M. Pertovaara

A longitudinal cohort study of Finnish patients with primary Sjögren's syndrome : clinical, immunological, and epidemiological aspects

OBJECTIVE To evaluate outcome in a cohort of Finnish patients with primary Sjögrens syndrome (pSS). METHODS Clinical and laboratory data from the time of diagnosis and follow up were collected from 110 patients with pSS (107 women, three men) diagnosed in 1977–1992 in central Finland. The standardised incidence ratio for cancers was determined as the ratio of the observed number of cases to the expected number based on regional population rates. Eighty one of the 93 patients still alive were interviewed, and clinical and laboratory examinations performed in 1994–1997. RESULTS The mean (SD) erythrocyte sedimentation rate (33 (22) v 45 (28) mm/1st h), serum IgG (18.8 (7.4) v 22.5 (8.5) g/l), and serum IgM (1.6 (1.1) v 2.0 (1.2) g/l) at the control visit were significantly (p<0.0001) lower than those at baseline. A similar change was observed in a subgroup of patients never treated with glucocorticosteroids or disease modifying antirheumatic drugs. Three non-Hodgkins lymphomas were diagnosed (standardised incidence ratio 13; 95% confidence interval 2.7 to 38). In a logistic regression model, the patients with pSS with subsequent lymphoma were found to have higher baseline levels of serum β2 microglobulin than the others (odds ratio 1.9; 95% confidence interval 1.1 to 3.4). CONCLUSION The results suggest that mean concentrations of serum IgG and IgM in patients with pSS decline with time, possibly reflecting diminishing inflammatory activity. As in previous studies, the incidence of non-Hodgkins lymphomas in this cohort of patients with pSS was significantly higher than in the reference population.

Clinical follow up study of 87 patients with sicca symptoms (dryness of eyes or mouth, or both)

OBJECTIVE To assess the prognosis of patients with sicca symptoms and to identify the clinical and immunological factors that most sensitively predict the later development of primary Sjögren’s syndrome (SS) or other connective tissue diseases. METHODS Eighty seven patients (72 female, 15 male) with sicca symptoms were re-evaluated after a median follow up time of 11 years (range 8–17). The clinical examination included ophthalmological examination (Schirmer’s test, break up time and Rose-Bengal staining). Labial salivary gland biopsy was performed and histological findings graded according to the Chisholm-Mason scale. The immunoserological tests included determination of rheumatoid factor (RF), antinuclear antibodies (ANA), anti-extractable nuclear antigen-antibodies (ENA), serum immunoglobulins IgA, IgG, and IgM, and serum β2-microglobulin (β2m). RESULTS At follow up 31 patients (36%) fulfilled modified Californian criteria (salivary flow measurements were not performed and Chisholm-Mason grades 3–4 were regarded as diagnostic histological findings) for possible or definite SS. Likewise, a significant progression of the histological findings was observed. Labial salivary gland re-biopsy was performed in 42 patients with grade 0–2 findings at baseline, progression to grades 3–4 being observed in 21 (50%) at follow up. The patients who later developed SS were at baseline significantly older (mean (SD) 52 (9)v 44 (14) years, p⩽0.005) compared with those not fulfilling the SS criteria at follow up; they also had significantly higher serum β2m (p⩽0.0005) and IgG concentrations (p⩽0.005), and they had positive ANA more frequently (p⩽0.01). CONCLUSION These results suggest that high age, increased values of serum β2m, ANA positivity and increased concentrations of serum IgG, might be useful indicators for the subsequent development of SS in patients with sicca symptoms. The prognosis of patients with these symptoms was favourable, and the clinical course was benign even in the 36% of patients who developed SS. No cases of lymphoma were observed.

Novel carbonic anhydrase autoantibodies and renal manifestations in patients with primary Sjögren's syndrome

OBJECTIVEnAnti-carbonic anhydrase II (anti-CA II) antibodies have been related to renal manifestations of primary SS (pSS), and animal studies have even suggested a pathogenic role for them. However, not all pSS patients with renal tubular acidosis (RTA) present with anti-CA II antibodies. Recently, several novel CA isoenzymes have been recognized and we aimed to investigate whether antibodies to these are associated with renal manifestations of pSS.nnnMETHODSnWe examined anti-CA II antibodies as well as anti-CA I, VI, VII and XIII antibodies by ELISA tests in 74 pSS patients on whom detailed nephrological examinations had been performed and, as controls, in 56 subjects with sicca symptoms, but no pSS.nnnRESULTSnThe levels of anti-CA I, II, VI and VII antibodies were significantly higher in patients with pSS compared with subjects with sicca symptoms but no pSS. None of the anti-CA antibodies was associated with the presence of complete or incomplete RTA or proteinuria or urinary α₁m excretion in patients with pSS. However, levels of anti-CA II, VI and XIII antibodies correlated significantly with urinary pH, and inversely with serum sodium concentrations. The degree of 24-h urinary protein excretion correlated weakly with levels of anti-CA VII antibodies.nnnCONCLUSIONnNot only antibodies to CA II, but also anti-CA VI and XIII antibodies seem to be associated with renal acidification capacity in patients with pSS.

