Design and implementation of a mobile app for the pharmacotherapeutic follow-up of patients diagnosed with immune-mediated inflammatory diseases: eMidCare (Preprint)

BACKGROUND Pharmacotherapeutic management of immune-mediated inflammatory diseases (IMID) has become more complex due to the development of new treatments, such as biological therapies. Mobile health, especially apps, can provide IMID patients with greater autonomy and facilitate communication with healthcare professionals. OBJECTIVE Our objective was to design and implement an app for remote monitoring and communication with IMID patients. We also assessed the usability of and satisfaction with the app. METHODS A multidisciplinary group comprising pharmacists, dermatologists, rheumatologists, gastroenterologists, and nurses was created to design and develop an app for IMID patients in a tertiary hospital. The app functionalities were identified through a focus group with IMID patients and through an observational, cross-sectional, descriptive study of all available apps for IMID patients at App Store and Play Store platforms. Once the app was designed and developed, we started offering the app to all IMID patients who initiated a new biological therapy. We performed an observational, longitudinal study of patients followed using the app to assess the tool's impact on safety, communication, satisfaction, and usability. The inclusion period was from December 2020 to August 2021. The inclusion criteria were age ≥ 18 years, diagnosis of an IMID, and ownership of a Smartphone. Patients with language barriers were excluded. RESULTS We designed an app (eMidCare®) with the following modules: My Medication, My Questionnaires, Adverse Events, Useful Information, Messages, and Patient Profile. A total of 86 patients were installed with the app (the median age was 48.3 [18.1-79.4] years and 62.4 were female). The median (range) follow-up time for app use was 123 (5-270) days. In the My Medication module, 100% of patients registered their biological therapy and 25.9% also used this module to record each dose of medication administered. A total of 82 adverse events (AEs) were registered. Thirty-two percent of the patients registered at least 1 AE. The most frequent AEs were fatigue, injection site reaction, headache, and nausea. Fifty-two percent of patients used the Messages module to communicate with healthcare professionals. The most frequent messages concerned doubts about managing AEs (26.2%) and drug interactions (18.9%). The satisfaction survey yielded a median (range) score of 9.1 (7-10) out of 10. The app sections that patients browsed for the longest time were Messages (21.9%), Start screen (20.9%), My questionnaires (20.4%), My medication (8.8%), and Adverse events (7.1%). CONCLUSIONS We developed an app, eMidCare®, which reminds patients to take their medication, enables them to record AEs, and helps them communicate with healthcare professionals. Approximately one-third of the patients registered the administration of the biological therapies and registered at least 1 AE. The most used and most satisfactory functionality was communication with health professionals. Patient satisfaction and retention were very high.

Biological Therapies and Tuberculosis Infection in Dermatology

After contact with a case of transmissible tuberculosis (TB), some of the exposed individuals may be infected and develop an immune reaction against Mycobacterium tuberculosis (Mtb), the causative agent of the disease. The replication of mycobacteria is usually stopped within cellular structures called granulomas, whose integrity relies on a complex interplay between cells and cytokines, the most prominent of them being TNF. In case of deficiency or inhibition of the activity of TNF, the granulomas may disrupt and release the surviving mycobacteria which may multiply, disseminate and lead to active TB disease. Several immune-mediated inflammatory diseases, among which rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis and psoriasis can be treated by biological therapies acting by the inhibition of TNF or cytokines like IL-17 and IL-23. If these therapies, in particular TNF-inhibitors, are administered to people infected by Mtb, there is a risk of decreasing the integrity of granulomas and increasing the probability of mutiplication of mycobacteria and TB reactivation. Therefore, in persons with rheumatological, gastro-enterological and dermatological diseases candidate to biological therapies there is a general recommendation of screening for TB infection (TBI) at baseline. The screening should include also a search for history of prior TB or contact with TB, a test for the presence of TBI, and if scored positive, a chest X-Ray

Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis

ObjectiveBiological therapies and small molecules continue to be evaluated in moderate to severely active ulcerative colitis, but are often studied in placebo-controlled trials, meaning their relative efficacy and safety is unknown. We examined this in a network meta-analysis.DesignWe searched the literature to October 2021 to identify eligible trials. We judged efficacy using clinical remission, endoscopic improvement, or clinical response, and according to previous exposure or non-exposure to antitumour necrosis factor (TNF)-α therapy. We also assessed safety. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs. Interventions were ranked according to their P-score.ResultsWe identified 28 trials (12 504 patients). Based on failure to achieve clinical remission, upadacitinib 45 mg once daily ranked first versus placebo (RR 0.73; 95% CI 0.68 to 0.80, P-score 0.98), with infliximab 5 mg/kg and 10 mg/kg second and third, respectively. Upadacitinib ranked first for clinical remission in both patients naïve to anti-TNF-α drugs (RR 0.69; 95% CI 0.61 to 0.78, P-score 0.99) and previously exposed (RR 0.78; 95% CI 0.72 to 0.85, P-score 0.99). Upadacitinib was superior to almost all other drugs in these analyses. Based on failure to achieve endoscopic improvement infliximab 10 mg/kg ranked first (RR 0.61; 95% CI 0.51 to 0.72, P-score 0.97), with upadacitinib 45 mg once daily, second, and infliximab 5 mg/kg third. Upadacitinib was more likely to lead to adverse events, but serious adverse events were no more frequent, and withdrawals due to adverse events were significantly lower than with placebo. Infections were significantly more likely with tofacitinib than placebo (RR 1.41; 95% CI 1.03 to 1.91).ConclusionIn a network meta-analysis, upadacitinib 45 mg once daily ranked first for clinical remission in all patients, patients naïve to anti-TNF-α drugs and patients previously exposed. Infliximab 10 mg/kg ranked first for endoscopic improvement. Most drugs were safe and well tolerated.

Asthma Control during COVID-19 Lockdown in Patients with Severe Asthma under Biological Drug Treatment

Introduction: Coronavirus disease 2019 (COVID-19) has deeply affected the management of patients with severe asthma, treated with add-on biological therapies. Objective: In this study, severe asthmatic patients on treatment with one of three different biologics (omalizumab, mepolizumab, benralizumab) underwent a survey to evaluate the effects of COVID-19 on the management of their clinical condition, with regard to the changes caused by the limited access to health facilities during the pandemic period. Methods: In this prospective observational study, 28 severe asthmatic outpatients referring to the Respiratory Unit of Magna Graecia University Hospital, Catanzaro (Italy), were asked to answer a telephone survey from May to July 2021. This survey included the evaluation of demographic and clinical data, as well as the number of lung function tests performed, exacerbations, biologic doses administered at hospital, or at general practitioner office, or through self-administration. Adherence to biological therapies before and during the pandemic period was also assessed. Moreover, the most recent asthma control test (ACT) score and the last forced expiratory volume in the first second (FEV1) measurement, recorded during the pandemic phase, were compared to the pre-pandemic (baseline) period. Results: When comparing the pre-pandemic data with the pandemic observations, the mean ACT score and the exacerbation rate did not significantly change [ACT, 21.5 ± 2.8 to 23.0 ± 3.9 (p = 0.1); exacerbation rate, 0.3 ± 0.6 and 0.5 ± 1.5 (p = 0.3)]. When considering some variables related to disease management in the same periods, a statistically significant difference was detected with regard to the mean number of outpatient visits (5.2 ± 3.8 vs. 0.9 ± 2.5, p < 0.0001), as well as to the mean number of accesses to health facilities for the administration of biological drugs (from 7.0 ± 3.4 to 2.5 ± 3.9, p < 0.0001). None of the patients reported to have been infected with the SARS-CoV-2 virus and no adverse drug reactions (ADR) occurred during the study. Conclusions: The above results suggest that COVID-19 pandemic did not induce any significant change related to severe asthma control. Indeed, add-on treatment with biological drugs was regularly continued, despite the obvious limited access to health facilities.

