Severe Refractory Disease Research Articles

A Position Statement on Diabetes with β-Cell Failure

Diabetes mellitus is a heterogeneous disease that encompasses a wide range of conditions, from mild cases to severe conditions where survival depends on insulin therapy. The Korean Diabetes Association Task Force Team for Diabetes with β-Cell Failure has established the term to classify severe refractory disease with β-cell failure. Individuals with β-cell failure are at high risk of diabetes-related complications. We propose that diabetes with β-cell failure can be diagnosed when individuals treated with multiple daily insulin injections or insulin pumps meet at least one of the following criteria: fasting C-peptide ≤ 0.6 ng/mL, non-fasting C-peptide ≤ 1.8 ng/mL, 24-hour urine C-peptide < 30 μg/day, or spot urine C-peptide/creatinine ratio ≤ 0.6 nmol/mmol. Among cases of diabetes with β-cell failure, β-cell failure with absolute insulin deficiency can be diagnosed when at least one of the following criteria is met: fasting C-peptide < 0.24 ng/mL, non-fasting C-peptide < 0.6 ng/mL, or spot urine C-peptide/ creatinine ratio < 0.2 nmol/mmol. Multiple daily insulin injections with long-acting insulin analogs and rapid-acting insulin analogs or insulin pumps are required for treatment of diabetes with β-cell failure. Continuous glucose monitoring and an automated insulin delivery system, sensor-augmented pump, or smart insulin pen, along with structured education, are necessary. We call for improvements in the relevant systems to ensure that such treatments can be provided.

A Review of JAK Inhibitors for Treatment of Alopecia Areata in the Military Health Care System.

Alopecia areata (AA) is a disease that manifests as patchy hair loss on the scalp and other parts of the body; severe disease may result in disfigurement, functional impairment, and significant psychological distress. This condition is understood to be caused by autoimmunity to the hair follicle and subsequent arrest of hair growth. New medications, baricitinib and ritlecitinib, belong to the Janus kinase (JAK) inhibitor family and are among the first FDA-approved treatments for severe AA. In this manuscript, we aim to answer the question: What treatment options exist for AA in the military health care system (MHS)? In doing so, we review the pathogenesis, physical and psychosocial impact of AA, conventional treatment of AA, and the efficacy and safety of baricitinib and ritlecitinib. A literature search was performed using PubMed, Embase, and Ovid for the history and pathogenesis of AA, psychosocial impact of disease, functional impairments, and current treatments. Keywords "alopecia areata," "current therapy for alopecia areata," "pathogenesis alopecia areata," "baricitinib," "ritlecitinib," "JAK inhibitor alopecia," "JAK inhibitor safety," "baricitinib efficacy," "alopecia eyelash," "alopecia nails," and "psychosocial impact of alopecia" were used for the search. The TRICARE manual was searched for guidelines applicable to the treatment of AA, DoD Instruction 6130.03 Volume 2 for medical standards for military service, and the U.S. Central Command Modification 15 for fitness of deployment to Central Command area of operations. Traditional treatments such as intralesional steroids may be effective for some patients, but difficulty lies in controlling extensive or refractory disease. Janus kinase inhibitors, baricitinib and ritlecitinib, are found effective at improving severe refractory disease; baricitinib induced hair regrowth in 32.6% more patients than placebo, and ritlecitinib was found to be superior to placebo by at least 24%. Currently, there is no coverage for therapeutic treatment of hair growth in the MHS. Additionally, military members are disqualified for continued service if they require immunomodulator medications such as baricitinib and ritlecitinib. Those on immunomodulators are unable to deploy worldwide. Baricitinib and ritlecitinib are effective treatments for widespread, progressive, and refractory AA. Although JAK inhibitors demonstrate improved effectiveness compared to non-immunomodulator treatments, their use in the MHS for this purpose is limited.

Indications, response, and side effects of biologic treatment in Behçet's disease: an 8-year study with follow-up.

