Relevance of TH2 Markers in the Assessment and Therapeutic Management of Severe Allergic Asthma: A Real-Life Perspective.

BACKGROUND: Although blood eosinophils are currently recognized as the main clinical marker of TH2-type inflammation, their relevance in identifying asthma severity remains a matter of debate. METHODS: Our retrospective real-life study on severe asthmatics included in the NEONet Italian database aimed to investigate the relevance of blood eosinophil count and fractional exhaled nitric oxide (FeNO) in the clinical assessment of severe asthma and their role as potential predictors of responsiveness to anti-IgE therapy. The cut-off values chosen were 300 eosinophils/mm3 and FeNO of 30 ppm. RESULTS: We evaluated 132 adult patients. No significant differences were observed between the groups (high and low baseline eosinophil counts) in terms of demographic data, total IgE, lung function, patient-reported outcomes, or nasal comorbidities. The Asthma Control Test score and Asthma Quality of Life Questionnaire scores were poorer in patients with FeNO ≥30 ppb than in patients with FeNO <30 ppb. In the high FeNO subgroup, more frequent hospital admissions and a higher number of working days lost in the previous year were registered. A combined score including both eosinophils and FeNO did not improve the accuracy of the individual parameters. In the high-eosinophil subgroup, the proportion of responders to omalizumab was greater and increased at each follow-up time point. CONCLUSIONS: Our findings show that blood eosinophil count is not an unequivocal marker of asthma severity, whereas a higher FeNO level is associated with more frequent hospital admissions and more working days lost. Blood eosinophils seem to act as a predictor of response to omalizumab.

Relevance of TH2 markers in the assessment and therapeutic management of severe allergic asthma: a real-life perspective

BACKGROUND: Although blood eosinophils are currently recognized as the main clinical marker of TH2-type inflammation, their relevance in identifying asthma severity remains a matter of debate. METHODS: Our retrospective real-life study on severe asthmatics included in the NEONet Italian database aimed to investigate the relevance of blood eosinophil count and fractional exhaled nitric oxide (FeNO) in the clinical assessment of severe asthma and their role as potential predictors of responsiveness to anti-IgE therapy. The cut-off values chosen were 300 eosinophils/mm3 and FeNO of 30 ppm. RESULTS: We evaluated 132 adult patients. No significant differences were observed between the groups (high and low baseline eosinophil counts) in terms of demographic data, total IgE, lung function, patient-reported outcomes, or nasal comorbidities. The Asthma Control Test score and Asthma Quality of Life Questionnaire scores were poorer in patients with FeNO ≥30 ppb than in patients with FeNO <30 ppb. In the high FeNO subgroup, more frequent hospital admissions and a higher number of working days lost in the previous year were registered. A combined score including both eosinophils and FeNO did not improve the accuracy of the individual parameters. In the high-eosinophil subgroup, the proportion of responders to omalizumab was greater and increased at each follow-up time point. CONCLUSIONS: Our findings show that blood eosinophil count is not an unequivocal marker of asthma severity, whereas a higher FeNO level is associated with more frequent hospital admissions and more working days lost. Blood eosinophils seem to act as a predictor of response to omalizumab

ANTECEDENTES: Aunque los eosinófilos en la sangre actualmente son reconocidos como el principal marcador clínico de la inflamación Th2, su relevancia en la identificación de la gravedad del asma sigue siendo un tema de debate. MÉTODOS: Nuestro estudio retrospectivo de la vida real sobre asmáticos graves, incluido en la base de datos italiana de NEONet, tuvo como objetivo investigar la relevancia del recuento de eosinófilos en sangre y el FeNO en la evaluación clínica del asma grave y su función como posible factor predictivo de la capacidad de respuesta al tratamiento con anti-IgE. Como valores de corte se eligieron 300 eosinófilos/mm3en sangre y 30 ppm para FeNO. RESULTADOS: En total se evaluaron 132 pacientes adultos. No se pudieron observar diferencias significativas entre los grupos de eosinófilos basales altos y bajos, en términos de datos demográficos, IgE total, función pulmonar, resultados informados por el paciente (PRO) o comorbilidades nasales. Los pacientes con ≥ FeNO 30 ppb mostraron una puntuación de ACT peor y una puntuación AQLQ más baja en comparación con los de FeNO <30 ppb. En el subgrupo de FeNO alto, se registraron ingresos hospitalarios con más frecuencia y un mayor número de días de trabajo perdidos en el último año. Una puntuación combinada que incluye tanto a los eosinófilos como el FeNO no mejoró la precisión de los parámetros individuales. En el subgrupo de eosinófilos altos, la proporción de pacientes que respondieron al tratamiento con omalizumab fue mayor y aumentó significativamente en cada punto de tiempo de seguimiento. CONCLUSIONES: De acuerdo con nuestros hallazgos, los eosinófilos en sangre no representan un marcador unívoco de la gravedad del asma, mientras que un nivel más alto de FeNO se asocia con más ingresos hospitalarios y más días de trabajo perdidos. Los eosinófilos de la sangre parecen actuar como predictores de la respuesta del tratamiento al omalizumab

Drop-out rate among patients treated with omalizumab for severe asthma: Literature review and real-life experience.