Periostin - A biomarker in adults with asthma

<p>Asthma is a common, heterogeneous condition where current treatment options are limited to a ‘one size fits all’ approach. Biological therapies targeting specific components of the Type 2 inflammatory pathway are emerging as potential alternatives for those who are inadequately controlled on current treatment options. Biomarkers, such as serum periostin, can be used in clinical settings to identify potential responders to these treatments. The aim of this research was to investigate the epidemiology of periostin and its ability to predict important clinical outcomes in asthma. Six studies were conducted: two cohort studies observing the change to periostin after bone and dental injury in non-asthmatic adults; a cohort study investigating reference ranges of periostin in Chinese adults with and without asthma; two longitudinal studies measuring the change in periostin in asthmatic adults with stable and unstable disease; and a longitudinal cohort study investigating the association between periostin and risk of exacerbation. There was a biphasic response of serum periostin after bone injury. This was particularly marked after joint replacement surgery where periostin fell within 48 hours by a ratio of geometric means 0.80 (95% CI 0.75 to 0.86) before rising to a maximum level at eight weeks with a ratio of geometric means 1.89 (95% CI 1.77 to 2.02). There was no significant change to periostin after simple or surgical tooth extractions with a maximal ratio of geometric means of 1.02 (95% CI 0.95 to 1.10). Serum periostin was higher in Chinese non-asthmatic adults versus Caucasian non- asthmatic adults, mean periostin 57 ng/ml and 49.7 ng/ml respectively, difference (95% CI) 8.2 (5.8 to 10.6) ng/ml. Serum periostin remained stable in adults with well- controlled asthma with an intra-class coefficient for variation of 0.93. In unstable asthma, there was a decrease in serum periostin one week after the start of a severe exacerbation and treatment with systemic corticosteroids, with a ratio of geometric means 0.86 (95% CI 0.82 to 0.92) before stabilising four weeks later. Finally, adults with mild to moderate asthma with low baseline levels of periostin were more likely to have a severe asthma exacerbation with a hazard ratio (95% CI) 0.62 (0.35 to 1.09) per 0.693 ng/ml increase of log periostin. In conclusion, serum periostin showed significant biphasic variation in response to bone injury, the magnitude and duration of which was proportional to bone size. Whilst this pattern was not replicated in adults undergoing dental surgery, it suggests that serum periostin can be affected by non-asthma related conditions. Periostin demonstrated higher mean values in Chinese adults than in Caucasian adults, indicating ethnicity-specific reference ranges may be required if it were to become a clinical biomarker. Intra-participant variability of serum periostin was low in a homogenous group of well controlled, moderate to severe asthmatic adults, but there was wide variability between individuals in this group suggesting that factors other than asthma are likely to affect serum periostin levels. Serum periostin was suppressed during and after treatment for a severe exacerbation for up to four weeks. This is likely due to the exacerbation and/or its treatment, suggesting the interpretation of periostin as a biomarker for response to biological therapies should not occur within four weeks of a severe exacerbation. The reported positive association between periostin and risk of severe exacerbation in populations with severe eosinophilic asthma does not extend to a general population of mild to moderate asthmatics, in which an inverse associated was observed. Serum periostin may be useful in predicting treatment responsiveness of patients to monoclonal antibody therapy directed against IL-4Rα, IL-13 and IgE. However, it may be difficult to use as a biomarker clinically, as numerous non-asthma related factors, such as bone injury and ethnicity, have been shown to significantly affect serum levels, making interpretation difficult.</p>

Periostin - A biomarker in adults with asthma

<p>Asthma is a common, heterogeneous condition where current treatment options are limited to a ‘one size fits all’ approach. Biological therapies targeting specific components of the Type 2 inflammatory pathway are emerging as potential alternatives for those who are inadequately controlled on current treatment options. Biomarkers, such as serum periostin, can be used in clinical settings to identify potential responders to these treatments. The aim of this research was to investigate the epidemiology of periostin and its ability to predict important clinical outcomes in asthma. Six studies were conducted: two cohort studies observing the change to periostin after bone and dental injury in non-asthmatic adults; a cohort study investigating reference ranges of periostin in Chinese adults with and without asthma; two longitudinal studies measuring the change in periostin in asthmatic adults with stable and unstable disease; and a longitudinal cohort study investigating the association between periostin and risk of exacerbation. There was a biphasic response of serum periostin after bone injury. This was particularly marked after joint replacement surgery where periostin fell within 48 hours by a ratio of geometric means 0.80 (95% CI 0.75 to 0.86) before rising to a maximum level at eight weeks with a ratio of geometric means 1.89 (95% CI 1.77 to 2.02). There was no significant change to periostin after simple or surgical tooth extractions with a maximal ratio of geometric means of 1.02 (95% CI 0.95 to 1.10). Serum periostin was higher in Chinese non-asthmatic adults versus Caucasian non- asthmatic adults, mean periostin 57 ng/ml and 49.7 ng/ml respectively, difference (95% CI) 8.2 (5.8 to 10.6) ng/ml. Serum periostin remained stable in adults with well- controlled asthma with an intra-class coefficient for variation of 0.93. In unstable asthma, there was a decrease in serum periostin one week after the start of a severe exacerbation and treatment with systemic corticosteroids, with a ratio of geometric means 0.86 (95% CI 0.82 to 0.92) before stabilising four weeks later. Finally, adults with mild to moderate asthma with low baseline levels of periostin were more likely to have a severe asthma exacerbation with a hazard ratio (95% CI) 0.62 (0.35 to 1.09) per 0.693 ng/ml increase of log periostin. In conclusion, serum periostin showed significant biphasic variation in response to bone injury, the magnitude and duration of which was proportional to bone size. Whilst this pattern was not replicated in adults undergoing dental surgery, it suggests that serum periostin can be affected by non-asthma related conditions. Periostin demonstrated higher mean values in Chinese adults than in Caucasian adults, indicating ethnicity-specific reference ranges may be required if it were to become a clinical biomarker. Intra-participant variability of serum periostin was low in a homogenous group of well controlled, moderate to severe asthmatic adults, but there was wide variability between individuals in this group suggesting that factors other than asthma are likely to affect serum periostin levels. Serum periostin was suppressed during and after treatment for a severe exacerbation for up to four weeks. This is likely due to the exacerbation and/or its treatment, suggesting the interpretation of periostin as a biomarker for response to biological therapies should not occur within four weeks of a severe exacerbation. The reported positive association between periostin and risk of severe exacerbation in populations with severe eosinophilic asthma does not extend to a general population of mild to moderate asthmatics, in which an inverse associated was observed. Serum periostin may be useful in predicting treatment responsiveness of patients to monoclonal antibody therapy directed against IL-4Rα, IL-13 and IgE. However, it may be difficult to use as a biomarker clinically, as numerous non-asthma related factors, such as bone injury and ethnicity, have been shown to significantly affect serum levels, making interpretation difficult.</p>

