Jacob K. Sont

Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death, with cigarette smoking among the main risk factors. Hallmarks of COPD include chronic airflow obstruction and chronic inflammation in the airway walls or alveolar septa. An earlier study reported elevated numbers of macrophages and mast cells within the bronchiolar epithelium in smokers with COPD, compared with smokers without. Since specific chemokines may be involved in this influx, the in situ protein and mRNA expression of monocyte chemoattractant protein 1 (MCP‐1) and of interleukin 8 (IL‐8) were studied in tumour‐free peripheral lung tissue resected for lung cancer of current or ex‐smokers with COPD (FEV1<75%; n=14) and without COPD (FEV1>84; n=14). MCP‐1 was expressed by macrophages, T cells, and endothelial and epithelial cells. Its receptor, CCR2, is expressed by macrophages, mast cells, and epithelial cells. IL‐8 was found in neutrophils, epithelial cells, and macrophages. In subjects with COPD, semi‐quantitative analysis revealed 1.5‐fold higher levels of MCP‐1 mRNA and IL‐8 mRNA and protein in bronchiolar epithelium (p<0.01) and 1.4‐fold higher levels of CCR2 in macrophages (p=0.014) than in subjects without COPD. The bronchiolar epithelial MCP‐1 mRNA expression correlated with both CCR2 expression on macrophages and mast cells (p<0.05) and the numbers of intra‐epithelial macrophages and mast cells (p<0.04). The epithelial IL‐8 expression did not correlate with the numbers of neutrophils, macrophages, CD45RO+, CD8+, or mast cells. These data suggest that MCP‐1 and CCR2 are involved in the recruitment of macrophages and mast cells into the airway epithelium in COPD. Copyright

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54371254.

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). OBJECTIVE To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. DESIGN Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) SETTING 2 university medical centers in The Netherlands. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD. MEASUREMENTS Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. INTERVENTION Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). RESULTS 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level. LIMITATIONS The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. CONCLUSION ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. .

Internet-Based Self-management Plus Education Compared With Usual Care in Asthma: A Randomized Trial

