Safety and immunogenicity of tetanus/diphtheria vaccination in patients with rheumatic diseases-a prospective multi-centre cohort study.

OBJECTIVES: We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs). METHODS: We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet's disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation. RESULTS: Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded. CONCLUSION: Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.

In vitro efficacy of triclabendazole and clorsulon against the larval stage of Echinococcus multilocularis.

Alveolar echinococcosis (AE) caused by the cestode Echinococcus multilocularis (E. multilocularis) is endemic in wide areas of the Northern hemisphere. Untreated AE progresses and leads to death in more than 90% of cases. Until the advent of benzimidazoles, no antihelminthic drugs were available to cure AE. Benzimidazoles have greatly improved the prognosis of patients with AE. However, benzimidazoles have only a parasitostatic effect on E. multilocularis. Albendazole (ABZ) must sometimes be withdrawn because of adverse events. Alternative drugs are urgently needed. The antihelminthic triclabendazole (TCZ) and clorsulon (CLS) are more effective than ABZ to cure infections by the liver flukes Fasciola spp. The efficacy of TCZ and CLS was investigated on an in vitro culture of E. multilocularis larval tissue. E. multilocularis vesicles were evaluated for their morphology before and after adding TCZ, TCZ sulfoxide (TCZSX) and CLS to the larval tissue culture. TCZ at the concentrations of 20 µg/ml culture solution led to maximum vesicle damage within 12 days and of 25 µg/ml within 13 days, and TCZSX at the concentrations of 20 µg/ml within 20 days and of 25 µg/ml within 14 days. Contrary, CLS added at 5, 10 and 15 µg/ml to culture solution did not lead to any vesicle damage. TCZ is a promising further candidate drug for the treatment of AE.

Infection and musculoskeletal conditions: Lyme borreliosis.

Lyme borreliosis is a tick-borne infectious disease caused by the spirochaetes Borrelia burgdorferi, B. garinii and B. afzelii. It comprises a wide spectrum of symptoms affecting skin, musculoskeletal system, heart, eyes, central and peripheral nervous system. The diagnosis is based on clinical findings in combination with detection of specific IgM and/or IgG antibodies. Diagnostic problems arise from patients with non-specific symptoms and positive IgG antibody detection. Adequate antibiotic therapy cures more than 90% of the patients. However, in some patients repeated therapy is necessary and a small number of patients develop chronic arthritis or other features. While there is currently no vaccine available, prevention of tick bite is the most effective prophylaxis.

Lyme disease (Lyme borreliosis).

Lyme borreliosis (Lyme disease) is a systemic infectious disease with a wide spectrum of symptoms affecting the skin, the heart, and the nervous and musculoskeletal systems. Lyme borreliosis is caused by the spirochaete Borrelia burgdorferi and transmitted by ticks. The disease occurs in endemic pockets with an incidence of from 50 to more than 100 cases per 100,000 inhabitants. Despite increasing knowledge about the virulence factors of the spirochaetes and the immune response of the host, many aspects of the pathogenesis, for example of chronic treatment-resistant disease, are still a matter of debate. The diagnosis is based on clinical findings and confirmed by serology. Diagnostic problems arise from patients with non-specific symptoms and a positive IgG serology. In about 80% of the patients, the disease can be cured by adequate antibiotic therapy. Evidence-based guidelines for treatment have been recently published. The only vaccine to prevent Lyme disease, licensed in the USA, has been discontinued due to disappointing sales despite good efficacy and tolerability.

Synovial fibroblasts from rheumatoid arthritis patients differ in their regulation of IL-16 gene activity in comparison to osteoarthritis fibroblasts.

BACKGROUND: In rheumatoid arthritis (RA), synovial fibroblast-like cells (SF) contribute significantly to articular inflammation. They express distinct patterns of genes associated with cell proliferation and differentiation and elevated levels of cytokines and chemoattractant factors, including IL-16. Here we investigated pathways regulating IL-16 expression in fibroblasts from RA patients in comparison to fibroblasts from osteoarthritis (OA) patients. METHODS: Fibroblasts were isolated from dermal and articular biopsies, expanded and pathways of IL-16 induction were investigated by real time quantitative RT/PCR, immuno blot and ELISA. RESULTS: Stimulation of cAMP dependent signal transduction by forskolin induced prominent IL-16 RT/PCR signals in OA-DF and OA-SF. In contrast, in RA-DF and RA-SF staurosporine significantly augmented IL-16 RT/PCR signals, but forskolin induced less IL-16 transcript amounts. Activation of protein kinase C by PMA induced a significant IL-16 response only in RA-SF. Addition of IL-1beta or TNF-alpha did not upregulate IL-16 mRNA but secretion of the mature IL-16 cytokine was activated in serum starved cells in presence of IL-1beta. CONCLUSION: Our results suggest that RA fibroblasts differ from OA fibroblasts with respect to their sensitivities to kinase/phospatase signal transduction pathways. The enhanced expression of IL-16 in the synovial membrane early in RA vs OA may be associated in part with these distinct signaling responses.

Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue.

The expression of oncofetal H19 RNA and its localization/cellular source was analyzed in synovial tissue (ST) and isolated synovial macrophages (Mphi) or synovial fibroblasts (SFBs) by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. RT-PCR showed significantly higher H19 expression in ST from patients with rheumatoid arthritis (RA) (P = 0.000) and osteoarthritis (OA) (P = 0.009) than in normal/joint trauma controls (N/JT), but comparable levels in reactive arthritis. In situ hybridization demonstrated strong signals in all RA-ST samples (n = 8), with > or =85% positive cells in the lining layer, diffuse infiltrates, and stroma regions. In lymphoid aggregates and endothelial cells only 20% were positive. RA-ST contained a significantly higher percentage of strongly positive lining cells than OA-ST and N/JT-ST. H19 RNA was expressed in both Mphi and SFBs, as confirmed by RT-PCR in isolated RA Mphi and SFBs (n = 3). In RA-SFBs, low constitutive H19 RNA expression in culture (10% fetal calf serum) was strongly increased on starvation (3.5-fold, 1% fetal calf serum), with or without the addition of interleukin-1beta (10 to 100 U/ml), tumor necrosis factor-alpha (1 to 25 ng/ml), or platelet-derived growth factor-BB (2.5 to 10 U/ml). In OA-SFBs, this starvation-induced increase was lower (twofold), reaching significant differences compared with RA-SFBs after stimulation with interleukin-1beta and platelet-derived growth factor-BB. In both RA- and OA-SFBs, the MAP-kinase ERK-1/2 pathway and the phosphatidylinositol-3 kinase pathway influenced H19 RNA expression, as shown by inhibitor studies. Significant overexpression of H19 RNA and its increased sensitivity to starvation/cytokine regulation in RA suggests a pathogenetic role of this oncofetal gene, possibly reflecting embryonal dedifferentiation of the adult ST and/or ongoing inflammatory/oxidative stress.