The Cytokine Mediated Molecular Pathophysiology of Psoriasis and Its Clinical Implications

Psoriasis is the result of uncontrolled keratinocyte proliferation, and its pathogenesis involves the dysregulation of the immune system. The interplay among cytokines released by dendritic, Th1, Th2, and Th17 cells leads to the phenotypical manifestations seen in psoriasis. Biological therapies target the cytokine-mediated pathogenesis of psoriasis and have improved patient quality of life. This review will describe the underlying molecular pathophysiology and biologics used to treat psoriasis. A review of the literature was conducted using the PubMed and Google Scholar repositories to investigate the molecular pathogenesis, clinical presentation, and current therapeutics in psoriasis. Plaque psoriasis’, the most prevalent subtype of psoriasis, pathogenesis primarily involves cytokines TNF-α, IL-17, and IL-23. Pustular psoriasis’, an uncommon variant, pathogenesis involves a mutation in IL-36RN. Currently, biological therapeutics targeted at TNF-α, IL-12/IL-23, IL-17, and IL-23/IL-39 are approved for the treatment of moderate to severe psoriasis. More studies need to be performed to elucidate the precise molecular pathology and assess efficacy between biological therapies for psoriasis. Psoriasis is a heterogenous, chronic, systemic inflammatory disease that presents in the skin with multiple types. Recognizing and understanding the underlying molecular pathways and biological therapeutics to treat psoriasis is important in treating this common disease.

Anti-SARS-CoV-2 immunogenicity decay and incident cases six months after Sinovac-CoronaVac inactivated vaccine in autoimmune rheumatic diseases patients: phase 4 prospective trial

We provide novel data on anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the 2nd dose of Sinovac-CoronaVac inactivated vaccine(D210) in 828 autoimmune rheumatic diseases(ARD) patients compared with 223 age/sex-balanced control group(CG). From D69 to D210, anti-S1/S2IgG positivity and GMT reduced 23.8% and 38% in ARD(p<0.001/p<0.001) and 20% and 51% in CG(p<0.001/p<0.001). From D69 to D210 NAb positivity and activity declined 41% and 54% in ARD(p<0.001/p<0.001) and 39.7% and 47% in CG(p<0.001/p<0.001). Multivariate logistic regression analysis showed that male(OR=0.56;95%CI0.40-0.79;p<0.001), prednisone(OR=0.56; 95%CI0.41-0.76;p<0.001), anti-TNF(OR=0.66;95%CI0.45-0.96;p=0.031), abatacept(OR=0.29; 95%CI0.15-0.56;p<0.001) and rituximab(OR=0.32;95%CI0.11-0.90;p=0.031) use were associated with a substantial reduction on IgG response at D210 in ARD patients. A decrease of COVID-19 cases(from 27.5 to 8.1/100 person-years;p<0.001) occurred during the study despite the Delta variant spread. In conclusion, after 6-months of Sinovac-CoronaVac 2nd dose, immunogenicity of ARD patients was markedly reduced, particularly in males and those under prednisone/biological therapies, without a concomitant rise in COVID-19 cases(NCT04754698).