Context Patient self-management is an essential component of asthma care, and the Internet is a medium to potentially support patients in self-management. Contribution This randomized trial compared Internet-based asthma self-management with usual care and found modest improvements in asthma control and lung function with the Internet intervention, but found no reduction in exacerbations and changes in asthma-related quality of life that were less than clinically significant at 12 months. Implication Although Internet-based self management can improve some asthma outcomes, the improvements were small and the program did not reduce the number of exacerbations. The Editors Asthma is a chronic disorder of the airways that is characterized by recurring respiratory symptoms, variable airflow obstruction, airway hyperresponsiveness, and underlying inflammation (1, 2). Recent clinical guidelines for the management of asthma distinguish 4 essential components of asthma care: assessment and monitoring, patient education, control of environmental and comorbid factors that affect asthma, and drug treatment. With appropriate medical care, well-informed and empowered patients can control their asthma and live full, active lives (1, 2). However, despite the availability of monitoring tools and effective therapy, asthma control is suboptimal in many patients worldwide, and long-term management falls far short of the goals set in the guidelines (3). Self-monitoring, education, and specific medical care are important aspects in improving the lives of patients with asthma (1, 2). However, many patients with mild or moderate persistent asthma do not attend checkups regularly or visit their physician with symptoms of the disease (4). In addition, in practice, both patients and their health care providers are reluctant to use written self-management plans (5). Internet technology is increasingly seen as an appealing tool to support self-management for patients with chronic disease in remote and underserved populations (68). However, to date, studies on Internet-based asthma self-management show only short-term improvements in asthma control, lung function, and quality of life (911). Long-term studies on the effect of Internet-based self-management, including all its essential features, are not available. Therefore, we developed a guided self-management tool for adult patients with asthma that included Internet-based home monitoring and treatment advice (action plan), online education, and remote Web communication with a specialized asthma nurse. The goal of our study was to assess the long-term clinical effectiveness of Internet-based self-management education compared with usual physician-provided care alone. Methods Design Overview We conducted a 12-month, multicenter, nonblinded, randomized, controlled trial. We randomly assigned patients to Internet-based self-management (Internet group) as an adjunct to usual care or to usual physician-provided care alone (usual care group). The Internet-based self-management program included weekly asthma control monitoring and treatment advice, online and group education, and remote Web communications with a specialized asthma nurse. The intervention continued for 12 months after enrollment. The Medical Ethics Committee of the Leiden University Medical Center, Leiden, the Netherlands, approved the study. Setting and Participants We recruited patients from 37 general practices (69 general practitioners) in the Leiden and The Hague area and the Outpatient Clinic of the Department of Pulmonology at the Leiden University Medical Center from September 2005 to September 2006. Inclusion criteria were physician-diagnosed asthma coded according to the International Classification of Primary Care in the electronic medical record (12), age 18 to 50 years, prescription of inhaled corticosteroids for at least 3 months in the previous year, no serious comorbid conditions that interfered with asthma treatment, access to the Internet at home, and mastery of the Dutch language. We excluded patients who were receiving maintenance oral glucocorticosteroid treatment. On the basis of diagnosis, age, prescribed asthma medication, and comorbid conditions, we sent eligible patients an invitation letter followed by 1 reminder letter after 2 to 4 weeks if they did not respond to the first. We continued this process until a total of 200 patients had entered the study (September 2006). All participants gave written consent. Randomization and Intervention In a 2-week baseline period before randomization, we collected data on patient demographic characteristics, asthma-related quality of life, symptom control, lung function, and medication level. We provided basic education about core information on asthma, action of medications, and inhaler technique instructions to all patients. We trained all participants to measure FEV1 daily with a hand-held electronic spirometer (PiKo-1, Ferraris Respiratory, Hertford, United Kingdom) and to report the highest value of 3 measurements in the morning before taking medication (2, 13). They were shown how to report these values on a personal page on a secure Web application by using a login password (or how to report by mobile telephone text message). Patients were also asked to report their nighttime and daytime asthma symptom scores on this Internet page or by text message. We asked all participants to complete the Asthma Control Questionnaire on their personal Internet page each week (14). We did not give any patients feedback about lung function or asthma control. After the 2-week baseline period, we randomly assigned participants to either the Internet group or the usual care group. We stratified according to care provider (primary vs. subspecialty care) and asthma control at baseline (15). We randomly assigned patients to the 2 groups (1:1 ratio) by using a computer-generated, permuted-block scheme. Allocation took place by computer after collection of the baseline data, ensuring concealment of allocation. The Internet-based self-management program consisted of the 4 principal components of asthma self-management and was accessed through the specially designed Web site, which allowed monitoring through the Web site (or text message on a mobile telephone), use of an Internet-based treatment plan, online education, and Web communications with a specialized asthma nurse (16). Patients monitored their asthma weekly by completing an electronic version of the Asthma Control Questionnaire on the Web site and instantly received feedback on the current state of their asthma control along with advice on how to adjust their treatment according to a predefined algorithm and treatment plan (Table 1 and Appendix Figures 1, 2, 3, 4, and 5). Depending on the scores submitted, patients received 4 types of self-treatment advice. When 4 consecutive Asthma Control Questionnaire scores were 0.5 or less, patients were advised to decrease treatment according to treatment plan. When 2 consecutive scores were greater than 0.5 but less than 1.0, patients were advised to increase treatment according to treatment plan. When 1 score was 1.0 or more but less than 1.5, patients were advised to immediately increase treatment according to treatment plan. Finally, when 1 score was 1.5 or more, patients were advised to immediately increase treatment and contact the asthma nurse. Table 1. Treatment Plan Appendix Figure 1. Algorithm based on consecutive ACQ scores to adjust medical treatment. * ACQ = Asthma Control Questionnaire. At entry of the algorithm, the evaluation period is bypassed. The evaluation period starts after treatment was stepped up. The optimal control period starts after 1 ACQ score 0.5 and ends after 1 ACQ score >0.5. Appendix Figure 2. Screen shot of daily lung function and symptom monitoring. Appendix Figure 3. Screen shot of feedback on daily lung function and symptom monitoring. Appendix Figure 4. Screen shot of weekly Asthma Control Questionnaire monitoring. Appendix Figure 5. Screen shot of feedback on Asthma Control Questionnaire, treatment advice according to personalized treatment plan, and results of past 6 months. We advised no medication changes during the 4 weeks after treatment was stepped up (evaluation period). In addition to weekly assessments, patients could optionally report daily symptoms and lung function and were able to contact our asthma nurse though the Web or by telephone. Thus, any acute deterioration warranting a visit to the general practitioner or hospital could be detected (Appendix Figures 2 and 3). We aimed to empower patients to use the Internet-based self-management tool and to develop a patientprovider partnership in asthma care (2). Self-management education consisted of both Web-based and face-to-face, group-based education. Web-based education included asthma information, news, frequently asked questions, and interactive communication with a respiratory nurse specialist. We scheduled 2 group-based education sessions, which lasted 45 to 60 minutes, for patients in the Internet-based self-management group within 6 weeks after entering the trial. Both sessions included exploration of a patients interests and previous knowledge (negotiating an agenda and patient-centered education), personalized feedback, and empowerment of self-management (self-efficacy and implementing a plan for change) (2, 17). The first educational session also included pathophysiology of asthma, information on the Web-based action plan, and information and review of inhalation technique. The second educational session gave information about the mechanisms and side effects of medication and explained trigger avoidance. Patients in the usual care group received asthma care according to the Dutch general practice guidelines on asthma management in adults, which recommend a medical review and treatment adjustment every 2 to 4 weeks in unstable asthma and medical review once or twice yearly

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: Results of an open study to assess feasibility, safety, and efficacy

