Factors predictive of renal involvement in patients with primary Sjögren's syndrome

AIM: To identify clinical and immunological risk factors underlying the development of renal involvement in primary Sj?gren's syndrome (pSS). SUBJECTS AND METHODS: Seventy-eight patients (75 females, 3 males) with pSS were carefully interviewed and clinical and laboratory data from the time of diagnosis recorded. The baseline data on patients shown to have either latent or overt distal renal tubular acidosis (dRTA), mild proteinuria or increased urinary excretion of alpha-1 microglobulin (alpha1m) after a mean disease duration of 9 +/- 4 years, were compared to the baseline data on those who did not have these manifestations at follow-up. RESULTS: Patients with subsequent latent or overt dRTA were found to have significantly higher baseline levels of serum total gamma-globulin (24 +/- 7 vs. 19 +/- 6 g/l, p = 0.011) and serum protein (84 +/- 7 vs. 79 +/- 7 g/l, p = 0.024) compared to those with normal renal acidification capacity. The baseline levels of serum beta-2 microglobulin (beta2m) were higher in patients with an acidification defect than in those with normal acidification capacity (3.1 +/- 1.1 vs. 2.6 +/- 0.8 mg/l, p = 0.072). In those with subsequent proteinuria the levels of serum beta2m were almost significantly higher at baseline as compared to those with normal urinary protein excretion (3.1 +/- 1.4 vs. 2.5 +/- 0.8 mg/l, p = 0.052). The subgroup of pSS patients who had increased urinary alpha1m excretion as a sign of tubular proteinuria, had higher baseline levels of ESR (55 +/- 27 mm/h vs. 40 +/- 23 mm/h, p = 0.076) and significantly higher baseline levels of serum beta2m (4.6 +/- 1 .8 vs. 2.6 +/- 0.8 mg/l, p = 0.029) as compared to those with normal urinary alpha1m excretion. CONCLUSIONS: High levels of serum total gamma-globulin, serum protein and serum beta2m were the best predictors of the development of dRTA in pSS patients. High baseline levels of serum beta2m were also associated with the subsequent occurrence of mild proteinuria and increased urinary alpha1m excretion in patients with pSS.     

Epidemiology and diagnostics of primary Sjögren's syndrome

This review paper contains selected aspects of Sj?gren's syndrome. It consists of epidemiology, ultrasound of salivary glands and antimuscarinic antibodies. The first part present studies aimed to determine the prevalence and the incidence of the disease with special emphasize on epidemiological studies performed in Slovenia. This is followed by the demonstration of the role of ultrasound of salivary glands in the diagnosis of Sj?gren's syndrome and the value of antimuscarinic antibodies in global assesment of the secretory failure.     

Autoimmune epithelitis in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is characterized by an autoimmune epithelitis associated with chronic inflammation of the exocrine glands. Alterations of extra-glandular functions in pSS is associated with lymphocytic infiltrates that invade the epithelial structures of affected organs. Within epithelial tissue, the expression of class II major histocompatibility complexes and costimulatory molecules by epithelial cells acting as non-professional antigen presenting cells, leads to the activation of T and B lymphocytes through multiple cellular crosstalk pathways. Although the pathogenetic mechanisms underlying pSS have not yet been elucidated, it is accepted that glandular epithelial cells are central regulators of the local autoimmune response.     

Prevalence of selected organ-specific autoantibodies in rheumatoid arthritis and primary Sj?gren's syndrome patients

Objectives

The aim of the study was to investigate the prevalence of selected organ-specific autoantibodies in rheumatoid arthritis (RA) and primary Sjögren''s syndrome (pSS) patients, and discuss their clinical significance.

Material and methods

The study included 121 RA and 30 pSS patients. Sera were tested for the presence of autoantibodies to thyroid peroxidase (anti-TPO), thyroglobulin (anti-TG), TSH receptor (TRAbs), mitochondrial antigen M2 (AMA-M2-3E) and gliadin-analogous fusion peptides (anti-GAF(3X)) using the ELISA method. Non-organ-specific antibodies were determined: rheumatoid factor in IgM class, anti-citrullinated peptide antibodies and antinuclear antibodies. The occurrence of antibodies was also examined with regards to RA activity.

