Quick viewing(Text Mode)

Sjögren's Syndrome

Sjögren's Syndrome

Sjögren's syndrome

Author: Doctor Menelaos N. Manoussakis1 Creation Date: November 2001 Update: June 2004

Scientific Editor: Professor Haralampos M. Moutsopoulos

1Department of Pathophysiology, School of Medicine, National University of Athens, 75 Mikras Asias str., 11527 Athens, Greece. [email protected]

Abstract Keywords name and synonyms Diagnosis Criteria/Definition Differential Diagnosis Prevalence Clinical Description Management including treatment Etiology Diagnostic methods Unresolved questions References

Abstract Sjögren's syndrome (SS) is a chronic autoimmune disorder. It is characterized by dysfunction and destruction of the exocrine glands associated with lymphocytic infiltrates and immunological hyperreactivity. Salivary and lacrimal glands are the most affected, thus leading to mouth and eye dryness. The disorder can occur alone (it is then known as ``primary-SS'') or in association with another autoimmune disease (it is then known as ``secondary-SS''). Prevalence of primary-SS in the general population has been estimated to be around 1 to 3%. Although patients of all ages and of both sexes may be affected, this disorder mostly affects women (9:1 female to male ratio) in their fourth or fifth decade of life. In the majority of patients, SS has an indolent or slowly progressive course with disease confined in exocrine glands. Mild rheumatic complaints have also been reported. At presentation or during the course of the disease, almost one third of the primary-SS patients experiences a more generalized disease, which does not usually evolve to the failure of the affected organ. However, stringent follow-up should be instituted in patients with adverse prognosis predictors such as purpura, low C4-complement levels or mixed monoclonal cryoglobulins. Risk of developing lymphoma and mortality are higher in these patients. To date, the management of patients has primarily aimed to provide symptomatic relief to lessen mucosal dryness-induced damage and to early recognize and treat disease complications.

Keywords Sjögren's syndrome, autoimmune epithelitis, autoimmune exocrinopathy, autoimmune rheumatic , exocrine glands, epithelial cells, primary Sjögren's syndrome, secondary Sjögren's syndrome, lymphoma, autoantibodies.

Sicca syndrome. Disease name and synonyms Sjögren's syndrome;(SS) Diagnosis Criteria/Definition Sjögren-Gougerot's syndrome; No single symptom, sign or test is Mickulitz' syndrome; pathognomonic for SS (1). However, diagnosis is autoimmune exocrinopathy; usually readily achieved by gathering information autoimmune epithelitis; obtained from the clinical, histopathologic and

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 1

serologic assessment of patients. A set of Revised rules for classification diagnostic and classification criteria for the For patients without any potentially associated disease the appraisal of the SS sicca manifestations have presence of any four of the six items is indicative of primary been determined (2). These include the SS. For patients with a potentially associated disease (for instance another connective tissue disease) item 1 or item 2 affirmation of subjective complaints about oral plus any two from items 3, 4, 5 is indicative of secondary and/or eye dryness, the objective evidence of SS. and/or ocular involvement, as well Exclusion criteria : pre-existing lymphoma, acquired as of autoimmune reactivity, namely the immunodeficiency disease (AIDS), , graft-versus- host disease, sialoadenosis, use of anti-depressant and presence of lymphocytic infiltrative lesions in the anti-hypertensive drugs, neuroleptics, parasympatholytic salivary glands () and of serum drugs. autoantibodies against Ro(SSA) and La(SSB). Test should be excluded from the criteria or not considered Recently, occurrence of sialadenitis and indicative for a diagnosis of SS in elderly subjects (older than 60 years). presence of serum anti-Ro(SSA)/La(SSB) autoantibodies were introduced as compulsory Differential Diagnosis classification criteria by the American-European Various acute or chronic medical conditions may Consensus Group (Table-1) (3). simulate SS. These include adverse effects of