The treatment of Behçet's disease has improved significantly with the introduction of biologic therapies. However, there is still a need for more information about their use. This study aimed to evaluate the indications, response, and side effects of biologic agents in patients with refractory or severe Behçet's disease in the south of Iran, their follow-up and reasons for changing the biologics. A retrospective analysis was conducted on 44 patients aged 16-65 years who were prescribed biologic agents for at least 6 months. The clinical history, partial and complete remission at 6 and 12 months, occurrence of side effects, and need for switching to a second or third biologic agent were recorded. The most common indications for starting biologic agents were ophthalmic (68.2%), parenchymal brain involvement (15.9%), and arthritis (11.4%). Improvement was observed in various manifestations of Behçet's disease, with complete remission in 86, 51.6, 92.8, 66.7, 42.9, 33.3, and 80.0% of oral aphthous lesions, ophthalmic activity, genital aphthous lesions, skin activity, arthritis, brain parenchymal lesions, and vascular activity, respectively, 6 months after starting biologic agents. These rates were unchanged or increased at the 12-month follow-up. In 25.0% of patients, a switch to a second biologic agent was necessary due to severe disease, side effects, or refractory disease. Side effects occurred in 16.3% and 33.3% of patients on the first and second biologic agents, respectively. The majority of side effects were not serious. We found a promising improvement at 6-month and 12-month follow-ups with various biologic agents in treating Behçet's disease with an acceptable safety profile.

Skin manifestations help identifying different phenotypes of paediatric SAPHO syndrome

Objectivesto evaluate whether the heterogeneous skin manifestations might influence the disease presentation and outcome of a cohort of SAPHO children. Methodsthe clinical, serological, imaging and therapeutic data of 14 SAPHO patients, followed between 2001 and 2022 at the Unit for Autoinflammatory diseases at the Gaslini Hospital, were reviewed. According to their cutaneous manifestations, patients were divided into 2 groups: the acne-hidradenitis suppurativa (HS) and the Palmo-Plantar Pustulosis (PPP) group. Data were retrieved from the Eurofever database. Resultsall patients presented bone involvement characterized by Chronic Recurrent multifocal Osteomyelitis (CRMO): 8 patients presented acne-HS while 6 patients had PPP. In the PPP group, all patients were female, characterized by a prepuberal disease onset with osteoarticular manifestations, followed by the appearance of PPP in the following 6 months. This group responded well to the treatments. In the acne-HS group, 7/8 patients were male: the disease onset was characterized by skin manifestations in pubertal age, followed by osteoarticular manifestations in the following year. This group presented a severe refractory skin disease that required in most cases the addition of biological therapies. A literature review confirmed our data highlighting the association males-acne-puberal age and female-PPP-prepuberal age. Conclusionpaediatric SAPHO patients should be mainly stratified according to their skin involvement. In fact, our data suggest that two different skin phenotypes may be identified in SAPHO: the first is constituted by prepuberal females with PPP and a prevalent osteoarticular involvement, while the second by puberal males with a difficult-to-treat acne-HS.

Neurosurgical Interventions for Umpteen Psychological Afflictions: a Substantial Cross-Disciplinary Clinical Abridged Frame of Reference