OBJECTIVE To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Nutrient supplementation with polyunsaturated fatty acids and micronutrients in rheumatoid arthritis: clinical and biochemical effects

Objective: To investigate in a double-blind placebo-controlled, parallel group study, the effects of a nutrient supplement, containing, among other ingredients, the omega-3 fatty acids eicosapentaenoic acid (1.4 g EPA), docosahexaenoic acid (0.211 g DHA), omega-6 fatty acid gamma-linolenic acid (0.5 g GLA) and micronutrients in patients with active rheumatoid arthritis (RA).Design, subjects and intervention: RA patients were randomized to receive either daily liquid nutrient supplementation or placebo for 4 months. The primary end point was the change in tender joint count at 2 and 4 months. Other clinical variables included swollen joint count, visual analogue scales for pain and disease activity, grip strength, functionality score and morning stiffness. Biochemical parameters included plasma concentrations of PUFA and vitamins C and E.Setting: Outpatient university clinic.Results: In all, 66 patients enrolled, 55 completed the study. No significant change from baseline in tender joint count or any of the other clinical parameters was detected in either group. Patients receiving nutrient supplementation, but not those receiving placebo, had significant increases in plasma concentrations of vitamin E (P=0.015), and EPA, DHA and docosapentaenoic acid concomitant with decreases of arachidonic acid (P=0.01). Intergroup differences for PUFA and vitamin E were significantly different (P=0.01 and 0.03, respectively).Conclusions: This double-blind, placebo-controlled study in RA patients did not show superior clinical benefit of daily nutrient supplementation with EPA, GLA and micronutrients at the doses tested as compared to placebo. The study adds information regarding doses of omega-3 fatty acids, below which anti-inflammatory effects in RA are not seen.

Validity and usability of low-cost accelerometers for internet-based self-monitoring of physical activity in patients with chronic obstructive pulmonary disease

Background The importance of regular physical activity for patients with chronic obstructive pulmonary disease (COPD) is well-established. However, many patients do not meet the recommended daily amount. Accelerometers might provide patients with the information needed to increase physical activity in daily life. Objective Our objective was to assess the validity and usability of low-cost Internet-connected accelerometers. Furthermore we explored patients’ preferences with regards to the presentation of and feedback on monitored physical activity. Methods To assess concurrent validity we conducted a field validation study with patients who wore two low-cost accelerometers, Fitbit and Physical Activity Monitor (PAM), at the same time along with a sophisticated multisensor accelerometer (SenseWear Armband) for 48 hours. Data on energy expenditure assessed from registrations from the two low-cost accelerometers were compared to the well validated SenseWear Armband which served as a reference criterion. Usability was examined in a cross-over study with patients who, in succession, wore the Fitbit and the PAM for 7 consecutive days and filled out a 16 item questionnaire with regards to the use of the corresponding device Results The agreement between energy expenditure (METs) from the SenseWear Armband with METs estimated by the Fitbit and PAM was good (r=.77) and moderate (r=.41), respectively. The regression model that was developed for the Fitbit explained 92% whereas the PAM-model could explain 89% of total variance in METs measured by the SenseWear. With regards to the usability, both the Fitbit and PAM were well rated on all items. There were no significant differences between the two devices. Conclusions The low-cost Fitbit and PAM are valid and usable devices to measure physical activity in patients with COPD. These devices may be useful in long-term interventions aiming at increasing physical activity levels in these patients.

Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma

Background Inflammatory and structural changes of the airway mucosa are chronic features of asthma. The mechanisms underlying these changes and their modulation by steroid prophylaxis have not been clarified.

Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNFα and IL18 but not CXCL12

Background: Tumour necrosis α (TNFα) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNFα independent pathways play a role in the disease. Objectives: To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNFα independent mechanisms. Methods: 12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38+ cells was studied by an immunofluorescent double labelling technique. Results: Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNFα, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38+ activated T cells were more resistant to treatment than CD38+ plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients. Conclusions: Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNFα independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

Cost-Effectiveness of Internet-Based Self-Management Compared with Usual Care in Asthma

Background Effectiveness of Internet-based self-management in patients with asthma has been shown, but its cost-effectiveness is unknown. We conducted a cost-effectiveness analysis of Internet-based asthma self-management compared with usual care. Methodology and Principal Findings Cost-effectiveness analysis alongside a randomized controlled trial, with 12 months follow-up. Patients were aged 18 to 50 year and had physician diagnosed asthma. The Internet-based self-management program involved weekly on-line monitoring of asthma control with self-treatment advice, remote Web communications, and Internet-based information. We determined quality adjusted life years (QALYs) as measured by the EuroQol-5D and costs for health care use and absenteeism. We performed a detailed cost price analysis for the primary intervention. QALYs did not statistically significantly differ between the Internet group and usual care: difference 0.024 (95% CI, −0.016 to 0.065). Costs of the Internet-based intervention were