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.

IL-3 but not monomeric IgE regulates FcεRI levels and cell survival in primary human basophils.

Binding of allergen-specific IgE to its primary receptor FcεRI on basophils and mast cells represents a central event in the development of allergic diseases. The high-affinity interaction between IgE and FcεRI results in permanent sensitization of these allergic effector cells and critically regulates their release of pro-inflammatory mediators upon IgE cross-linking by allergens. In addition, binding of monomeric IgE has been reported to actively regulate FcεRI surface levels and promote survival of mast cells in the absence of allergen through the induction of autocrine cytokine secretion including interleukin-3 (IL-3). As basophils and mast cells share many biological commonalities we sought to assess the role of monomeric IgE binding and IL-3 signaling in FcεRI regulation and cell survival of primary human basophils. FcεRI cell surface levels and survival of isolated blood basophils were assessed upon addition of monomeric IgE or physiologic removal of endogenous cell-bound IgE with a disruptive IgE inhibitor by flow cytometry. We further determined basophil cell numbers in both low and high serum IgE blood donors and mice that are either sufficient or deficient for FcεRI. Ultimately, we investigated the effect of IL-3 on basophil surface FcεRI levels by protein and gene expression analysis. Surface levels of FcεRI were passively stabilized but not actively upregulated in the presence of monomeric IgE. In contrast to previous observations with mast cells, monomeric IgE binding did not enhance basophil survival. Interestingly, we found that IL-3 transcriptionally regulates surface levels of FcεRI in human primary basophils. Our data suggest that IL-3 but not monomeric IgE regulates FcεRI expression and cell survival in primary human basophils. Thus, blocking of IL-3 signaling in allergic effector cells might represent an interesting approach to diminish surface FcεRI levels and to prevent prolonged cell survival in allergic inflammation.

Effectiveness of the Bern Ambulatory Interprofessional Rehabilitation (BAI-Reha) programme for patients with chronic musculoskeletal pain: a cohort study.

QUESTIONS UNDER STUDY: Chronic pain has a high impact on individuals and society. (Cost-)effective interventions are desperately needed. We evaluated short- and long-term effects of the Bern Ambulatory Interprofessional Rehabilitation (BAI-Reha) for patients with chronic musculoskeletal pain. METHODS: We analysed data prospectively collected from patients with chronic musculoskeletal pain before and after BAI-Reha (at 12 weeks, 1 year and 2 years) using linear mixed-models and logistic generalised estimating equations. RESULTS: The first thirty consecutive patients with chronic musculoskeletal pain, aged between 20 and 73 years (mean 44.83, standard deviation 12.57 years) were included. We found significant changes over time compared with baseline for return to work (p <0.001), Euro quality of life visual analogue scale score (p = 0.026), burden of suffering (p = 0.001), self-rated and observed quality of daily life task motor performance (p <0.001 and p = 0.012, respectively) but not for pain intensity (p = 0.16) and observed quality of daily life task process performance (p = 0.28). At the first postintervention visit we found significant differences compared with baseline in return to work (odds ratio 5.26, 95% confidence interval [CI] 1.80-15.39], burden of suffering (mean difference 5.26, 95% CI 2.09-8.44], self-rated quality (mean difference 2.31, 95% CI 1.57-3.05) and satisfaction (mean difference 2.80, 95% CI 1.95-3.66) with daily life task performance, and observed quality with daily life task motor performance (mean difference 0.31, 95% CI 0.02-0.60). CONCLUSIONS: This study confirms earlier data and supports the effectiveness of interprofessional rehabilitation for patients with chronic musculoskeletal pain.

Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study.

PROBLEM: Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25‒ cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed. RESULTS: Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-α, interferon-γ, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-ß1, increased the proportion of Treg most effectively and was able to induce interleukin-10-secreting-Treg from CD4+CD25‒cells. CONCLUSIONS: Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy.

The physiologic increase in expression of some type I IFN-inducible genes during pregnancy is not associated with improved disease activity in pregnant patients with rheumatoid arthritis.

During pregnancy, most patients with rheumatoid arthritis (RA) experience a spontaneous improvement in their condition. Since type I interferons (IFN) have immunomodulatory properties, we investigated whether type I IFN-inducible genes are upregulated in pregnant patients with RA. Peripheral blood mononuclear cells were evaluated using quantitative real-time polymerase chain reaction for type I IFN-inducible genes (IFI 35, IFI44, IFI44L, IFIT3, OAS1, and Siglec1) in patients with RA and healthy women during and after pregnancy as well as in nonpregnant controls. IFN-alpha and IFN-beta levels in sera of patients and healthy donors were analyzed by enzyme linked immunosorbent assay. It was found that healthy women did not show a change of gene expression levels from the second trimester until postpartum, yet some type I IFN-inducible genes were significantly upregulated in pregnant and postpartum women compared with nonpregnant individuals. In patients with RA, a pronounced upregulation of IFI35 and IFI44 at the second trimester and a peak expression of Siglec1 at the third trimester were observed. Pregnancy levels of IFI35 and IFI44 in patients with RA were higher than those of nonpregnant patients with RA. No significant association of gene expression levels with disease activity was found. In the sera of patients and healthy women, IFN-beta was undetectable and IFN-alpha levels remained stable throughout pregnancy and postpartum. Thus, pregnancy can give rise to an increased expression of type I IFN-inducible genes, reflecting an upregulation of the innate immune system. However, an association of type I IFN-inducible genes with pregnancy induced disease amelioration seems unlikely.