Results

The following autoantibodies were detected in RA patients: anti-TPO – 13 (10.7%), anti-TG – 6 (5%), AMA-M2-3E – 3 (2.5%), anti-GAF(3X) – 5 (4.1%). The respective levels of these autoantibodies in pSS patients were 3 (10%), 2 (6.7%), 4 (13.3%) and 2 (6.7%). Polyautoimmunity was confirmed in 34 RA patients (including 20 cases of autoimmune thyroid disease [AITD]) and in 6 pSS patients (6 cases of AITD). When RA patients were divided into anti-TPO positive and anti-TPO negative groups, we found a statistically significant relationship between groups regarding age and hemoglobin concentration. In pSS patients the anti-TPO positive group was less likely to use immunosuppressive drugs as compared with the anti-TPO negative group. Anti-TPO was significantly more frequently detected in RA + AITD vs. RA, RA + SS + AITD vs. RA and in pSS + AITD vs. pSS patients.

Conclusions

Organ-specific autoantibodies are relatively frequently observed in patients with RA and pSS. Their presence is connected with the clinical picture of the diseases.     

Elderly-onset primary Sjögren's syndrome focused on clinical and salivary gland ultrasonographic features

ObjectiveTo assess the clinical, laboratory, and salivary gland ultrasound (SGUS) characteristics of elderly-onset of primary Sjögren's syndrome (EopSS).MethodsWe included pSS patient from two referral hospitals over a 4-year period. The SGUS scores (0–48) and SG volumes were assessed. Clinical, laboratory, and SGUS data were compared according to age at onset: EopSS (≥ 65 years), adult-onset (AopSS) (≥ 40 and < 65 years), and young-onset (YopSS) (< 40 years).ResultsThis cross-sectional study included a total of 221 patients, 43 (19.5%) of which had EopSS. Subjective sicca symptoms, results of the Schirmer's test, and unstimulated salivary flow rate revealed no significant differences between the groups. EopSS patients presented a significantly higher frequency of interstitial lung disease (ILD) (EopSS: 51.2% vs. AopSS: 13.5% vs. YopSS: 8.7%, P < 0.001) and lower frequency of arthritis (7% vs. 22.6% vs. 39.1%, P < 0.01). They also had significantly lower positivity of anti-Ro/SSA (51.2%) and anti-La/SSB (7.0%) and lower levels of rheumatoid factor, C4, and IgG. The EopSS group had significantly lower SGUS positivity (defined as total scores ≥ 14) (44.2% vs. 64.5% vs. 78.3%, P < 0.05), lower SGUS scores, and smaller submandibular gland volume.ConclusionWe report a specific phenotype of EopSS, characterised by high prevalence of ILD, less involvement of the peripheral joint, and low biological activity. SGUS evaluation showed less parenchymal abnormalities but more atrophic changes in major SGs in EopSS patients. Considering the low positivity of anti-Ro/SSA and SGUS in EopSS, SG biopsy remains the only way to confirm the diagnosis of pSS, especially in elderly patients.     