Adverse drug reactions in Sjögren's syndrome. Frequent allergic reactions and a specific trimethoprim-associated systemic reaction.

Trimethoprim-associated systemic reactions, including aseptic meningitis, have been reported to be very rare adverse drug reactions. Patients with Sjögrens syndrome have been overrepresented, but no epidemiological surveys of the reaction have been conducted. To study the overall frequency of adverse drug reactions, and especially trimethoprim-associated reactions, we interviewed 85 primary Sjögrens syndrome patients and compared the results with those of 45 similarly interviewed osteoarthritis patients. Antimicrobial allergy was more common among Sjögrens syndrome patients than in osteoarthritis patients (46% vs. 27%). Eleven Sjögrens syndrome patients (13%), but no osteoarthritis patient, had experienced at least a partial, non-allergic systemic reaction with trimethoprim. Of them five (6%) had had a full-blown systemic reaction including both chills/fever and headache/backache and at least one of the following: malaise, vomiting, dizziness, confusion or meningeal irritation. Our findings confirm that allergic reactions to antimicrobials are frequent in Sjögrens syndrome. In addition to allergic reactions Sjögrens syndrome patients are prone to a specific trimethoprim-associated systemic reaction. This should be remembered when prescribing antimicrobials.

The significance of mannan-binding lectin gene alleles in patients with primary Sjögren's syndrome.

Objective and methods : To investigate the significance of mannan-binding lectin (MBL) gene alleles in patients with primary Sjögrens syndrome (pSS). Genotypes were determined in 65 pSS patients and 138 controls. Results : No difference in MBL genotype or allele frequencies was detected between the pSS patients and controls. However, when the effect of MBL genotypes on the diagnostic findings in pSS patients was assessed, none of the eight patients with 52/w genotype fulfilled four (definite) Californian criteria (P= 0.007). Among these eight the Chisholm-Mason histological grade was f 3 in only three (P= 0.017). Furthermore, the MBL concentration was lower in patients with 52/w genotype compared to those with wild-type (w/w) genotype (P= 0.035). Conclusion : Our findings suggest that MBL structural gene polymorphisms do not influence on susceptibility to pSS. However, MBL may be associated with salivary gland destruction in pSS, and its concentration may be comparable with the intensity of inflammatory reaction. Further studies are warranted to clarify the possible mechanisms involved.

ESSPRI and other patient-reported indices in patients with primary Sjögren’s syndrome during 100 consecutive outpatient visits at one rheumatological clinic

OBJECTIVEnA European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and a patient-reported index (ESSPRI) have recently been developed and validated. In our previous study the ESSDAI correlated significantly with serum β2 microglobulin concentration. We now aim to establish whether the ESSPRI is also associated with serum β2 microglobulin or with other patient-reported indices.nnnMETHODSnThe data on 100 consecutive visits of patients with primary SS (pSS) were reviewed from the patient charts. Patients who had filled out the ESSPRI questionnaire and fulfilled at least four of the revised American-European consensus group criteria for pSS were included. Data were gathered on the ESSPRI (0-10 cm) and on the patients global health assessment [visual analogue scale (VAS) 0-10 cm] (PGH-VAS), pain-VAS (0-10 cm) and HAQ (range 0-3).nnnRESULTSnThe ESSPRI correlated significantly with the PGH-VAS (r = 0.753, P < 0.0001), pain-VAS (r = 0.656, P < 0.0001) and HAQ (r = 0.542, P < 0.0001) (Spearmans correlation). It also correlated weakly with serum β2 microglobulin (r = 0.214, P = 0.043) and ESR levels (r = 0.235, P = 0.019).nnnCONCLUSIONnThe ESSPRI correlated significantly with other patient-reported indices, serum β2 microglobulin and ESR in patients with pSS. Our results support the view that the ESSPRI is a useful tool in the follow-up of patients with pSS.

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

Limited data are available regarding the intracellular responses to different cytokines in primary Sjögrens syndrome (pSS). We studied the signal transducer and activator of transcription (STAT) activation profile in response to cytokine stimulations in peripheral blood mononuclear cells (PBMCs) from pSS patients by multicolor flow cytometry. The expression of the suppressors of cytokine signaling (SOCS), and interferon (IFN)-γ target genes in PBMCs was studied using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The induction of STAT1 phosphorylation in response to stimulation with IFN-α, IFN-γ or interleukin (IL)-6 was significantly increased in B cells and monocytes from pSS patients. Accordingly, the STAT1-mediated gene responses were significantly enhanced in PBMCs from pSS patients. Finally, the expression of SOCS1 and SOCS3 mRNA was increased in pSS patients. The results indicate increased sensitivity of immune cells from pSS patients to STAT1-activating signals, and may partly explain the IFN signature observed in pSS.