Purpose: Clinical society faces tremendous difficulties while treating people with mental illnesses, and the best possible care can only be provided by using an integrative approach to assessment and therapy. Particularly, the field of "psychosurgery," or the neurosurgical management of mental diseases, has piqued interest as a possible means of changing behavior and awareness throughout human history. In cases of severe refractory mental disease, psychological surgery - including "deep brain stimulation" and "stereotactic ablation" - is a key therapy option. Recent developments in neuroimaging, as well as psychosurgery, have increased the focus on these therapy techniques. In this paper, the benefits and drawbacks associated with psychological surgery will be thoroughly examined. Objective: The main objective of the paper is to aid individuals in understanding the basics of psychosurgery and its applications. Additionally, it focuses on how to remove the stigma associated with psychosurgery by providing reliable scientific data. Basic information and an overview were supplied thoroughly and simply to fulfill the aforementioned claim. In order to address the "psychosurgery versus psychopharmacology" debate, this paper focuses on analyzing information from many sources and outlining the core principles of each of these treatment modalities. Design/Methodology/Approach: Psychological surgery, which includes "deep brain stimulation as well as "stereotactic ablation," is a crucial treatment strategy in situations of severe refractory mental illness. The fact that several large studies have shown a median rate of response of approximately fifty percent highlights the importance of choosing and selecting participants beforehand. This concept has received attention as a result of recent developments in neurological imaging. Markers of reaction in scientific journals on neuroimaging in psychological operations have also been carefully investigated in order to evaluate the current state of knowledge for imaging prior to surgery. Scientific information was acquired for this research from a variety of trustworthy and legitimate sources. Information has also been extracted from a variety of journal papers. Findings/Result: Even today, managing patients with mental diseases can be challenging, especially when it is felt that they lack the capacity to make intelligent decisions. Due to all of these factors, the practice of psycho-surgery should adopt an integrated method for assessment and therapy. The way psychological therapies are provided in the future will undoubtedly be impacted by concurrent breakthroughs in the fields of behavioral neuroscience, brain imaging, psychological medications, and neurosurgical procedures. According to studies, ablative neurosurgery and “deep brain stimulation” are successful experimental therapies for people with chronic, acute, and “treatment-resistant obsessive-compulsive disorder”, “major depressive disorder”, and “Tourette syndrome”. The careful identification of competent applicants has been guided by suggested criteria. After presenting the details and the expected outcome of the procedure, it is imperative to obtain the person's consent. Originality and Value: In order for readers from all academic disciplines to understand the basic concepts behind psychosurgery and how it can be used to treat a variety of psychological issues, all of the clinical material has been extracted from reliable, scientific publications and organized effectively in this paper without the use of many medical expressions. The scientific complexity of any theoretical or clinical information was avoided, and the material was organized so as to preserve consistency and systematization. Paper Type: Clinical/Healthcare management

Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes

AbstractIdiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert–confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6–directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6–directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.

Association of Sex Hormones and Androgens with Disease Activity in Premenopausal Females with Rheumatoid Arthritis.

Gonadal sex hormone dysfunction is frequently reported in patients with Rheumatoid arthritis (RA). The relationship of these hormones with disease activity is still not clear and whether the hormone imbalance leads to increased severity of RA is not well studied in this part of the world. The present study aimed to elucidate this fact. It was a cross-sectional observational study performed in 80 premenopausal females with definite RA at a tertiary care hospital in New Delhi, India over one year. Patients were subjected to investigations as per the protocol and a fasting venous blood sample for hormone levels was collected in the follicular phase of their menstrual cycle. A statistically significant correlation by linear logistic regression analysis was found between disease activity (as measured by DAS28) and serum progesterone, FSH, and prolactin, while serum testosterone and DHEAS showed an inverse relationship with disease activity. Low s. prolactin, and s. FSH as well as high s. testosterone and s. DHEAS were found to be associated with target clinical goals in RA (ie, remission and low disease activity). On multivariate logistic regression analysis, serum prolactin showed a direct association. (p=0.016, OR= 1.009. C.I.= 1.0021.017) and serum testosterone were found to have an inverse relationship (p=0.002, OR= 0.017, C.I.=0.001-0.237) with disease activity in this group of individuals. Serum levels of sex hormones may be helpful in predicting disease activity among patients with RA, and in future, may be used to guide treatment of severe refractory disease, unresponsive to conventional treatment with DMARDs, especially in resource-poor settings.