Fibromyalgia in Italian patients with primary Sjögren's syndrome

OBJECTIVE: To assess the prevalence of fibromyalgia in primary Sj?gren's syndrome and to evaluate the clinical differences between patients affected with both primary fibromyalgia and primary Sj?gren's syndrome and those affected only with primary fibromyalgia. METHODS: Clinical features of fibromyalgia were evaluated in 100 consecutive outpatients with primary Sj?gren's syndrome and, as controls, in 90 patients with non-insulin-dependent diabetes mellitus, in 75 patients with primary fibromyalgia and in 30 healthy subjects. RESULTS: Fibromyalgia was recorded in 22% of patients with primary Sj?gren's syndrome, in 12.2% with diabetes and in 3.3% of healthy controls. In the primary Sj?gren's syndrome group the prevalence was significantly higher than in healthy controls (P < 0.01), but not significantly different than in diabetes. Moreover, primary Sj?gren's syndrome with fibromyalgia and primary fibromyalgia patients did not differ with respect to the number of tender points, while the mean pain threshold was lower in the latter (P = 0.05). Purpura, hypergammaglobulinemia, rheumatoid factor, and a focus score > or = 1 on lip biopsy were significantly more frequent in primary Sj?gren's syndrome patients without than with fibromyalgia. CONCLUSIONS: As recently reported by other authors, our study confirms the moderate increase of fibromyalgia prevalence in primary Sj?gren's syndrome. Typical fibromyalgic findings are quite similar to those of primary fibromyalgia, but surprisingly, primary Sj?gren's syndrome patients with fibromyalgia show a less severe global involvement than those with primary Sj?gren's syndrome alone.     

Current and potential treatments for primary Sjögren's syndrome

A precise definition of primary Sj?gren's syndrome resting on 'revised' or 'international' criteria has been accepted by most experts. This is important because the symptoms of primary Sj?gren's syndrome, namely, dryness, fatigue, and pain, are common in the population at large and can occur in the absence of autoimmune disease as a result of medication use, anxiety and depression, or normal aging. This widely accepted definition is particularly valuable as a tool for obtaining homogenous patient populations for trials of new therapeutic agents. In this review article, before discussing treatments for complications and current hopes about second-line drugs, we present an update on available treatments forthe symptomatic triad (dryness, fatigue, and diffuse pain) seen in autoimmune Sj?gren's syndrome and in some cases of isolated sicca syndrome. These very bothersome and permanent symptoms have a negative effect on quality of life. The most recent data show that systemic cholinergic agonists (pilocarpine and cevimiline) are effective in the symptomatic treatment of dryness, that cyclosporine eye drops may relieve ocular symptoms, and that TNFalpha inhibitors may find a new indication in Sj?gren's syndrome.     

Associations between ocular and extra-ocular assessment in primary Sjögren's syndrome*

ObjectivesTo assess associations between ophthalmological features and the main systemic biomarkers of primary Sjögren's Syndrome (pSS), and to identify systemic biomarkers associated with severe keratoconjunctivitis sicca (KCS) in pSS patients.MethodsIn this cross-sectional study, data was retrospectively extracted from the monocentric cohort of the French reference centre for pSS. We analysed data from the initial visit of patients admitted for suspicion of pSS and included patients validating pSS ACR/EULAR classification criteria. Ophthalmological assessment included Schirmer's test, tear break-up time, ocular staining score (OSS), and visual analogue scale (DED-VAS) for dry eye disease (DED) symptoms. Results of minor salivary gland biopsy, unstimulated whole salivary flow rate, anti-SSA/Ro antibodies, anti-SSB/La antibodies, and rheumatoid factor (RF) were collected.ResultsA total of 253 patients (245 females) with confirmed pSS, aged 56.6 ± 13.0 years, were included, among which 37% had severe KCS. Multivariate analysis showed that the presence of anti-SSA/Ro antibodies, anti-SSB/La antibodies and RF were associated with conjunctival OSS (odds ratio–OR– = 1.25 per OSS unit increase; confidence interval–CI–95% = 1.05–1.49; P = 0.01; OR = 1.31 per OSS unit increase; CI95% = 1.09–1.58, P = 0.002, and OR = 1.34 per OSS unit increase; CI95% = 1.12–1.59; P = 0.001, respectively). Both anti-SSB/La antibodies and DED-VAS ≥ 5 were significantly associated with severe KCS (OR = 2.03; CI95% = 1.03–4.00; P < 0.05 and OR = 2.52, CI95% = 1.31–4.90; P < 0.01, respectively).ConclusionAssociation between conjunctival OSS and systemic biomarkers of pSS indicate the crucial importance of conjunctival staining when pSS is suspected as a cause of DED. Conversely, patients with anti-SSB and DED-VAS ≥ 5 features should be prioritized for extensive evaluation by an ophthalmologist due to their association with severe KCS.     