drugs, infection, tumor, metabolic disorders and Table 1. The revised international irradiation. In particular, sarcoidosis, classification criteria for Sjögren's syndrome lipoproteinemia (types-II, -IV and -V), chronic I. Ocular symptoms A positive response to at least one of the three following graft-versus-host disease, lymphoma, questions: amyloidosis and infection by hepatite C virus Have you had daily, persistent, troublesome dry eyes for (HCV) or human immunodeficiency virus (HIV) more than three months? might be misdiagnosed as SS (Table-2). In the Have you had recurrent sensation of sand or gravel in the eyes? elderly, mucosal dryness is frequently an age- Do you use tear substitutes more than three times a day? related process characterized by degeneration II. Oral symptoms and liposis of the exocrine glands. A positive response to at least one of the three following questions: Table 2. Differential diagnosis of idiopathic Have you had a daily feeling of dry mouth for more than three months? primary SS from the SS-like disorder which is Have you had recurrent or persistent swollen salivary gland associated with infection by HIV or HCV as an adult? viruses, or sarcoidosis. Do you frequently drink liquids to aid in swallowing dry food? HIV HCV III. Ocular signs infection infection Objective evidence of ocular involvement is defined as a Primary with with Sarcoidos positive result in at least one of the following two tests: SS sicca sicca is Schirmer's I test, performed without anesthesia (< 5 mm in 5 syndrom syndrom minutes) e e Rose-Bengal score or another ocular dye score (> 4 Age Middle-age Young All ages Middle-age according to van Bijsterveld's scoring system) Sex No No Female Male IV. Histopathology predilection difference difference Presence of focal lymphocytic sialadenitis in minor salivary glands (obtained through normal-appearing mucosa), Anti-Ro(SSA) and anti- evaluated by an expert histopathologist with a focus score Frequently La(SSB) Absent Absent Absent >1, defined as a number of lymphocytic foci which are present adjacent to normal-appearing mucous acini and contain autoantibodie more than 50 lymphocytes per 4 mm2 of glandular tissue. s V. Salivary gland involvement Predominant T-cell type in Objective evidence of salivary gland involvement is defined CD4 CD8 CD4 Granuloma as a positive result in at least one of the following three lymphoid tests: infiltrates Unstimulated salivary flow (< 1,5 ml in 15 min) Diagnostic Parotid sialography showing the presence of diffuse viral serologic None HIV tests HCV tests None sialectasias (punctate, cavitary or destructive pattern), test without evidence of obstruction in the major ducts. DR3, Salivary scintigraphy showing delayed uptake, reduced HLA- DRw53, HLA-DR5 Unknown Unknown concentration and/or delayed excretion of tracer association DQA1*050 1 VI. Autoantibodies Presence in the serum of the following autoantibodies: antibodies to Ro(SSA) or La(SSB) or both. Prevalence Sjögren syndrome is a homogeneous disease that occurs worldwide with similar prevalence. The disorder mostly affects women (9:1 female to male ratio) in their fourth or fifth decade of life.

