Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus--report of 17 cases and review of the literature

Cutaneous manifestations occur frequently in systemic lupus erythematosus (SLE) and are pathognomonic in subacute-cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Although B-cell depletion therapy (BCDT) has demonstrated efficacy in SLE with visceral involvement, its usefulness for patients with predominant skin manifestations has not been fully established. In this single-centre, retrospective study 14 consecutive SLE, one CCLE and two SCLE patients with recalcitrant skin involvement were treated with 2 × rituximab 1 g, and 1 × cyclophosphamide 750 mg. Six months after BCDT, nine of 17 (53%) patients were in complete (CR) or partial remission (PR). Relapses occurred in 12 patients (71%) at a mean time of 10 ± 1.8 months after BCDT. A second cycle of BCDT achieved a more sustained remission in seven of nine patients (78%) lasting for a mean time of 18.4 ± 2.7 months. Minor adverse events were experienced by three patients. Mean follow-up was 30 months. Our own results and the literature review demonstrate that BCDT based on rituximab is well tolerated and may be effective for cutaneous lesions of lupus erythematosus. Randomized controlled trials are necessary to further evaluate the value of BCDT for this group of patients

Brucella endocarditis of the aortic valve

Brucella endocarditis was diagnosed in two patients with acute renal failure. Both patients had major aortic insufficiency, congestive cardiac failure and clinical and laboratory signs of an active infection, although adequate antibacterial therapy had already been introduced. Replacement of the aortic valve, together with the aortic root in one of the cases, were carried out as emergency procedures, followed by antibacterial treatment with rifampicin, doxycycline and co-trimoxazole. Both patients left the hospital cured and are well 2.5 and 2 years after the surgery, respectively

Bronchiectasis in rheumatoid arthritis. A clinical appraisial

Bronchiectasis is defined as irreversibly damaged and dilated bronchi and is one of the most common pulmonary manifestations in patients with rheumatoid arthritis (RA). The model of RA-associated autoimmunity induced in some individuals by chronic bacterial infection in bronchiectasis is becoming increasingly acceptable, although a genetic predisposition to RA-associated bronchiectasis has also been demonstrated. Bronchiectasis should be suspected in RA patients with chronic cough and sputum production or frequent respiratory infections and the diagnosis must be confirmed by thoracic high-resolution computed tomography. Management of patients with RA-associated bronchiectasis includes a multimodal treatment approach. Similar to all patients with non-cystic fibrosis bronchiectasis, patients with RA-associated bronchiectasis benefit from a pulmonary rehabilitation program, including an exercise/muscle strengthening program and an education program with a specific session on airway clearance techniques. Prophylactic antibiotics are recommended for patients with frequent (3 or more infective exacerbations per year) or severe infections requiring hospitalization/intravenous antibiotics and inhaled corticosteroids and long-acting β2-agonists should be used in patients with non-cystic fibrosis bronchiectasis and associated airway hyper-responsiveness. In patients with RA-associated bronchiectasis the use of immunomodulatory drugs has to be carefully considered, as they are essential to control disease activity, despite being associated with an increased infectious risk. Pneumococcal and influenza vaccines are advised to all patients with RA-associated bronchiectasis in order to reduce the risk of infection. Patients with RA-associated bronchiectasis have a poorer prognosis than those with either RA or bronchiectasis alone and require regular follow-up, under the joint care of a rheumatologist and a pulmonologist

Characterization of B cells in healthy pregnant women from late pregnancy to post-partum: a prospective observational study

BACKGROUND: B cells play a role in pregnancy due to their humoral and regulatory activities. To our knowledge, different maturational stages (from transitional to memory) of circulating B cell subsets have not yet been characterized (cell quantification and phenotype identification) in healthy pregnant women. Thus, the objective of our study was to characterize these subsets (as well as regulatory B cells) from late pregnancy to post-partum and to compare them with the circulating B cells of non-pregnant women. METHODS: In all of the enrolled women, flow cytometry was used to characterize the circulating B cell subsets according to the expression of IgD and CD38 (Bm1-Bm5 classification system). Regulatory B cells were characterized based on the expression of surface antigens (CD24, CD27, and CD38) and the production of IL-10 after lipopolysaccharide stimulation. RESULTS: Compared to the absolute counts of B cells in the non-pregnant women (n = 35), those in the pregnant women (n = 43) were significantly lower (p < 0.05) during the 3rd trimester of pregnancy and on delivery day (immediately after delivery). The percentages of these cells on delivery day and at post-partum were significantly lower than those in the non-pregnant women. In general, the absolute counts and percentages of the majority of the B cell subsets were significantly lower in the 3rd trimester of pregnancy and on delivery day than in the non-pregnant women. However, these counts and percentages did not differ significantly between the post-partum and the non-pregnant women. The most notable exceptions to the above were the percentages of naïve B cells (which were significantly higher in the 3rd trimester and on delivery day than in the non-pregnant women) and of CD24(hi)CD38(hi) regulatory B cells (which were significantly higher in the post-partum than in the non-pregnant women). CONCLUSION: According to our study, the peripheral B cell compartment undergoes quantitative changes during normal late pregnancy and post-partum. Such findings may allow us to better understand immunomodulation during human pregnancy and provide evidence that could aid in the development of new strategies to diagnose and treat pregnancy-associated disturbances. Our findings could also be useful for studies of the mechanisms of maternal responses to vaccination and infection

Pragmatic treatment of patients with Systemic Lupus Erythematosus with rituximab: Long-term effects on serum immunoglobulins

OBJECTIVE: B cell depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with Systemic Lupus Erythematosus (SLE). The aim of this observational study was to document long-term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice. METHODS: We included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti-dsDNA antibodies over a median of 48 months most recent follow-up. Flow cytometry was used prospectively to assess B-cell phenotypes in 17/57 patients. RESULTS: Twelve patients (21%) had persistent IgM hypogammaglobulinemia (1000IU/ml; normal<50IU/ml). Factors predictive of low serum IgM included: baseline serum IgM ≤0.8g/L (receiver-operated-curve analysis) and subsequent therapy with mycophenolate mofetil (MMF) (odds ratio=6.8 compared with other immunosuppressants). In patients maintaining normal IgM levels (9/17), the frequency of circulating IgD+CD27+ B cells was significantly higher (p=0.05). At 12 months after rituximab, 7/30 SLE patients with baseline anti-dsDNA≤1000 IU/ml had lost seropositivity. CONCLUSIONS: Lower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti-dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE. This article is protected by copyright. All rights reserved

In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS

Introduction: Disturbances of energy metabolism contribute to the clinical manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Previously, we found that B cells from ME/CFS patients have an increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand was compared. Methods: CD24, the ectonucleotidases CD39 and CD73, the NAD-degrading enzyme CD38, and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor and costimulation with either T-cell-dependent or Toll-like-receptor-9-dependent agonists. The levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analyzed in relation to cell growth and immunophenotype. Results: Proliferating B cells from patients with ME/CFS showed a lower mitochondrial mass and a significantly increased usage of essential amino acids compared with those from HC, with a significantly delayed loss of CD24 and an increased expression of CD38 following stimulation. Discussion: The immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with the increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations

B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell-activating factor-binding receptors on B cell subsets

Serum levels of B cell‐activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF‐binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre‐RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/μl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR+ expression compared to HC and pre‐RTX patients. The percentage of BAFFR+ B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI+ memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR+ or percentage of BCMA+ B cells or serum BAFF levels. The lower percentage of TACI+ memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse

User needs elicitation via analytic hierarchy process (AHP). A case study on a Computed Tomography (CT) scanner

Background: The rigorous elicitation of user needs is a crucial step for both medical device design and purchasing. However, user needs elicitation is often based on qualitative methods whose findings can be difficult to integrate into medical decision-making. This paper describes the application of AHP to elicit user needs for a new CT scanner for use in a public hospital. Methods: AHP was used to design a hierarchy of 12 needs for a new CT scanner, grouped into 4 homogenous categories, and to prepare a paper questionnaire to investigate the relative priorities of these. The questionnaire was completed by 5 senior clinicians working in a variety of clinical specialisations and departments in the same Italian public hospital. Results: Although safety and performance were considered the most important issues, user needs changed according to clinical scenario. For elective surgery, the five most important needs were: spatial resolution, processing software, radiation dose, patient monitoring, and contrast medium. For emergency, the top five most important needs were: patient monitoring, radiation dose, contrast medium control, speed run, spatial resolution. Conclusions: AHP effectively supported user need elicitation, helping to develop an analytic and intelligible framework of decision-making. User needs varied according to working scenario (elective versus emergency medicine) more than clinical specialization. This method should be considered by practitioners involved in decisions about new medical technology, whether that be during device design or before deciding whether to allocate budgets for new medical devices according to clinical functions or according to hospital department