Topical and systemic medications for the treatment of primary Sjögren's syndrome

The treatment of primary Sj?gren's syndrome (SS) is based principally on the management of sicca features and systemic manifestations. Sicca manifestations are treated symptomatically through administration of topical therapies, such as saliva substitutes and artificial tears; in patients with residual salivary gland function, stimulation of salivary flow with a sialogogue is the therapy of choice. The management of extraglandular features must be tailored to the specific organ or organs involved; however, limited data have been obtained from controlled trials in SS to guide the treatment of systemic symptoms using therapies including antimalarials, glucocorticoids, immunosuppressive drugs and biologic agents. Nevertheless, randomised controlled trials of biologic agents that target molecules and receptors involved in the aetiopathogenesis of primary SS have initiated a new era in the therapeutic management of the disease, although the potential risks and benefits of these agents must be carefully considered. In this Review, we analyse the evidence regarding the efficacy of the therapeutic agents currently available to treat the manifestations of SS. On the basis of this evidence, we provide guidance on the use of these agents in different clinical scenarios.     

Analysis of TNFalpha microsatellites in 35 patients with primary Sjögren's syndrome

OBJECTIVES: Although the cause of Sj?gren's syndrome remains unknown, many arguments suggest a role for both environmental and genetic factors. An association with HLA molecules has been established. Other genes on the short arm of chromosome 6 may be involved, most notably the TNF gene, which may be pivotal in the development of the epithelial lesions. METHODS: We investigated TNFalpha microsatellites in 35 patients with primary Sjogren's syndrome and in 146 healthy controls. RESULTS: The frequency of the TNFalpha10 allele showed a non-significant increase in the Sj?gren's disease group (28.6% vs 15.8%; P = NS). We found significant increases when we considered only those Sj?gren's disease patients with joint manifestations (N = 24; 37.5% vs 15.7%; P < 0.05) or only those with anti-Ro(SSA) antibodies (N = 10; 50% vs 15.7%; P < 0.05). CONCLUSION: Our data support a role for the TNFalpha10 allele in primary Sj?gren's syndrome, particularly those forms with joint symptoms and anti-Ro(SS-A) antibodies.     

Geoepidemiology of Sjögren's syndrome in Latin America

ObjectiveTo evaluate the geoepidemiology of Sjögren's syndrome (SS) in Latin America.MethodsThis was a three phase study in which original data from a Colombian cohort of patients with SS is presented, followed by a systematic review of Colombian and Latin American studies. Lastly, the geoepidemiology of SS in Latin America was assessed by comparing the clinical characteristics of the region with those of the rest of the world by means of a meta-analysis approach.ResultsData from 2970 patients from Latin America and 18019 patients from Europe, North America and Asia were analyzed. Colombian patients have a lower age at disease onset than those from other Latin American countries and a higher rate of positivity of antinuclear antibodies and rheumatoid factor. A significant difference in the proportion of female patients in Latin America compared with Europe and North America was observed. The spectrum of disease in Latin American was similar to North American patients, while strong differences were noticed between Latin American and European and Asian patients. Noteworthy, a paucity of reports including African and African-descendent patients was observed.ConclusionsThe clinical spectrum of SS differs between countries and continents. Genetic differences relying upon ancestry could explain these findings. However, environmental factors have proven to be important determinants in the development of autoimmune diseases (i.e., autoimmune ecology). Thus, ancestry and the autoimmune ecology should be considered in studies aimed to evaluate the geoepidemiology of SS and other autoimmune diseases.     

Tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy and primary Sjögren's syndrome

We report a case of hypokalemic nephropathy associated with primary Sj?gren's syndrome (SS). The patient presented with profound and persistent hypokalemia secondary to distal renal tubular acidosis (RTA). A renal biopsy exhibited tubular degeneration, marked interstitial fibrosis and intense macrophage infiltration. Hypokalemia has been reported to induce macrophage infiltration in experimental animal models but not in humans. This is the first report of intense tubulointerstitial macrophage infiltration in a patient with hypokalemic nephropathy associated with SS.     