BACKGROUND: In patients with asthma, particularly severe asthma, poor adherence to inhaled drugs negatively affects the achievement of disease control. A better adherence rate is expected in the case of injected drugs, such as omalizumab, as they are administered only in a hospital setting. However, adherence to omalizumab has never been systematically investigated. The aim of this study was to review the omalizumab drop-out rate in randomized controlled trials (RCTs) and real-life studies. A comparative analysis was performed between published data and the Italian North East Omalizumab Network (NEONet) database. RESULTS: In RCTs the drop-out rate ranged from 7.1 to 19.4 %. Although the reasons for withdrawal were only occasionally reported, patient decision and adverse events were the most frequently reported causes. In real-life studies the drop-out rate ranged from 0 to 45.5 %. In most cases lack of efficacy was responsible for treatment discontinuation. According to NEONet data, 32 % of treated patients dropped out, with an increasing number of drop outs observed over time. Patient decision and lack of efficacy accounted for most treatment withdrawals. CONCLUSIONS: Treatment adherence is particularly crucial in patients with severe asthma considering the clinical impact of the disease and the cost of non-adherence. The risk of treatment discontinuation has to be carefully considered both in the experimental and real-life settings. Increased knowledge regarding the main reasons for patient withdrawal is important to improve adherence in clinical practice.

Asthma control in elderly asthmatics. An Italian observational study.

BACKGROUND: The exponential increase of individuals aged >64 yrs is expected to impact the burden of asthma. We aimed to explore the level of asthma control in elderly subjects, and factors influencing it. METHODS: A multicenter observational study was performed on consecutive patients >64 years old with a documented physician-diagnosis of asthma. Sixteen Italian centers were involved in this 6-month project. FINDINGS: A total of 350 patients were enrolled in the study. More than one-third of elderly asthmatic patients, despite receiving GINA step 3-4 antiasthmatic therapy, had an Asthma Control Test score ≤19, with a quarter experiencing at least one severe asthma exacerbation in the previous year. Twenty-nine percent of patients (n = 101) were classified as having Asthma-COPD Overlap Syndrome (ACOS) due to the presence of chronic bronchitis and/or CO lung diffusion impairment. This subgroup of patients had lower mean Asthma Control Test scores and more exacerbations compared to the asthmatic patients (18 ± 4 compared to 20 ± 4, p < 0.01, and 43% compared to 18%, p < 0.01, respectively). Modified Medical Research Council dyspnea mMRC scores and airway obstruction, assessed on the basis of a FEV(1)/FVC ratio below the lower limit of normal, were more severe in ACOS than in asthma, without any difference in responses to salbutamol. In a multivariate analysis, the mMRC dyspnea score, FEV(1)% of predicted and the coexistence of COPD were the only variables to enter the model. INTERPRETATION: Our results highlight the need to specifically evaluate the coexistence of features of COPD in elderly asthmatics, a factor that worsens asthma control.

Vascular changes in psoriatic knee joint synovitis.

OBJECTIVE: To evaluate the diagnostic utility of standard arthroscopy supported by a computerized image analysis system; and to examine and quantify the macroscopic appearance of blood vessels in selected anatomical areas, comparing 2 groups of patients with PsA and RA with refractory knee joint synovitis (KJS) for vascular marking (VM) features and VM scores, as well as for the relationship between respective VM scores and local and systemic KJS disease activity indices. METHODS: Standard arthroscopy was carried out on 39 knees (20 PsA, 19 RA). Videorecordings of the examination were reanalyzed using a computer image analysis system and software. The appearance of vascular markings was assessed and separately scored for the areas of surface synovium (capsular, CVM), villous proliferation (villous, VVM), and synovium adherent to cartilage (pannus, PVM). Indices of systemic (erythrocyte sedimentation rate, ESR) and local KJS disease activity (clinical index) were obtained before arthroscopy. The morphology and scores of the distinct VM were compared between PsA and RA groups, as was the relationship between respective VM scores and ESR and KJS clinical indices. RESULTS: Distinctive VM features were observed for PsA and RA KJS in each separate synovial architecture examined. VVM and CVM scores were significantly correlated with each other in PsA knees, and were significantly higher in PsA compared with RA. In both diseases, VVM and CVM scores were not related to KJS duration or activity or to ESR values, but in RA they were directly correlated with KJS activity. Moreover, the VVM capillary feature "meandering with tight convolutions," considered unique to psoriatic skin, was observed in the synovium of 13 PsA (65%) and one RA KJS (5.5%). The mean KJS duration of the PsA group with typical VVM was significantly lower than the group without VVM (2.6 +/- 1.77 vs 9.4 +/- 8.28 yrs). CONCLUSION: Our macroscopic observations of distinct changes in VM expression in selected anatomical areas of PsA and RA KJS suggest possible pathogenetic differences between the 2 diseases. The typical morphology and higher intensity of villous vascularization, in both early and chronic disease, and the different clinical relevance of VVM scores in PsA compared with RA KJS support the potential use of vascular markings as reliable outcome measures of the PsA process in KJS.

Arthroscopic synovectomy in rheumatoid and psoriatic knee joint synovitis: long-term outcome.

A long-term prospective study was performed to evaluate the safety and long-term outcome of surgical arthroscopy (AS) for persistent rheumatoid (RA) and psoriatic (PsA) knee joint synovitis (KJS). Local signs of joint inflammation (tenderness, swelling, "ballottement') and range of motion (ROM) were scored and the sum, taken as a global outcome measure, was recorded in 17 RA and 18 PsA knees, both before and at follow-up periods of 2, 6, 12, 24 and 36 months after surgical AS (knee joint synovectomy; meniscal curettage, cartilage shaving or chondrectomy, according to the degree of cartilage damage). A survival analysis (Kaplan-Meier) of the long-term outcome of surgical AS treatment and of the predictive value of clinical parameters of knee joint involvement was also performed. No intra- or post-operative morbidity, pain worsening or loss of joint motion was observed and all patients were discharged within 48 h. Comparison of the parameters of knee joint evaluation showed a significant reduction of the signs of joint inflammation and a significant increase in the ROM in all follow-up periods. At 36 months, the survival curves showed a 61.2% cumulative probability of clinical remission and 72.8% of definite improvement. No significant differences in the prognostic importance of RA, compared to PsA diagnosis, were observed, although higher percentages of PsA compared to RA knees (86.3% and 45.7% respectively) reached the end point of clinical remission at 36 months. KJS duration, radiographic severity and cartilage damage were not predictors of poor long-term outcome of AS synovectomy. Surgical AS treatment for PsA knees with more advanced cartilage damage gave a better long-term outcome. A total of 50.7% of operated knees reached the end point of a KJS relapse at 36 months, the majority (82%) within the initial 18 months of follow-up. Our study indicates that AS synovectomy is a safe procedure requiring short hospitalization which, in combination with second-line medical treatment, can reduce local inflammation in RA and PsA KJS, and preserve knee joint ROM for up to 3 yr.

Long-term sonographic follow-up of rheumatoid and psoriatic proliferative knee joint synovitis.

The potential role of sonography in evaluating the response to therapy of persistent knee joint synovitis (KJS) was assessed in a longitudinal study in pre-and post-arthroscopic (AS) synovectomy in rheumatoid and psoriatic patients. At entry to the study ultrasound (US) detection of synovial proliferation was compared with arthroscopic visualization as the 'gold standard' reference. US joint effusion and synovial thickness measures and predominant patterns of synovial proliferation were recorded by comparing clinical and US indices before and at 2, 6 and 12 months after AS synovectomy, or after KJS relapse up to 24 months. A 12 month survival analysis of clinical and US outcomes of arthroscopic synovectomy was also performed. US detection of morphology and degree of synovial proliferation was correlated with AS macroscopic evaluation. After AS synovectomy, the clinical index and both US joint effusion and synovial thickness were significantly reduced, whereas US patterns of synovial proliferation did not show significant changes. US and clinical indices were significantly correlated in all follow-up measurements and US joint effusion was significantly increased in the relapsed compared with the non-relapsed KJS group. The probability at 12 months of reaching maximum improvement in US joint effusion and synovial thickness outcomes was 99 and 58%, respectively; that for clinical remission of KJS was 72%. Ultrasound evaluation has proven reliable and accurate by the arthroscopic gold standard in detecting changes of rheumatoid arthritis and psoriatic arthritis knee joint synovitis. The correlation of US with clinical findings in pre-and post synovectomy patients suggests that sonography can be used as an objective method in monitoring the response to therapy of inflammatory knee joint disease.

Pancreatic exocrine involvement in primary Sjögren's syndrome.

Exocrine pancreatic involvement of primary Sjögren's syndrome (SS) was studied. Pancreatic enzyme levels (total amylase, pancreatic isoamylase and immunoreactive trypsin) along with anti-ductuli antibodies (Ab) were studied in 77 patients with primary SS. In 10 patients with normal and 10 with abnormal enzyme levels pancreatic CT scans were also obtained. All enzyme levels were significantly increased in comparison to the control group. Immunoreactive trypsin was found to be the most frequently increased enzyme (35.3% of pSS patients). Anti-ductuli Ab were not found in any patient. Pancreatic CT scans were normal in all subjects with enzymatic increase, whereas 2 abnormal scans were demonstrated in patients without enzyme changes. Our study suggests that exocrine pancreatic involvement is frequent when measured by enzyme levels. Nevertheless, we were unable to demonstrate any morphological lesion by CT scan.

Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns.

In reactive arthritis (ReA) a specific T cell response to the triggering bacterial antigen is present in the synovial fluid, while in paired peripheral blood T cells the response is markedly reduced. The proliferative response to ReA-associated bacteria in the peripheral blood of ReA patients was compared with that seen in the blood of healthy adults, who denied exposure to these microbes, and in the umbilical cord blood of newborns, who have clearly not been exposed to bacterial antigen. Peripheral blood mononuclear cells (PBMC) from non-exposed adults and those from umbilical cord blood proliferated to ReA-associated bacteria, whilst little response was seen in ReA PBMC. The response was MHC class II-restricted, required processing of the bacterial antigen, was seen in both CD45RO+ and CD45RA+ subsets, and was not oligoclonal. These T cell responses are similar to those previously demonstrated in non-exposed individuals to malaria, leishmania and trypanosoma antigen, and may reflect the existence of 'natural' T cell immunity to ReA-associated bacteria. The lack of such responses in ReA peripheral blood may suggest that such 'natural' responses may restrict the dissemination or progression of infection.

The role of interleukin-8 and other cytokines in the pathogenesis of Felty's syndrome.

OBJECTIVE: Felty's syndrome (FS) is defined as rheumatoid arthritis (RA) with neutropenia and, in some cases, splenomegaly; the outcome is primarily determined by the risk of infection, which is related to the degree of neutropenia. We analysed whether the clinical manifestations of FS, especially neutropenia, could be explained by abnormalities in cytokine production. METHODS: We examined the production in FS of five cytokines involved in the maturation and activation of polymorphonuclear cells (PMNs): IL-1 beta, TNF alpha, IL-8, G-CSF and GM-CSF. Because of the role of systemic IL-8 in neutrophil migration, serum IL-8 levels were also evaluated. RESULTS: Spontaneous and anti-CD16 stimulated cytokine production was similar in FS, RA and healthy controls (NC). However, anti-CD3 stimulated IL-8 production was significantly increased compared to NC in both RA and FS. FS patients who spontaneously produced G-CSF in culture were protected from bacterial infections. Serum IL-8 levels were elevated in FS and RA compared to NC (p < 0.001 for both groups). In FS, serum IL-8 was higher in patients with a history of bacterial infections compared to those without (p < 0.01) and there was a weak inverse correlation between neutropenia and serum IL-8 levels (Kendal's tau B = -0.31, p = 0.05). CONCLUSION: The neutropenia of FS cannot be explained by changes in peripheral blood cytokine production, although changes in the bone marrow microenvironment cannot be excluded. Our data do suggest a possible role for G-CSF and IL-8 in the development of certain FS complications.

An immunohistochemical study of immunological phenomena in minor salivary glands in patients with Sjögren's syndrome.

Using different monoclonal antibodies, we performed an immunofluorescent technique on labial salivary glands in order to investigate the immunological phenomena involved in Sjögren's syndrome (SS). An aberrant expression of HLA-DR molecules was detected on cytoplasm of epithelial labial salivary cells in 9 out of 19 (47%) patients, with SS. No such expression was found in 8 patients without SS or in 3 normal controls. HLA-DQ molecules were demonstrated also in two out of ten SS patients without HLA-DR. A lymphocytic infiltration was not correlated with the expression of class II molecules. T cells bearing gamma delta receptors were not detected. The intracellular adhesion molecules (ICAM-1) and lymphocyte function associated antigen-1 (LFA-1) were not found on epithelial glandular salivary cells of patients and controls. In conclusion, these data suggested that the absence of ICAM-1 and LFA-1 in salivary cells and the absence of infiltrating T cells bearing gamma delta receptors exclude their immunopathogenetic role in SS; moreover, these data demonstrated that the aberrant expression of HLA class II molecules on epithelial salivary cells of patients with SS is not a phenomenon correlated with the lymphocytic infiltration.

Synovial fluid lymphocyte proliferation to tuberculin protein product derivative: a novel way of diagnosing tuberculous arthritis.

We report a case of tuberculous arthritis in which the diagnosis was aided by lymphocyte proliferation assay to a panel of bacterial antigens. It illustrates that the lymphocyte proliferation assay may be a useful diagnostic tool in patients with tuberculous and reactive arthritis. It also supports the notion that there is a selective accumulation of antigen specific T cells at the site of inflammation in both septic and reactive arthritides.