Idiotype, anti-idiotype network of autoantibodies. Pathogenetic considerations and clinical application

A common serologic finding in autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Recent data suggest that an anti-idiotypic network exists in these diseases, regulating the production of autoantibodies (idiotypic response). The anti-idiotypic antibodies can be monitored using complementary epitopes, designed according to the "molecular recognition" theory. The role of anti-idiotypic antibodies in neonatal lupus and type 1 diabetes are discussed. In neonatal lupus, mothers with high antiidiotypic antibody activity against anti-La autoantibodies are at lower risk of giving birth to a healthy child, as compared with mothers without anti-idiotypic antibodies. Similarly, the lack of particular anti-idiotypic antibodies, against anti-GAD65 autoantibodies predispose in type 1 diabetes. These findings imply that anti-idiotypic antibodies may confer protection from the harmful effect of autoantibodies in certain autoimmune diseases. A common serologic finding in autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Recent data suggest that an anti-idiotypic network exists in these diseases, regulating the production of autoantibodies (idiotypic response). The anti-idiotypic antibodies can be monitored using complementary epitopes, designed according to the "molecular recognition" theory. The role of antiidiotypic antibodies in neonatal lupus and type 1 diabetes are discussed. In neonatal lupus, mothers with high anti-idiotypic antibody activity against anti-La autoantibodies are at lower risk of giving birth to a healthy child, as compared with mothers without anti-idiotypic antibodies. Similarly, the lack of particular anti-idiotypic antibodies, against anti-GAD65 autoantibodies predispose in type 1 diabetes. These findings imply that anti-idiotypic antibodies may confer protection from the harmful effect of autoantibodies in certain autoimmune diseases

Availability, attitudes and costs of selected dental services in a low-income country

ABSTRACT The aim of this study was to determine the availability of selected dental services, attitudes towards such services and economic factors associated with their utilization in a low-income country. Data utilized for this study was collected in two phases. Phase I was a survey of all dental facilities in four selected regions in Tanzania. The survey was administered to officers-in-charge of dental facilities and other dental practitioners working within these facilities. Phase II was a series of cross-sectional studies conducted among outpatients attending four selected regional hospitals in Tanzania. Data was collected using self-administered questionnaires. Dental materials and equipment were inconsistently available and only 3/28 studied dental facilities had all the seven investigated equipment fully functional and in use. The self-rated competency among dental practitioners ranged from 6.4 to 9.8 for all six procedures questioned, but equal scores between cadres were only for tooth extractions (9.7 vs. 9.1 respectively). Competencies for placing restorations were all rated lower by other cadres (p varied from <. 05 to < .001). Most of the patients had a negative overall attitude (-1.99) towards tooth filling treatment although those with previous tooth filling experience had positive attitudes (1.00). The mean willingness-to-pay (WTP) values for tooth filling (7,398 and 7,726 Tshs for anterior and posterior teeth, respectively) were higher (p < 0.001) than for tooth extraction irrespective of tooth type (5,448 and 6,188 Tshs, respectively). Being 45+ years increased the likelihood to offer lower WTP values. More than half (55%) of the patients would experience significant financial impacts as a result of their utilization of dental services. The findings clearly suggest that there are a multitude of factors that influence the observed dental treatment patterns being predominated by tooth extractions in Tanzania. Keywords: Willingness-to-pay, costs, dental services, attitudes, TanzaniaTIIVISTELMÄ Valikoitujen hammashoitopalvelujen saatavuus, niihin liittyvät asenteet ja käytön kustannukset vähävaraisessa maassa Tutkimus selvitti valikoitujen hammashoitopalveluiden saatavuutta sekä niihin liittyviä asenteita ja käyttöön liittyviä taloudellisia tekijöitä vähävaraisessa maassa. Ensin tehtiin kyselytutkimus kaikissa hammashoitopalveluja tarjoavissa yksiköissä neljällä valitulla tansanialaisella hallintoalueella näiden yksiköiden johtajien ja hammashoitoa antavien työntekijöiden keskuudessa. Toiseksi toteutettiin sarja poikkileikkaustutkimuksia kyselyin näiden neljän hallintoalueen avohoitopotilaiden keskuudessa. Kyselyissä selvitettiin valikoitujen hammashoitopalvelujen kustannuksia, hammashoitomateriaalien ja -laitteiden saatavuutta, hammashoidon työntekijöiden kokemia valmiuksia, potilaiden asenteita ja maksuhalukkuutta paikkaushoitoon sekä potilaille hammashoidosta aiheutuviin kustannuksia. Materiaaleja ja laitteita oli vaihtelevasti saatavilla. Vain kolmessa tutkitusta 28 hoitolasta kaikki seitsemän tutkimuksessa tarkasteltua laitetta olivat käytössä ja toimintakunnossa. Hammaslääkärien kokemat valmiudet toimenpiteisiin vaihtelivat (6,4–9,8) ja olivat saman tasoisia muiden ammattiryhmien kanssa vain poistoissa (9,7 vs. 9,1). Paikkausvalmiudet olivat alempia muilla ammattiryhmillä (p <0,05–<0,001). Useimmilla potilailla oli negatiivinen kokonaisasenne (-1,99) paikkaushoitoon. Heillä, joilla oli aiempaa kokemusta paikkaushoidosta, oli positiivinen asenne (1,00). Paikkaushoidon maksuhalukkuuden keskiarvot olivat huomattavasti korkeammat (7398 Tansanian shillinkiä (Tshs) etualueella ja 7726 Tshs taka-alueella) kuin hammaspoistojen maksuhalukkuuden (5448 Tshs etualueella ja 6188 Tshs taka-alueella, p<0,001). Hammashoitopalvelujen käyttö aiheutti yli puolelle (55 %) tutkituista potilaista merkittäviä taloudellisia vaikutuksia. Tulokset osoittavat selvästi, että Tansaniassa monet tekijät vaikuttavat hammashoitopalvelujen tuotantoon, jota hallitsevat hampaiden poistot. Avainsanat: Maksuhalukkuus, kustannukset, hammashoitopalvelut, asenteet, Tansani