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 2

This predominance of SS in women seems to be polyarthritis may also occur. Despite related to the immunoregulatory properties of the and easy fatigue, frank myositis is unusual. sex hormones (20). However, patients of both sexes and all ages may be affected. Prevalence Respiratory tract of primary-SS in the general population has In patients with primary-SS, involvement of been estimated to be around 1 to 3% (4,5), respiratory system is frequent, however it is whereas secondary-SS has been observed in usually of limited clinical significance. Dry cough approximately 10-20% of patients with (due to xerotrachea or bronchitis sicca) is very , systemic common. Approximately half of the patients erythematosus (SLE) and scleroderma (1). It is present with evidence of interstitial-like disease estimated that Sjögren syndrome is the second in plain chest radiography. High resolution most common rheumatologic disorder, behind computerized tomography often reveals only SLE. bronchial or peribronchial thickening, usually associated with the presence of bronchiolar Clinical Description lymphoid infiltrates and follicular bronchiolitis. Lung nodules or hilar and/or mediastinal Glandular Features lymphadenopathy should always raise suspicion Chronic dryness of the mouth (xerostomia) for lymphoma development. and/or the eyes (keratoconjuctivitis sicca) due to diminished secretion of the and tears is Gastrointestinal tract and hepatobiliary system characteristic of the disorder (1). Moistening The dryness of the pharynx and oesophagus glands in the nose, the pharynx, the may produce . Chronic atrophic tracheobronchial tree, the skin and the stomach gastritis and lymphocytic infiltrates of gastric may be also affected. Troubles in chewing and mucosa may be observed, largely reminiscent of swallowing, sore mouth and recurrent dental those in minor salivary glands. involvement caries are common. The tongue is typically in primary-SS patients is rare (5%) and smooth with fissures and atrophy of the filiform subclinical. By contrast, sicca manifestations are papillae. Edentulous patients report very poor found in 50-80% of the patients with primary comfort with conventional , however biliary cirrhosis. Small bowel reveals the implant-retained prostheses are very well occurrence of celiac-like disease in tolerated. Enlargement of the major salivary approximately 15% of the primary-SS patients. gland occurs in 25-66% of the primary-SS patients, but is uncommon in patients with Urinary tract secondary-SS. Bacterial infection or salivary Approximately one third of the SS patients gland tumor should always be suspected in present with evidence of distal renal tubular unilateral salivary gland enlargement, even in acidosis (type-I), which is usually subclinical. patients with established diagnosis of SS. However, these patients can present with Chronic eye dryness leads to persistent irritation hypokalemic muscular weakness, recurrent renal and to destruction of the corneal and bulbar colici which can lead to nephrocalcinosis if they conjunctival epithelium (keratoconjuctivitis are not treated. In a series of 471 primary-SS sicca). Sandy or burning sensation is a patients followed-up for 10 years, approximately complaint frequently reported and patients may 4% of the patients had clinically important renal be unable to tolerate smoke, air drafts or light. disease manifested by interstitial nephritis or glomerulonephritis (6). Interstitial nephritis is Systemic manifestations found early in the disease course and is benign. Approximately half of the patients with primary- On the contrary, immune complex SS show evidence of extraglandular glomerulonephritis (membranoproliferative or involvement, however, these systemic mesangial proliferative) is associated with manifestations are often mild (1). Easy fatigue cryoglobulinemia and hypocomplementemia and and low-grade are more frequent in can lead to chronic renal insufficiency (6). patients with clinically significant extraglandular Frequent micturition and suprapubic pain may disease. imply interstitial cystitis often associated with lymphocytic infiltrative lesions. Musculoskeletal Most patients suffer from fatigue, whereas Vasculature and skin evidence of fibromyalgia is found in 12-30% of Raynaud's phenomenon is found in more than the patients. , myalgia and morning 35% of the patients. Nailfold capillaroscopy often stiffness are very frequent. Non-erosive arthritis reveals scleroderma-like lesions in primary-SS as well as a rheumatoid arthritis-like symmetric patients with anti-centromere antibodies. Small-

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 3

vessel vascular inflammatory disease has been major risk factors for lymphomatous described in 20-30% of the primary-SS patients. transformation in SS patients include persistent Vasculitis of the skin is mostly observed, unilateral or bilateral enlargement, presenting with palpable purpuric or petechial and lymphadenopathy, as well as lesions. Recurrent urticaria and annular type II mixed monoclonal cryoglobulinemia. of the face and trunk may also be Various histologic subtypes of MNHL have been found. Systemic necrotizing vasculitis with described, including follicle center lymphoma, visceral involvement affecting kidney, lung and lymphoplasmacytoid lymphoma, diffuse, large B- gastrointestinal tract may occur. However, it is cell lymphoma, and mucosa-associated rare. lymphoid tissue (MALT) lymphoma. According to a recent multi-center study of 33 primary-SS Neuroendocrine and psychiatric system patients with MNHL, low-grade marginal-zone B- Entrapment syndromes, peripheral sensory or cell lymphoma (a term, which includes MALT sensory-motor polyneuropathy and/or and monocytoid B-cell lymphomas) was the mononeuritis multiplex may occur. Hemiparesis, predominant type (8). In most cases, the patients seizures, cerebellar defects and transverse had good clinical performance status. Extranodal myelopathy have been described in primary-SS localization is very frequent and involves the patients, but this has not been confirmed. salivary glands in approximately 55% of total Evidence of autonomic dysfunction is found in lymphoma cases. The survival of these patients certain patients with primary-SS, possibly is closely associated with the histological grade mediated by antagonistic anti-M3 muscarinic of lymphoma; high- and intermediate- grade receptor autoantibodies. , depressed lymphomas have the worst prognosis, whereas mood and personality disorders are frequently low-grade lymphoma in SS patients may either observed and may be associated with altered remain stable for several years, or show perception of emotional stress and/or temporary spontaneous regression or transform dysregulated stress responses. Hypoactivity of to a high-grade form. Patients at high risk of hypothalamic-pituitary-adrenal axis has been MNHL should be followed regularly. When this demonstrated. transformation occurs, treatment decisions rely on the stage and the grade of lymphoma. Other manifestations Anti-thyroid antibodies and abnormal thyroid- Secondary Sjögren's syndrome hormone stimulation tests are common, but Features of SS may occur in almost every clinically overt autoimmune thyroiditis is not autoimmune rheumatic disease, including frequent. In a recent study, no significant rheumatoid arthritis (RA), systemic lupus difference has been observed in the prevalence erythematosus (SLE), scleroderma, primary of autoimmune and non-autoimmune thyroid biliary cirrhosis and mixed connective tissue disease between SS patients and controls (7). disease (1). In some respects, sicca Sensorineural hearing loss is reported to occur syndrome(s) that occur(s) in the context of in 20-45% of the SS patients. Fertility, parity and distinct rheumatic diseases may take different sexual activity are not affected apparently, forms. Sicca complaints are common (20%) in whereas insufficient vaginal lubrication causing RA patients; however, clinically significant SS is dyspareunia appears to be correlated with found in only 5% of all the patients. atrophic vaginitis and perivascular infiltration. Keratoconjunctivitis sicca is the main sicca Elevated erythrocyte sedimentation rate is manifestation, whereas xerostomia and salivary detected in approximately 70% of the patients. gland enlargement are quite uncommon. In addition, autoantibodies against Ro(SSA) and Lymphoma development La(SSB), as well as distinct HLA haplotypes In primary-SS, predisposition for development of which typically characterize primary-SS, are malignant non-Hodgkin's lymphoma (MNHL), rather uncommon in RA with secondary-SS. By which usually occurs later in the course of the contrast, patients with primary-SS and those with disease, is well established (1). Whether SS associated with SLE may present with similar secondary-SS also predisposes to lymphoma clinical manifestations, i.e. , rash, remains unclear. In primary-SS, lymphoma has peripheral neuropathy and glomerulonephritis. been estimated to occur in approximately 4-6% Almost 20% of the patients with systemic of the patients followed-up for about 8 years. sclerosis present with oral or ocular dryness This frequency is considerably higher than that often due to extensive fibrosis of the exocrine of rhumatoid arthritis (RA), where in the absence glands. By contrast, sicca manifestations of immunosuppressive treatment, lymphoma associated with frank lymphocytic infiltrative occurs in approximately 1% of the patients. The

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 4

lesions are extremely common (60%) in patients Management including treatment with limited scleroderma. General measures Clinical course No clinical trial has shown the efficacy of any The initial presentation of the disorder at drug in altering the course of the disease yet. diagnosis essentially determines its outcome (9). Patients follow-up and treatment aim to provide In the vast majority of patients, the glandular symptomatic relief to lessen mucosal dryness- sicca features and serologic profile remain induced damage and to early recognize and unchanged through the disease course (9,10). treat disease complications (12). The decision This is apparently the case for most systemic for systemic therapeutic intervention remains extraglandular manifestations, except for the largely empirical and is primarily reserved for development of lymphoma and severe extraglandular disease. Since no or glomerulonephritis which are usually late events. hardly any clinical benefit has been observed Occurrence of palpable purpura, low C4- and due to potential side effects, administration complement levels and mixed monoclonal of immunosuppressive agents is not cryoglobulins are adverse prognostic factors (9). recommended for the every-day treatment of SS. The overall mortality of primary-SS is not Aggressive treatment with cytotoxic drugs, such different from that of general population (11). as cyclophosphamide, should be reserved for However, mortality is higher in patients with life-threatening systemic manifestations such as adverse predictors (9). necrotizing vasculitis. Recently, the oral administration of a low-dose natural human Biological findings interferon-alpha has been reported to provide Polyclonal B-cell hyperreactivity is one of the relief for sicca symptoms and to improve saliva most prominent immunological features of SS flow. When acute relief of symptomatology is and manifests itself by profound needed, the patient may benefit of hypergammaglobulinemia, circulating immune plasmaferesis. Infliximab (anti tumor necrosis complexes and multiple autoantibodies directed factor-alfa antibodies) has shown some against both organ and non-organ specific usefulness in the treatment of extraglandular autoantigens (1). Rheumatoid factors (RF), anti- symptoms and peripheral nervous system nuclear antibodies (ANA), anti-histone and anti- manifestations. This agent might be considered single-stranded DNA antibodies are found in when all other treatment modalities have failed notably high levels and quite frequently (over given the presumed importance of tumour 70% of the cases). By standard gel precipitation necrosis factor in the pathogenesis of Sjogren's methods, antibodies to Ro(SSA) and La(SSB) syndrome (21). Use of localised gene transfer are found in 40-60% and 25-40%, respectively, has been proposed to develop new treatment of primary-SS patients. Mothers with these strategies for the salivary component of autoantibodies are at a relatively increased risk Sjogren's syndrome (22). of giving birth to children with congenital complete heart block. Recently, the cytoskeletal Dryness of mucosae protein alpha-fodrin has been proposed as a The main objectives of treatment are to prevent candidate autoantigen in primary-SS, based on keratoconjuctivitis sicca and dental disease to the antibody and T-cell reactivities found in stimulate residual saliva and tear secretion and patients. to treat infection when required. Protective Oligoclonal B-cell expansions in the form of measures against windy or dry climates, dust monoclonal light chains or immunoglobulins in and smoke should be taken. , the serum and urine are found in 80-100% of antihypertensive drugs, and patients with systemic involvement, compared to should be used with caution. Eye approximately 25-40% of patients with only lubricants are used for keratoconjuctivitis sicca glandular disease (1). In addition, approximately as often as necessary. Patients with residual one third of primary-SS patients exhibit high glandular function may benefit significantly from serum levels of mixed polyclonal/monoclonal the administration of the muscarinic M3 receptor cryoglobulins (type II), which usually contain an agonists, and (13,14). IgMk-monoclonal RF. Signs of in situ Infection should always be suspected when lymphomatous transformation are frequently sudden aggravation of symptoms and/or noted at the lymphoepithelial lesions of SS excessive mucus production occurs. patients, whereas in the majority of patients with Corticosteroid-containing ophthalmic solutions overt lymphoma, neoplastic tissue is located in should be avoided. Dental treatment with fluoride the salivary glands. delays damage of teeth surfaces. Propionic acid gels or other vaginal lubricants may be used to

