Clio P. Mavragani

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies

Objective: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. Methods: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1α, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon γ (IFNγ), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. Results: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by ⩾20% in three or more variables of the disease activity core set, four were unchanged and two worsened ⩾30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. Conclusions: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

The management of Sjögren's syndrome

Sjögrens syndrome is a chronic autoimmune disorder, characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. The syndrome can present either alone (primary Sjögrens syndrome) or in the context of an underlying connective tissue disease (secondary Sjögrens syndrome). Systemic features, resulting from cutaneous, respiratory, renal, hepatic, neurologic, and vascular involvement, often occur. Two types of primary Sjögrens syndrome are currently recognized: a benign disease that affects quality of life, and a systemic syndrome associated with increased morbidity and mortality owing to a high risk of malignant transformation, and that requires close follow-up. Ocular involvement, manifested as keratoconjunctivitis sicca, is managed with local and systemic stimulators of tear secretion and supportive surgical procedures. Treatment of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline, are helpful in patients with residual salivary function, and ciclosporin ocular drops seem to be of some benefit. Systemic immunosuppressives are reserved for treatment of severe extraglandular manifestations of Sjögrens syndrome. Anti-B-cell therapy is a new potential therapy for the glandular and extraglandular manifestations, such as glomerulonephritis or vasculitis, in addition to the management of lymphoma associated with Sjögrens syndrome. Induction of oral tolerance and gene-transfer modalities were recently attempted in animal models, with promising results.

Sjögren's syndrome.

Sjögrens syndrome (SS) is a chronic autoimmune disorder that typically affects exocrine glands--mainly labial and lacrimal--leading to complaints of dry mouth and eyes. Given that periepithelial mononuclear cell infiltrates, both in exocrine glands and in other parenchymal organs (kidney, lung, and liver), are the histopathological disease hallmark, the term autoimmune epithelitis has been proposed. B cell hyperactivity is another cardinal SS feature manifested by the presence of autoantibodies and hypergammaglobulinemia, as well as clinical/serological phenotypes mediated by immune complexes, such as peripheral neuropathy, vasculitic lesions, and hypocomplementemia. These have been designated adverse predictors for lymphoma development in approximately 5% to 10% of patients. Activation of the type I interferon/B cell-activating factor axis in SS has recently attracted particular attention. Inappropriate overexpression of endogenous nucleic acids in a genetically susceptible individual might provide a plausible scenario for the immune activation observed in SS.

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome

IntroductionIn Sjögrens syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögrens syndrome.MethodsMale NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21. Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein. Leukocytes from lacrimal glands were analyzed by flow-cytometry. Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining. The chemokine CXCL13 was measured by ELISA in sera from Sjögrens syndrome patients (n = 27) and healthy controls (n = 30). Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores.ResultsLTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands. Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression. The reduction of CXCL13, CCL21, CCL19 mRNA and the HEV-associated gene GLYCAM-1 was confirmed by PCR analysis. CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg/mg (+/- 2.7) from 51 pg/mg (+/-5.3) in lacrimal glands of 16 week old control mice. Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (P = 0.001), and had a significantly improved ocular surface integrity score (P = 0.005). The mean CXCL13 concentration in sera from Sjögrens patients (n = 27) was 170 pg/ml, compared to 92.0 pg/ml for sera from (n = 30) healthy controls (P = 0.01).ConclusionsBlockade of LTBR pathways may have therapeutic potential for treatment of Sjögrens syndrome.

Sjögren’s Syndrome: Autoantibodies to Cellular Antigens

Autoantibodies to cellular autoantigens are usually found in sera of patients with systemic autoimmune rheumatic diseases. Patients with Sjögren’s syndrome (SS) frequently present autoantibodies to both organ and non-organ-specific autoantigens. The most commonly detected autoantibodies are those directed against the ribonucleoproteins Ro/SSA and La/SSB. The presence of the antibodies in SS is associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the minor salivary glands. Over the past several years, the structure and function of these autoantigens have been extensively studied. Several centers, using different techniques, have investigated the B cell epitopes on the protein components Ro 60 kD, Ro 52kD, and La 48 kD. Finally, increased evidence of direct involvement of anti-Ro/SSA and anti-La/SSB autoantibodies in the pathogenesis of tissue injury has been contributed by several studies.

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogrens syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n = 31), SS patients complicated by lymphoma (n = 13) and healthy controls (HC, n = 30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFNγ as well as for IFNα and IFNγ genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFNα, but higher IFNγ and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFNγ/IFNα mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFNγ/IFNα mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.

Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta/alpha ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort.

OBJECTIVE Despite the substantial clinical efficacy of tumor necrosis factor alpha (TNFalpha) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy. METHODS RA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in baseline plasma samples using a commercial enzyme-linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA. RESULTS Plasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05-1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFNbeta/alpha ratio >0.8 (indicating elevated plasma IFNbeta levels). Consistent with the capacity of IFNbeta to induce IL-1Ra, elevated baseline IL-1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1-3.29], P = 0.027). CONCLUSION The plasma type I IFN activity, the IFNbeta/alpha ratio, and the IL-1Ra level were predictive of the therapeutic response in TNF antagonist-treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.

Endocrine alterations in primary Sjogren's syndrome: An overview

Involvement of several components of the endocrine system has been proposed as significant player in primary Sjogrens syndrome (SS) pathogenesis and clinical expression. Hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been previously demonstrated in patients with primary SS as a result either of a pituitary defect and/or of adrenal gland dysfunction. In support of the latter hypothesis, antibodies to 21-hydroxylase (OH)--a marker of autoimmune adrenal disease--have been detected in sera from approximately one fifth of primary SS patients, in association with B-cell activating cytokines and adrenal hyporesponsiveness. As a result of HPA hypofunction, adrenal androgens and particularly dehydroepiandrosterone-sulfate (DHEA-S) have been reportedly low in primary SS individuals. Epithelial salivary gland cells undergo apoptosis in lack of both estrogens and active androgens. In the absence of a compensatory action of the latter, menopausal status can lead to salivary gland apoptotic process triggering an aberrant immune response. On the other hand, given that salivary gland tissue remodeling has been shown to be under androgenic control, the observed androgen deficiency in these patients might account for the observed alterations in the salivary gland architecture. Heightened serum and salivary gland tissue prolactin levels in primary SS patients have been also suggested as contributors in disease pathogenesis. Finally, autoimmune thyroid disease (ATD) occurs quiet commonly in the setting of primary SS and subclinical hypothyroidism is the main functional abnormality observed in these patients.

Stress, coping strategies and social support in patients with primary Sjogren's syndrome prior to disease onset: a retrospective case control study

Objectives: Previous evidence suggests the role of psychological stress in triggering the onset of autoimmunity. We aimed to investigate whether stress following major and minor life events could precede the onset of primary Sjögren’s syndrome (pSS). The role of coping strategies and social support, as compensating buffering mechanisms, was also explored. Methods: 47 patients with pSS were compared with two control groups: 35 patients with lymphoma (disease controls, DC) and 120 healthy controls (HC) with disease onset within the previous year. All subjects completed questionnaires assessing the occurrence of major and minor stressful events, coping strategies and social support prior to disease onset. Data analysis was performed by univariate and multivariate logistic regression models. Results: A higher number of patients with pSS reported the occurrence of negative stressful life events prior to disease onset compared with patients with lymphoma and HC, while the number and impact of daily hassles did not differ between the three groups. Coping strategies were defective and the overall social support was lower in patients with pSS compared with DC and HC groups. In the multivariate model, pSS status was associated with maladaptive coping and lower overall social support relative to DC and HC, as well as with an increased number of negative stressful life events compared with HC but not DC. Conclusions: Prior to disease onset, patients with pSS experience high psychological stress following major negative life events, without developing satisfactory adaptive coping strategies to confront their stressful life changes. Lack of social support may contribute to the relative risk of disease development.

Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I Interferon in Patients With Systemic Autoimmune Disease

Increased expression of type I interferon (IFN) and a broad signature of type I IFN–induced gene transcripts are observed in patients with systemic lupus erythematosus (SLE) and other systemic autoimmune diseases. To identify disease‐relevant triggers of the type I IFN pathway, this study sought to investigate whether endogenous virus‐like genomic repeat elements, normally silent, are expressed in patients with systemic autoimmune disease, and whether these retroelements could activate an innate immune response and induce type I IFN.