and of mortality and lymphoproliferative disease and predictive clas-
etanercept) does not appear to be effective in reduc- sification of primary Sjgrens syndrome. Arthritis Rheum 2002;
46:741-7.
ing subjective and objective measures of salivary 10. Sumida T, Tsuboi H, Iizuka M, et al. Anti-M3 muscarinic acetyl-
and lacrimal function or joint inflammation; aug- choline receptor antibodies in patients with Sjgrens syndrome.
Mod Rheumatol 2013;23:841-5.
mentation of the already activated type I inter- 11. Skopouli FN, Papanikolaou S, Malamou-Mitsi V, et al. Obstetric
feron/B-cell activating factor (BAFF) axis has been and gynaecological profile in patients with primary Sjgrens
suggested to account for this failure.77,78 syndrome. Ann Rheum Dis 1994;53:569-73.
12. Skopouli FN, Talal A, Galanopoulou V, et al. Raynauds phenome-
Cytotoxic drugs (e.g., cyclophosphamide) are non in primary Sjgrens syndrome. J Rheumatol 1990;17:618-20.
reserved for severe extraglandular manifestations, 13. Ng WF, Bowman SJ. Primary Sjgrens syndrome: too dry and
too tired. Rheumatology (Oxford) 2010;49:844-53.
including cutaneous vasculitis and glomerulo- 14. Skopouli FN, Barbatis C, Moutsopoulos HM. Liver involvement
nephritis. Given that B-cell activation is a disease in primary Sjgrens syndrome. Br J Rheumatol 1994;33:745-8.
15. Goules A, Masouridi S, Tzioufas AG, et al. Clinically significant
cornerstone, choosing targeted therapies against B and biopsy-documented renal involvement in primary Sjgren
cells is a logical approach.6,72 Improvement in fa- syndrome. Medicine (Baltimore) 2000;79:241-9.
16. Mavragani CP, Fragoulis GE, Moutsopoulos HM. Endocrine alter-
tigue scores in a randomized controlled trial and ations in primary Sjgrens syndrome: an overview. J Autoimmun
demonstrated efficacy in extraglandular features 2012;39:354-8.
17. Mavragani CP, Schini M, Gravani F, et al. Brief report: adrenal
(e.g., cryoglobulinemic vasculitis) and peripheral autoimmunity in primary Sjgrens syndrome. Arthritis Rheum
neuropathy with reduction of disease activity in- 2012;64:4066-71.
dices imply that rituximab is a promising therapeu- 18. Euthymiopoulou K, Aletras AJ, Ravazoula P, et al. Antiovarian
antibodies in primary Sjgrens syndrome. Rheumatol Int 2007;
tic strategy for Sjgren syndrome.73,75,7982 27:1149-55.
19. Tsokos M, Lazarou SA, Moutsopoulos HM. Vasculitis in pri-
mary Sjgrens syndrome. Histologic classification and clinical
Unanswered questions presentation. Am J Clin Pathol 1987;88:26-31.
20. Ramos-Casals M, Anaya JM, Garcia-Carrasco M, et al. Cutaneous
vasculitis in primary Sjgren syndrome: classification and clinical
Key questions remain with regard to disease significance of 52 patients. Medicine (Baltimore) 2004;83:96-106.
pathogenesis, clinical spectrum and therapeutic 21. Brito-Zern P, Akasbi M, Bosch X, et al. Classification and char-
acterisation of peripheral neuropathies in 102 patients with pri-
strategies. Four main questions are the focus of mary Sjgrens syndrome. Clin Exp Rheumatol 2013;31:103-10.
basic and clinical research: the identification of 22. Pavlakis PP, Alexopoulos H, Kosmidis ML, et al. Peripheral
proximal triggers (exogenous or endogenous fac- neuropathies in Sjgren syndrome: a new reappraisal. J Neurol
Neurosurg Psychiatry 2011;82:798-802.
tors) that account for epithelial activation and 23. Alexander EL, Arnett FC, Provost TT, et al. Sjgrens syndrome:
immunological injury; the thorough characteriza- association of anti-Ro(SS-A) antibodies with vasculitis, hemato-
logic abnormalities, and serologic hyperreactivity. Ann Intern Med
tion of various clinical phenotypes and association 1983;98:155-9.
