Moshe Tishler

Assessment of the European classification criteria for Sjögren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjögren's Syndrome.

OBJECTIVE: To assess the recently proposed preliminary criteria for the classification of Sjögrens syndrome (SS) in a multicentre European study of a new series of clinically defined cases. METHODS: The criteria included six items: I = ocular symptoms; II = oral symptoms; III = evidence of keratoconjunctivitis sicca; IV = focal sialoadenitis by minor salivary gland biopsy; V = instrumental evidence of salivary gland involvement; VI = presence of autoantibodies. Each centre was asked to provide five patients with primary SS, five with secondary SS, five with connective tissue diseases (CTD) but without SS, and five controls (patients with ocular or oral features that may simulate SS). The preliminary six item classification criteria set was applied to both the SS patients and the non-SS controls, and the performance of the criteria in terms of sensitivity and specificity was tested. RESULTS: The criteria set was tested on a total of 278 cases (157 SS patients and 121 non-SS controls) collected from 16 centres in 10 countries. At least four of the six items in the criteria set (limiting item VI to the presence of Ro(SS-A) or La(SS-B) antibodies) were present in 79 of 81 patients initially classified as having primary SS (sensitivity 97.5%), but in only seven of 121 non-SS controls (specificity 94.2%). When the presence of item I or II plus any two of items III-V of the criteria set was considered as indicative of secondary SS, 97.3% (71 of 73) of the patients initially defined as having this disorder and 91.8% (45 of 49) of the control patients with CTD without SS were correctly classified. CONCLUSION: This prospective study confirmed the high validity and reliability of the classification criteria for SS recently proposed by the European Community Study Group.

Elevated tear interleukin-6 levels in patients with Sjögren syndrome

OBJECTIVE The purpose of the study was to investigate interleukin-6 (IL-6) levels in the tear fluid and sera of patients with Sjögren syndrome (SS). PARTICIPANTS Twelve patients with primary SS and 12 normal control subjects participated. INTERVENTION Tear fluid and sera were obtained from the study and the control groups. Evaluation of tear fluid and sera IL-6 levels was done by using a quantitative enzyme-linked immunosorbent assay kit. All assays were carried out blindly with respect to diagnosis. MAIN OUTCOME MEASURES Tear fluid IL-6 levels were measured. RESULTS The mean concentration (+/- standard error) of IL-6 in the tears of patients with SS was elevated significantly compared to that of normal control subjects (88.6+/-16.2 vs. 42.1+/-10.6 pg/ml; P < 0.05). No significant differences were noted in the serum IL-6 levels between the two groups. A significant correlation (r = 0.742, P = 0.006) was found between tear fluid IL-6 levels and the focus score of lip biopsy specimens in patients with SS. CONCLUSION Tear fluid IL-6 levels may serve as an important marker for tear gland involvement in SS.

Hydroxychloroquine treatment for primary Sjögren’s syndrome: its effect on salivary and serum inflammatory markers

OBJECTIVE To evaluate the effect of hydroxychloroquine treatment on interleukin 6 (IL6), hyaluronic acid (HA), and soluble interleukin 2 receptor (sIL2R) concentrations in the saliva and serum of patients with primary Sjögren’s syndrome (SS). METHODS Fourteen SS patients treated with hydroxychloroquine 200 mg/day for 12 months were investigated in an open prospective study. Clinical parameters of efficacy and routine biochemical and haematological data to assess drug safety and tolerability were determined every three months. Salivary and serum IL6, sIL2R, and HA values were determined at study entry, 6 and 12 months, using ELISA and radiometric assays. RESULTS After hydroxychloroquine treatment, salivary IL6 concentrations decreased from 13.2 (1.2) to 7.3 (1.1) pg/ml (mean (SEM)) (p < 0.0001). Similarly, salivary HA concentrations were also reduced from 577.8 (120) to 200 (34) ng/ml (mean (SEM) (p < 0.003). Serum IL6 concentrations decreased from 5.4 (0.6) to 2.9 (0.2) pg/ml (mean (SEM) (p < 0.001), while serum HA concentrations remained unchanged. No change has been detected in salivary or serum sIL2R concentrations after 12 months of treatment with hydroxychloroquine. Treatment also resulted in significant reduction in erythrocyte sedimentation rate, serum γ globulin, and C reactive protein values while only partial clinical improvement was noted in some patients. A more pronounced decrease of salivary IL6 and HA levels was found in the two patients in whom a reduction in the swelling of the parotid gland was noted. CONCLUSION In this open label study of hydroxychloroquine treatment for SS a significant reduction of some salivary inflammatory markers was seen at the end of 12 months. Although during the treatment period only a partial clinical effect could be noted, the findings suggest that a double blind controlled study of hydroxychloroquine in SS is indicated.

Anti-heat-shock protein antibodies in rheumaticand autoimmune diseases

The heat-shock proteins (hsp) are a family of molecules that have different molecular weights and are thought to operate as scavengers that trap abnormal proteins and protect the stressed cells. These molecules, which have been conserved during evolution, have highly identical stretches of their amino acid sequence in bacteria as well as in humans. Experiments show that arthritis patients manifest T-cell responses to the hsp-65-kD molecule, as do rats with adjuvant arthritis. The B cell response to hsp has not been extensively studied. Autoantibodies against hsp 65, 70, and 90 have been detected in various rheumatic and autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, and inflammatory bowel diseases. The frequency of these antibodies varies among studies and is mainly dependent on the methods of detection. Studies on sensitivity and specificity of these antibodies do not exist; therefore, their significance should be interpreted cautiously.

Saliva: An additional diagnostic tool in Sjögren's syndrome

OBJECTIVE To assess the available data and the place of salivary analysis in the diagnosis of Sjögrens syndrome (SS). METHODS A Medline search of English language articles published between 1985 and 1996 and a manual search of the reference lists of relevant articles formed the data sources. These were combined with our clinical and experimental experience in this field. Each method of salivary analysis was assessed according to study design, type of saliva used for the study, sensitivity/ specificity for the diagnosis of SS, and correlation to the histopathological findings. RESULTS Increased levels of salivary Na+, immunoglobulins (particularly IgA), anti-Ro and La antibodies, lactoferrin, lysozyme, beta 2 microglobulin, prostaglandin E2, thromboxane B2, interleukin-6, and hyaluronic acid have been detected in various studies. Results varied according to the different methods used for saliva collection. CONCLUSION Although many changes have been detected in various constituents of saliva in SS patients, no test has proved sensitive or specific enough for diagnosing SS.

Long-term experience with low dose methotrexate in rheumatoid arthritis.

SummaryOne hundred twenty-six patients with rheumatoid arthritis (RA) were treated with weekly low doses of methotrexate (MTX) for a mean period of 36.8 months (range 13–110 months). The overall probability of continuing with MTX therapy was 72% at 2 and 3 years, 67% at 4 years and 65% at 5–7 years. Seronegative patients had a higher probability of continuing therapy than seropositive patients (P<0.05). Out of the whole group, 8% showed no improvement, 16% showed mild improvement, and 30% showed moderate improvement, and 45% experienced marked improvement. Eight patients (6%) of the latter group achieved complete clinical remission. In the course of the follow-up period there was a significant decrease in the mean daily dosage of prednisone and NSAIDs. Minor side effects were common (68%), but therapy was discontinued in only 27 patients (21%) because of major complications. In most of them (25 out of 27) these occured within the first 24 months of therapy. Although malignancy was revealed in 5 patients during the follow-up period, its occurrence did not differ from expected rates.

Fibromyalgia in diabetes mellitus

ObjectiveThe aim of this study was to evaluate the prevalence of fibromyalgia (FM) in patients with diabetes mellitus (DM).SubjectsThe study included 100 consecutive unselected patients with DM attending our diabetes clinic. Patients were divided into two groups: 45 patients with type 1 diabetes and 55 patients with type 2 diabetes. A group of 50 healthy hospital staff members served as controls. The FM was diagnosed according to the 1990 American College of Rheumatology criteria. Counts of 18 tender points were performed by thumb palpation and assessed by dolorimeter. Routine biochemical tests and levels of HbA1c were recorded in each patient.ResultsThe main outcome measure was the association of FM with DM. Fibromyalgia was diagnosed in 17 patients (17%) with DM and in only one (2%) healthy control (P=0.008). No differences in patients were noted in the prevalence of FM between type 1 and type 2 diabetes (18.5% vs 15.5%, respectively). Patients with both FM and DM had significantly higher levels of HbA1c than DM patients without FM (9.2±1.1% vs 6.4±1.5%) (P<0.05). Similarly, the numbers of tender points, pain scores, and the prevalence of sleep disturbances, fatigue, and headaches were higher in this group of patients. A significant correlation was observed between the numbers of tender points and HbA1c levels in the DM patients with FM (r=0.72, P=0.027).ConclusionFibromyalgia is a common finding in patients with types 1 and 2 diabetes, and its prevalence could be related to control of the disease. As with other diabetes complications, FM might be prevented by improved control of blood glucose levels.