Proximal tubular dysfunction in primary Sjögren's syndrome: a clinicopathological study of 2 cases

Tubulointerstitial nephritis is the most common renal complication in primary Sj?gren's syndrome (SS). It is usually associated with symptoms of distal tubular dysfunction, type I (distal) renal tubular acidosis (RTA) and nephrogenic diabetes insipidus. Proximal tubular abnormalities are considered to be less frequent, and Fanconi's syndrome has been only exceptionally reported in patients with SS. We describe 2 patients with primary SS, characterized by xerostomia, dry eyes, extensive lymphocytic infiltrate on salivary gland biopsy, positive tests for anti-SSA/SSB antibodies and/or antinuclear antibodies, who presented in renal failure with proteinuria, microscopic hematuria and type I RTA. Further studies revealed proximal tubular dysfunction, including renal glucosuria, generalized aminoaciduria, phosphaturia, uricosuria, together with proximal (type II) RTA in 1 case. Neither of these patients had Bence Jones proteinuria or monoclonal gammopathy. Kidney biopsy showed focal proximal tubulitis, associated with proximal tubular cell atrophy and dedifferentiation, and diffuse interstitial nephritis with fibrosis. No significant glomerular or peritubular deposits of immunoglobulin light or heavy chain were observed. These findings demonstrate that diffuse, distal and proximal, tubular dysfunction may occur in patients with SS and interstitial nephritis. Lymphocytic infiltration of proximal tubular cells is probably involved in the pathogenesis of Fanconi's syndrome in SS. However, the mechanisms involved in the alteration of sodium-dependent apical transports remain to be elucidated.     

Assessment of major salivary gland size in primary Sjögren's syndrome: Comparison between clinical examination and ultrasonography

ObjectiveParotidomegaly is a criterion of the EULAR Primary Sjögren Syndrome Disease Activity Index (ESSDAI). The cut-off value was set at 3 cm in length for the parotid gland, 2 cm for the submandibular glands. However, clinical appreciation of salivary glands size remains hazardous. The objective is to evaluate inter-observer reproducibility of parotid gland measurement by palpation, and to secondary evaluate its reliability compared to US assessment.MethodsOutpatients with primary Sjögren Syndrome (pSS) or with a diagnostic suspicion, in a single reference centre, were included. They underwent clinical examination by two independent investigators (VDP and DC), evaluating: parotid gland swelling, parotid gland size (direct measurement with a decameter under the mandibular angle), and pain. Cohen's kappa coefficient was calculated to determine inter-observer concordance for parotid gland swelling, and intraclass correlation coefficient to determine inter-observer agreement of gland size measurement.ResultsThirty-four patients (33 women, 1 man) were included. Clinical data were complete for 33 patients. Inter-observer concordance Kappa coefficient was 0.90 [0.76–1.00] for detection of parotidomegaly over 66 parotid glands. It was of 0.60 [0.42–0.73] for gland length measurement. For one observer, the median cut-off for defining parotidomegaly was 4.15 cm; for the second observer, it was of 4.92 cm. For submandibular glands palpation, no correlation was found between investigators. A significant association between clinical parotidomegaly and a larger echographic surface was found.ConclusionClinical measurement of parotidomegaly was concordant between two observers on a binary mode (presence/absence). However, concordance on direct measurement was weak. US could be a complementary examination.     

Primary Sjögren's syndrome and hypokalaemic paralysis--case report

We report a case of hypokalaemic quadriparesis in 31-year old woman in whom the discovery of distal renal tubular acidosis led to the diagnosis of primary Sj?gren's syndrome. Hypokalaemic paralysis as initial manifestation of primary Sj?gren's syndrome is rare, but when it occurs it may precede symptoms of xerostomia and xerophthalmia. The diagnosis of primary Sj?gren's syndrome should be considered in young women who present with progressive weakness, hypokalaemia and metabolic acidosis.