with distinct pathogenetic pathways such as type I 24. Soliotis FC, Mavragani CP, Moutsopoulos HM. Central nervous
system involvement in Sjgrens syndrome. Ann Rheum Dis 2004;
interferon/BAFF axisdesignation of tailored ther- 63:616-20.
apies; determination of the underlying genetic, 25. Tsampoulas CG, Skopouli FN, Sartoris DJ, et al. Hand radi-
ographic changes in patients with primary and secondary Sj-
epigenetic and immunologic mechanisms of grens syndrome. Scand J Rheumatol 1986;15:333-9.
lymphomagenesis related to Sjgren syndrome; 26. Kassan SS, Moutsopoulos HM. Clinical manifestations and
early diagnosis of Sjgren syndrome. Arch Intern Med 2004;
and the implementation of preventative therapeu- 164:1275-84.
tic strategies against lymphoma development in 27. Youinou P, Pennec YL, Katsikis P, et al. Raynauds phenomenon
high-risk patients with Sjgren syndrome. in primary Sjgrens syndrome. Br J Rheumatol 1990;29:205-7.
28. Garca-Carrasco M, Siso A, Ramos-Casals M, et al. Raynauds
phenomenon in primary Sjgrens syndrome. Prevalence and clin-
ical characteristics in a series of 320 patients. J Rheumatol 2002;
References 29:726-30.
1. Mavragani CP, Moutsopoulos HM. The geoepidemiology of 29. Papiris SA, Maniati M, Constantopoulos SH, et al. Lung
Sjgrens syndrome. Autoimmun Rev 2010;9:A305-10. involvement in primary Sjgrens syndrome is mainly related to
2. Routsias JG, Tzioufas AG. Autoimmune response and target the small airway disease. Ann Rheum Dis 1999;58:61-4.
autoantigens in Sjgrens syndrome. Eur J Clin Invest 2010;40: 30. Papiris SA, Tsonis IA, Moutsopoulos HM. Sjgrens syndrome.
1026-36. Semin Respir Crit Care Med 2007;28:459-71.
3. Yoshimi R, Ueda A, Ozato K, et al. Clinical and pathological 31. Hatzis GS, Fragoulis GE, Karatzaferis A, et al. Prevalence and
roles of Ro/SSA autoantibody system. Clin Dev Immunol. 2012; longterm course of primary biliary cirrhosis in primary Sjgrens
2012:606195. syndrome. J Rheumatol 2008;35:2012-6.
4. Drosos AA, Andonopoulos AP, Costopoulos JS, et al. Prevalence 32. Maripuri S, Grande JP, Osborn TG, et al. Renal involvement in
of primary Sjgrens syndrome in an elderly population. Br J primary Sjgrens syndrome: a clinicopathologic study. Clin J Am
Rheumatol 1988;27:123-7. Soc Nephrol 2009;4:1423-31.
5. Haugen AJ, Peen E, Hulten B, et al. Estimation of the prevalence 33. Moutsopoulos HM, Cledes J, Skopouli FN, et al. Nephrocalci-
of primary Sjgrens syndrome in two age-different community- nosis in Sjgrens syndrome: a late sequela of renal tubular aci-
based populations using two sets of classification criteria: the dosis. J Intern Med 1991;230:187-91.
Hordaland Health Study. Scand J Rheumatol 2008;37:30-4. 34. Goules AV, Tatouli IP, Moutsopoulos HM, et al. Clinically signif-
6. Voulgarelis M, Ziakas PD, Papageorgiou A, et al. Prognosis and icant renal involvement in primary Sjgrens syndrome: clinical
outcome of non-Hodgkin lymphoma in primary Sjgren syn- presentation and outcome. Arthritis Rheum 2013;65:2945-53.
drome. Medicine (Baltimore) 2012;91:1-9. 35. Caramaschi P, Biasi D, Caimmi C, et al. The co-occurrence of
7. Skopouli FN, Dafni U, Ioannidis JP, et al. Clinical evolution, and Hashimoto thyroiditis in primary Sjgrens syndrome defines a
morbidity and mortality of primary Sjgrens syndrome. Semin subset of patients with milder clinical phenotype. Rheumatol Int
Arthritis Rheum 2000;29:296-304. 2013;33:1271-5.