P635 Risankizumab - real world Israeli data in severe refractory IBD patients

Abstract Background The landscape of inflammatory bowel disease (IBD) treatment is rapidly expanding with the development of new therapeutic options. Risankizumab (Skyrizi®), a humanised IgG monoclonal antibody that targets the p19 subunit of IL-23, was developed for the treatment of immunological and inflammatory disorders, and recently began to be investigated also in the field of IBD. Most patients who receive Risankizumab do so as part of clinical trials, but there are a number of patients with severe refractory disease who have received it as a compassion treatment and they present preliminary Real-World data for this drug. Aim to present the real-world data of patients with severe refractory IBD who received Risankizumab as a compassion treatment. Methods Retrospective Israeli multicenter study from 6 tertiary IBD centers (Shaare Zedek medical center, Wolfson, Ichilov, Hadassah , Sheba and Barzilai ) on 21 patients with severe refractory IBD (18 CD, 3 UC) who received Risankizumab (IV 600 mg at 0, 4, 8 weeks; then SC 180 or 360 mg SC every 8 weeks) as compassionate treatment with a median follow up of 30 weeks (4-52 weeks). Results Although some of the clinical and laboratory parameters are still being collected, we can present some trends. 21 patients were included in the analysis. 17 /21 were after ustekinumab failure. At week 12, there was a significant reduction in Harvey-Bradshaw index (HBI) for Crohn's disease, in CRP values and Calprotectin as compared with the baseline data (10.13 to 4.82, p=0.03; 4.16 to 1.62, p=0.004; 3758 to 961, p=0.02, Respectively). In addition, there was a reduction in the percentage of steroids dependent patients (0.44 to 0.14, p=0.07). In the margins of the study, it is worth noting that particularly patients with difficult and resistant disease, who were TPN dependent or on the verge of surgery, as a result of treatment were weaned from TPN or were able to avoid surgery. Conclusion According to real-world data, Risankizumab holds a great therapeutic promise even for patients with particularly serious and resistant diseases.

Perioperative Management of Pediatric Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory condition that may affect any part of the gastrointestinal tract. It is transmural in nature and complications such as fistula, strictures and peri-anal disease may occur. There is more extensive anatomic involvement (50% ileocolonic, 20% colonic, 30% with upper GI symptoms) and a higher surgical risk in pediatrics than adults (50% vs 14% by age 30). Studies have shown 3.4%-7.9% of patients require surgery in first year after diagnosis, 13.8-47.2% by 5 years and 28%-35% by 10 years (1). There are three major surgical categories: ileocecal resection, treatment of complication, (fistula/stricture-figure 1,2) or salvage procedure for severe refractory disease. In addition, surgery may be considered with active short segment disease or children illustrating poor growth despite optimized medical therapy (ESPGHAN). Unfortunately, much data on pediatrics is derived from single centers rather than population-based cohorts and the most recent societal reports were based on studies with minimal biologic use (18-24%) (1). Despite larger use of biologics, resection is still needed in 20%- 34%, thus effective peri-operative management of pediatric CD is imperative (1).

Severe refractory active thyroid eye disease: an unmet clinical need in Europe

Severe refractory active thyroid eye disease: an unmet clinical need in Europe

Tofacitinib Appears Well Tolerated and Effective for the Treatment of Patients with Refractory Crohn's Disease.

Active Crohn's disease increases the risk of strictures, fistulas, and abscesses. Less than 30% of patients with Crohn's disease achieve endoscopic remission on any therapy. Tofacitinib may be a therapeutic option for patients with refractory Crohn's disease. We aimed to evaluate the safety and effectiveness of off-label tofacitinib for refractory Crohn's disease. We retrospectively assessed adverse events and clinical/endoscopic response after therapy. Forty-four patients were included in the safety analysis and 35 were included in the clinical and/or endoscopic assessments. The mean age was 41.8years and the mean disease duration was 17.4years. All patients had prior biologic exposure. Adverse events were reported in 52.3% of patients; 13.6% had ≥ 1 serious adverse event after a median 54.6weeks of treatment. Seventy percent achieved clinical response after a mean 29.4 (SD 15.1) weeks, and 33.3% achieved clinical remission after a mean 33.4 (SD 17.6) weeks of therapy. Endoscopic improvement occurred in 25.0%, endoscopic remission in 12.5%, and endoscopic healing in 4.2% of patients after a mean 52.0 (SD 15.0) weeks of therapy. The mean Simple Endoscopic Score in Crohn's disease significantly improved from 23.1 ± 3.7 to 18.0 ± 13.7 after treatment (P = .02). In the short term, tofacitinib appears well tolerated. The most common adverse event was minor infection. One serious infection and one colorectal cancer occurred. While half of patients reported adverse events, this likely reflects the severe refractory disease in this population and no new safety events were observed. Tofacitinib achieved clinical and endoscopic improvement in some patients with refractory Crohn's disease. Further research is needed to understand the long-term safety and efficacy of tofacitinib in Crohn's disease.