Trial of canakinumab, an IL-1β receptor antagonist, in patients with inclusion body myositis.

Objective: To assess whether canakinumab, a monoclonal antibody against IL-1β approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM). Methods: Because in sIBM IL-1β colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1β with canakinumab may arrest disease progression. On this basis, 5 ambulatory patients with sIBM participated in an institutional review board--approved open-labeled study with 150 mg canakinumab [4 bimonthly, then monthly subcutaneous injections] for a mean period of 15.8 months. Patients were assessed bimonthly with a manual dynamometer in 12 proximal and distal muscles and with grip force (GF) in both hands. Total muscle strength (TMS) was expressed in kilograms. Efficacy was defined as \u3e15% increased strength after 12 months. Results: Patient 1 stopped at month 5 because of 23% loss in TMS and 32.35% in GF; patient 2 showed 37.1% increase in TMS and 13% in GF by month 9; patient 3 exhibited 26.7% reduction in TMS and 10% in GF at month 33; patient 4 showed 6.5% reduction in TMS and 1.6% in GF after 15 months, denoting relative stability; and patient 5 showed 30.4% loss in TMS and 20.8% in GF after 18 months. In patients 2 and 4, in whom 3-year longitudinal data were available, no effect on disease progression was noted. Conclusions: In this long-term, open-label study, canakinumab showed small, but not clinically appreciable, stabilizing benefits in 2 of 5 patients with sIBM over 1 year, was ineffective in 2 others, and might have worsened one. No patient improved. Classification of evidence: This study provides Class IV evidence that canakinumab was ineffective for patients with sIBM

Incidence and prevalence of major central nervous system involvement in Systemic Lupus Erythematosus: A 3-year prospective study of 370 patients

Background: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P#0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P,0.001). Conclusions: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes

The contribution of epigenetics in Sjögren's Syndrome.

International audience: Sjögren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers

Lipoprotein-Associated Phospholipase A2: A Novel Contributor in Sjögren’s Syndrome-Related Lymphoma?

BackgroundB-cell non-Hodgkin’s lymphoma (B-NHL) is one of the major complications of primary Sjögren’s syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)—a product mainly of tissue macrophages—is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma.ObjectiveThe purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS.MethodsLp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsSerum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: &lt;0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64–0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66–0.88, p-value: &lt;0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71–0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79–1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC.ConclusionsLp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS

International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement

Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording

Objective: Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. Results: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. Conclusion: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis