Cryoglobulinemic vasculitis in primary Sjögren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease.

OBJECTIVE: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjögren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. METHODS: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. RESULTS: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7-20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7-14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. CONCLUSION: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.

Epigenetic alterations in Sjögren's syndrome patient saliva.

Epigenetic mechanisms have been implicated in the pathogenesis of Sjögren's syndrome (SS). Extensive alterations in DNA methylation have been described in minor salivary gland (MSG) epithelial cells and lymphocytes derived from SS patients compared to sicca controls. In an effort to identify novel potential epigenetic markers that could prove useful in diagnosis and disease monitoring, we explored whether DNA methylation differences can also be detected in saliva from SS patients compared to sicca controls. We performed DNA methylation analysis by methylation-sensitive restriction digestion followed by quantitative real-time polymerase chain reaction of selected genomic loci in saliva samples of 16 SS patients and 10 sicca controls with negative MSG biopsy. We identified reduced DNA methylation of the imprinting control region (ICR) of the H19 locus in SS patient saliva compared to sicca controls. Levels of saliva H19 ICR methylation were negatively correlated with C4 serum complement levels. Consistent with the reduced methylation of the ICR, H19 RNA levels were increased in SS patient peripheral blood mononuclear cells (PBMCs), while no significant change was observed in MSG H19 RNA levels compared to sicca controls. Our findings support that H19 ICR methylation could be a useful molecular epigenetic marker in monitoring patients with SS, highlighting saliva as a valuable biological sample in SS research and clinical practice. The role of H19 in SS pathogenesis remains to be addressed.

Cost-utility analysis of certolizumab pegol in combination with methotrexate in patients with moderate-to-severe active rheumatoid arthritis in Greece.

We aimed to evaluate the cost-effectiveness of certolizumab pegol (CZP), a pegylated fc-free anti-TNF, as add-on therapy to methotrexate (MTX) versus etanercept, adalimumab, or golimumab in patients with moderate-to-severe active rheumatoid arthritis (RA) not responding to the conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). A Markov model (6-month cycle length) assessed health and cost outcomes of CZP versus other anti-TNFs recommended for RA in Greece over a patient's lifetime. Following discontinuation of first-line anti-TNF, patients switched to second anti-TNF and then to a biologic with another mode of action. Sequential use of csDMARDs followed third biologic. Clinical data and utilities were extracted from published literature. Analysis was conducted from third-party payer perspective in Greece. Costs (drug acquisition, administration, monitoring, and patient management) were considered for 2014. Results presented are incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY). Probabilistic sensitivity analysis (PSA) ascertained robustness of base-case findings. Base-case analysis indicated that CZP+MTX was more costly and more effective compared with Etanercept+MTX (base-case ICER: €3,177 per QALY), whilst versus adalimumab/golimumab, CZP was dominant (less costly, more effective). For all comparisons, CZP treatment resulted in greater improvements in life expectancy and QALYs. PSA indicated that at the willingness-to-pay threshold of €34,000/QALY, CZP+MTX was associated with a 71.6, 97.9, or 99.2% probability of being cost-effective versus etanercept, golimumab, or adalimumab, respectively, in combination with MTX. This analysis demonstrates CZP+MTX to be a cost-effective alternative over Etanercept+MTX and a dominant option over Adalimumab+MTX and Golimumab+MTX for management of RA in Greece.

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis.

Anti-citrullinated peptide antibodies (ACPA) are highly specific for rheumatoid arthritis (RA). However, the predominant B cell epitopes have not yet been defined. The aim of this study was to examine the reactivity of ACPA against different peptides derived from citrullinated proteins and to investigate whether or not these antibodies constitute a homogeneous population. For this purpose, sera from patients with RA (n = 141), systemic lupus erythematosus (SLE) (n = 60), Sjögren's syndrome (SS) (n = 54) and healthy controls (n = 100) were tested for their reactivity against six citrullinated peptides derived from peptidyl arginine deiminase (PAD), vimentin (vim), alpha-enolase (enol), fibrin, type II collagen (col-II) and filaggrin, respectively. A non-citrullinated control peptide derived from PAD was used as control (ctrlPAD(621-40)). Antibody reactivity against each individual peptide was evaluated by enzyme-linked immunosorbent assay (ELISA). Specificity and cross-reactivity of ACPA were tested by using two prototype sera with homologous and cross-inhibition assays. Specificity of ACPA from two prototype sera was confirmed by purification of anti-peptide antibodies and homologous-inhibition experiments. We found that sera from patients with RA reacted diversely with the six citrullinated peptides. More specifically, PAD(211-30) displayed 29·08% sensitivity, vim(60-75) 29·08%, enol(5-21) 37·59%, fibrin(617-31) 31·21%, col-II(358-75) 29·97% and filaggrin(306-24) 28·37%, while control ctrlPAD(621-40) showed no reactivity. All reactive peptides were found to be highly specific for RA. A notable cross-reaction (>70%) was found mainly between filaggrin and the majority of anti-citrullinated peptide antibodies. We concluded that ACPA in RA constitute a heterogeneous population with limited cross-reactivity and without a predominant epitope.

Pathogenesis of subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) is a photosensitive form of lupus-specific skin lesion that is strongly associated with the presence of anti-Ro/SSA autoantibody. The pathogenesis of SCLE includes genetic, environmental and immunologic factors. Recent studies provide strong evidence for the involvement of innate and cell-mediated immunity, underlying the important role of plasmacytoid dendritic cells, interferon-alpha and antibody-dependent cell cytotoxicity. In addition, a variety of cytokines, chemokines and adhesion molecules have been found to participate in the expansion phase of the autoimmune effector mechanisms. This article summarizes the recent immunological findings and reviews the current mechanisms which are implied in the development of the disease.

Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome.

Clinically significant renal involvement in patients with primary Sjögren syndrome (pSS) has been described previously only in isolated case reports. The prevalence and significance of the 2 described syndromes, interstitial nephritis (IN) and glomerulonephritis (GMN), are not well known. In a cohort of 471 patients with pSS who were followed for a mean of 10 years, 20 patients (4.2%) developed overt renal disease. Eighteen patients underwent a percutaneous renal biopsy; 2 patients declined. Ten patients had IN, 8 patients had GMN, and 2 patients presented with both entities. Glomerular histology disclosed changes compatible with membranoproliferative GMN in 5 patients and mesangial proliferative GMN in 4 patients. Patients with IN had a younger disease onset compared with patients with GMN (mean, 36.8 compared with 46.0 yr, p 5 0.063). Patients with GMN had longer disease duration compared with patients with IN (mean, 2.2 compared with 8.0 yr, p 5 0.001). The majority of patients with GMN (80%) had mixed monoclonal cryoglobulinemia IgMk (type II) and lower complement C4 levels. Two patients (both with GMN) developed chronic renal failure requiring hemodialysis. Overall, clinically significant renal involvement is infrequent in pSS. IN occurs early in the disease process, while GMN is a late sequela and may have a less favorable prognosis.