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 5

treat vaginal dryness and dyspareunia. In Malignant lymphoma menopause, the administration of conjugated Treatment of malignant lymphoma in SS patients estrogens as vaginal cream or oral tablets may is based on its histological type, location and be helpful. extent, as for lymphoid neoplasias in general. For low-grade lymphomas of the exocrine glands Salivary gland enlargement a watchful attitude is recommended. Swelling of parotid and submandibular glands is frequent and most often regresses Etiology spontaneously without treatment. Local The etiology of SS remains largely obscure. A application of moist heat may be helpful, as well viral etiology has long been suspected for the as non-steroidal anti-inflammatory drugs. A induction of SS, however, no definite conclusion tender gland with permanent enlargement has been drawn (1). Although genetic influences should always raise suspicion for bacterial are thought to be responsible for pathogenesis, infection. Corticosteroids may be used with no such single factor has been identified. caution, as they may exacerbate infection. Studies from different countries and ethnic Performing tissue biopsy should be always groups have revealed associations with various considered to exclude lymphoma. HLA-DR alleles (DRB1 genes), including DR3, DR5, DRw11 and DRw53. The association of Musculoskeletal manifestations primary-SS with DQA1*0501, DQB1*0201 and Non-steroidal anti-inflammatory drugs or DQBI*0301 alleles appears to cross ethnic hydroxychloroquine are frequently used for the barriers. On the basis of focal lymphoid treatment of arthralgia, myalgia and infiltrative lesions and prominent autoantibody constitutional symptoms. Treatment with responses, SS exocrinopathy is considered as hydroxychloroquine has been reported to an autoimmune disorder. The autoantibody improve features of immunological responses may contribute significantly to hyperreactivity in primary-SS patients, however, glandular epithelial dysfunction of patients. double-blind controlled studies are lacking. For Recently, it has been shown that antagonistic persistent arthritis, methotrexate may be used, anti-M3 muscarinic receptor autoantibodies are as recommended for RA. capable of having inhibitory influence on parasympathetic neurotransmission (15). Renal involvement Increasing body of evidence suggests that the To avoid the development of nephrocalcinosis, affected glandular epithelia may have a role in patients with overt distal renal tubular acidosis the induction and maintenance of chronic should receive sodium or potassium bicarbonate immune activation in SS patients (16). Cultured orally at a dose sufficient to diminish acidosis, non-neoplastic salivary gland epithelial cell lines hypokalemia and hypercalciuria. derived from SS patients have been shown to Membranoproliferative glomerulonephritis is manifest increased spontaneous expression of initially treated with . In refractory various activation- and immune response- cases, monthly intravenous pulses of associated molecules, which possibly indicates cyclophosphamide should be administred. the operation of intrinsic activation processes in SS epithelia (17,18). Epithelial cells of salivary Pulmonary involvement gland are functionally competent to stimulate the For severe dry cough from desiccation of the growth of activated T cells, suggesting the tracheobronchial tree, hydration, humidifiers at potential of these cells to participate in antigen- bedtime and muscarinic M3 receptor agonists mediated activation and proliferation of T should be tried. Yearly pulmonary function tests lymphocytes (19). are recommended. Diagnostic methods Vascular manifestations For patients with Raynaud's phenomenon, Oral and ocular components exposure to cold, emotional stress and smoking Overt SS is associated with severely reduced should be avoided. Nifedipine given orally may production of unstimulated whole saliva (less help to reduce frequency and severity of than 1,5 ml in 15 min). Digital subtraction vasospasm. Leukocytoclastic vasculitis is a or scintigraphy (99mTc-sodium common problem that does not require specific pertechnate) can be used with high diagnostic therapy. Systemic necrotizing vasculitis can be accuracy for SS. Wetting of a paper strip (placed treated with prednisone and intravenous at the lower lid) of less than 5-mm/5 min is a cyclophosphamide pulses, as mentioned above, strong indication of diminished tear secretion as well as plasmapheresis. (Schirmer's test). Staining of damaged corneal