Increased incidence of urinary tract infection in patients with rheumatoid arthritis and secondary Sjögren's syndrome.

The incidence of lower urinary tract infection in 120 women with rheumatoid arthritis and secondary Sjögrens syndrome was evaluated retrospectively. Thirty one patients (26%) had secondary Sjögrens syndrome. Recurrent urinary tract infection was significantly more common in these patients (11/31) than in patients without Sjögrens syndrome (4/89). Habitual leucocyturia was also more common in patients with secondary Sjögrens syndrome (18/31) than in patients with rheumatoid arthritis without Sjögrens syndrome (8/89). Of seven patients with vaginal sicca symptoms, six had recurrent urinary tract infection. Urinary 24 hour mucopolysaccharide excretion in 20 patients with Sjögrens syndrome was similar to the excretion in 10 patients without Sjögrens syndrome. These results show that recurrent urinary tract infection is significantly more common in women with rheumatoid arthritis and secondary Sjögrens syndrome. A local deficit in protective urinary mucosal secretion or other immune mechanisms may be responsible for this susceptibility.

Salivary eicosanoid concentration in patients with Sjögren's syndrome.

OBJECTIVE: To investigate eicosanoid concentrations in the saliva of patients with primary Sjögrens syndrome (SS). METHODS: Whole mixed saliva of 36 subjects was assayed for eicosanoid concentrations using a radioimmunoassay. Patients with primary SS having positive lip biopsy served as the study group; their results were compared with data from patients with dry mouth and negative lip biopsy (dry mouth group), and with a group of normal healthy controls. RESULTS: Concentrations of thromboxane B2 were significantly (p < 0.01) increased in 18 patients with primary SS compared with 10 patients with dry mouth and eight healthy normal controls (1.95 (SD 0.51) ng/ml saliva compared with 0.52 (0.1) ng/ml and 0.3 (0.1) ng/ml, respectively). Similarly, prostaglandin E2 concentrations were also significantly increased (p < 0.01) in 11 patients with primary SS compared with five patients with dry mouth and eight normal controls (3.75 (0.82) ng/ml saliva compared with 0.32 (0.1) ng/ml and 0.41 (0.1) ng/ml, respectively). CONCLUSION: Salivary concentrations of eicosanoids are significantly increased in patients with primary SS, and this may prove helpful in the diagnosis of this disease.

Allergic Disorders in Primary Sjögren's Syndrome

Allergic disorders have been described in a variety of connective tissue disorders. Although an association between allergy and primary Sjögrens syndrome has been suggested, it has not been well documented. The purpose of this study was to analyze the prevalence of several types of allergic disorders in a cohort of primary Sjögrens syndrome patients. The presence of an allergic disorder was evaluated by a specific questionnaire in 65 randomly selected primary Sjögrens syndrome patients and was compared to control groups of 67 rheumatoid arthritis patients, 53 patients with rheumatoid arthritis and sicca symptoms, and 31 patients with osteoarthritis. At least one type of allergic manifestation was reported by 42 of the 65 Sjögrens syndrome patients (65%). This rate was significantly higher than each of the three control groups (p < 0.01). Only drug allergy and skin contact allergy were found to be more prevalent in Sjögrens syndrome patients than in the control groups (p< 0.05). Allergic reactions were more common in Sjögrens syndrome patients who were anti-Ro positive (p < 0.05). As drug and skin contact allergies are a frequent finding in Sjögrens syndrome patients, obtaining a careful history is needed before prescribing drugs in these patients.