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 6

and conjunctival epithelia by Rose Bengal dye is 5. Dafni UG, Tzioufas AG, Staikos P, et al: a more specific assay for keratoconjuctivitis Prevalence of Sjögren's syndrome in a closed sicca than Schirmer's test in elderly subjects. rural community. Ann Rheum Dis; 56:521-525, 1997. Histological assessment 6. Goules A, Masouridi S, Tzioufas AG, et al.: The presence of focal or diffuse sialadenitis is Clinically significant and biopsy-documented one of the most consistent features of SS. renal involvement in primary Sjögren syndrome. Typical lesions consist of multiple focal Medicine (Baltimore) ;79:241-9, 2000. mononuclear aggregates that replace glandular 7. Ramos-Casals M, Garcia-Carrasco M, structures. A focus score >1 is considered to be Cervera R, et al.: Thyroid disease in primary an indicator of SS, with "focus score" defined as Sjögren syndrome. Study in a series of 160 the number of lymphocytic foci which are patients. Medicine (Baltimore); 79:103-108, adjacent to normal-appearing mucous acini and 2000. contain more than 50 lymphocytes per 4 mm2 of 8. Voulgarelis M, Dafni UG, Isenberg DA, et al.: glandular tissue. Malignant lymphoma in primary Sjögren 's syndrome: a multicenter, retrospective, clinical Serological tests study by the European Concerted Action on Strongly positive tests for ANA, RF and Sjögren 's Syndrome. Arthritis Rheum; 42:1765- antibodies to Ro(SSA) and La(SSB) antigens 1772, 1999. corroborate the diagnosis. In particular, the 9. Skopouli FN, Dafni U, Ioannidis JP, et al.: identification of serum autoantibodies to Clinical evolution, morbidity and mortality of Ro(SSA) or La(SSB) proteins in a patient with primary Sjögren 's syndrome. Semin Arthritis sicca complaints is a strong clue for the Rheum; 29:296-304, 2000. diagnosis of the disorder. Monitoring of the 10. Gannot G, Lancaster HE, Fox PC. Clinical serum levels of the above-mentioned course of primary Sjögren 's syndrome: salivary, autoantibodies is not helpful for the following-up oral, and serologic aspects. J Rheumatol; or the prognosis of the patients. 27:1905-1909, 2000. 11. Martens PB, Pillemer SR, Jacobsson LT, et Unresolved questions al.: Survivorship in a population based cohort of To determine the origin of chronic and persistent patients with Sjögren 's syndrome, 1976-1992. J activation of immune system. Rheumatol; 26:1296-1300, 1999. To elucidate the role of immunologic, 12. Moutsopoulos NM, Moutsopoulos HM: immunogenetic and neuroendocrine factors in Therapy of Sjögren's syndrome. Springer Semin the pathogenesis of the disease. Immunopatho.; 23:131-145, 2001. To find a specific immunological intervention to 13. Fox PC, Atkinson JC, Macynski AA, et-al: alleviate disease Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch References Intern Med; 151:1149, 1991. 1. Manoussakis MN, Moutsopoulos HM: 14. Iga Y, Arisawa H, Ogane N, et al.: (+/-)-cis-2- Sjögren's Syndrome: autoimmune epithelitis. methylspiro[1,3-oxathiolane-5,3'-quinuclidine] Baillieres Best Pract Res Clin Rheumatol; 14: hydrochloride, hemihydrate (SNI-2011, 73-95, 2000. cevimeline hydrochloride) induces saliva and 2. Vitali C, Bombardieri S, Moutsopoulos HM, et tear secretions in rats and mice: the role of al.: Assessment of the European classification muscarinic receptors. Jpn J criteria for Sjögren's syndrome in a series of Pharmacol;78:373-780, 1998. clinically defined cases: results of a prospective 15. Waterman SA, Gordon TP, Rischmueller M: multicentre study. Ann Rheum Dis; 55:116-121, Inhibitory effects of muscarinic receptor 1996. autoantibodies on parasympathetic 3. Vitali C, Bombardieri S, Jonsson R, et al.: neurotransmission in Sjögren 's syndrome. Classification criteria for Sjögren's syndrome: A Arthritis Rheum; 43:1647-1654, 2000. revised version of the European criteria 16. Moutsopoulos HM: Sjögren's syndrome: proposed by the American-European Consensus Autoimmune epithelitis. Clin Immunol Group. Ann Rheum Dis; in press, 2001. Immunopathol; 72:162-165, 1994. 4. Jacobsson LTH, Axell TE, Hansen BU, et al: 17. Manoussakis MN, Dimitriou ID, Dry eyes or mouth. An epidemiological study in Kapsogeorgou EK, et al.: Expression of B7 Swedish adults with special reference to primary costimulatory molecules by salivary gland Sjögren's syndrome. J ; 2:521-527, epithelial cells in patients with Sjögren's 1989. syndrome. Arthritis Rheum; 42:229-239, 1999.

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 7

18. Abu-Helu RF, Dimitriou ID, Kapsogeorgou 20. Yamamoto K. Pathogenesis of Sjogren’s EK, et al.: Induction of salivary gland epithelial syndrome. Autoimmun Rev; 2:13-8, 2003. cell injury in Sjögren 's syndrome: the role of T 21. Rogers SJ, Williams CS, Roman GC. cell-derived cytokines and Fas protein Myelopathy in Sjogren’s syndrome: role of expression. J Autoimmun;17:141-153, 2001. nonsteroidal immunosuppressants. Drugs; 19. Kapsogeorgou EK, Moutsopoulos HM, 64:123-32, 2004. Manoussakis, MN: Functional expression of a 22. Kok MR, Baum BJ, Tak PP, Pillemer SR. costimulatory B7.2 (CD86) protein on human Use of localised gene transfer to develop new salivary gland epithelial cells that interacts with treatment strategies for the salivary component the CD28 receptor, but has reduced binding to of Sjogren’s syndrome. Ann Rheum Dis; 62: CTLA4. J Immunol; 166:3107-13, 2001. 1038-46, 2003.

Manoussakis M.N.. Sjögren 's syndrome.Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-sjogren.pdf 8

Top View