Erythrodermic psoriasis revealed an HIV infection

Patients with psoriasis and HIV infection often present with more severe and treatment refractory cutaneous disease. We report two clinical cases in which psoriatic erythroderma revealed HIV infection, and who have responded well to antiretroviral therapy Keywords: psoriasis; HIV infection; severe form; antiretroviral therapy.

P593 Biologicals and small molecule combotherapies: promising experience in refractory IBD patients

Abstract Background It has been hypothesized that combination of two biologics or with a small molecule could ”break the ceiling” of the efficacy (~60%) of currently available biological therapies for IBD patients. The best combinations and their safety are, however, unknown. Methods A chart review of Inselspital, Bern University hospital und Crohn and colitis center Beaulieu Lausanne, of IBD patients on combination therapy have been performed. Data on disease phenotype, previous treatment and efficacy and safety of the new combinations have been collected and studied to help moving forward the use of this armentarium. Results Among 18 identified IBD patients (39% women, 10 ulcerative colitis, 8 Crohn’s disease) with extended and refractiry luminal disease (indication) who received 21 combination therapies between June 2017 and November 2021. They suffered from steroid-dependency and half of them were refractory to at least two anti-TNF alpha agents. These treatments have been started after a median duration of disease of 6 years (range 1–25) for a mean period of combo treatment of 11 months (range 1–52), 8 were still ongoing. Various combotherapies and clinical response (arrows; red=bad, green=good response) are presented in Figure 1. A partial or complete response was observed in 15/21 therapies (71%) with a mean decrease of CRP of 11 mg/l (range+23 to -59) and calprotectin of 399 mcg/g (range 0 – 1745) among the reponders. Concerning safety, 2 infections (otitis media, skin mycosis), 1 non hodgkin Lymphoma and 4 minor adverse events (tumefaction left parotide, eczema, 2x lymphopenia) have been reported, mostly when small molecules have been involved. Conclusion Ustekinumab combined with anti-TNF agents in Crohn’s disease is more effective than vedolizumab and tofactinib in ulcerative colitis. Combining with small molecules increases the risk of lymphopenia, of cancer (1 case of non hodgkin lymphoma) and minor infections in severe refractory and steroid-dependent inflammatory bowel disease patients.

Severe Neutrophilic Asthma: Pathogenesis and Treatment

Asthma is a common chronic airway disease affecting about 358 million people worldwide, and an estimated 7 million children globally. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids and other modifiers. Among these, are patients with severe neutrophilic asthma. Neutrophilic asthma is a severe phenotype of asthma, characterized by frequent exacerbations, persistent airway obstruction, and poor lung function. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the airways and lungs. Interleukin-17 produced by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines and chemokines for the recruitment, and activation of neutrophils. Interleukin-8 is a powerful chemoattractant and activator of neutrophils. Activated neutrophils produce an oxidative burst, releasing multiple reactive oxygen species, proteinases, cytokines, which cause airway epithelial cell injury, inflammation, airway hyperresponsiveness, and remodeling. Furthermore, exasperated neutrophils due to viral, bacterial or fungal infections, and chemical irritants can release extracellular nucleic acids (DNA), designated as NETs (neutrophil extracellular traps), which are more toxic to the airway epithelial cells, and orchestrate airway inflammation, and release alarmin cytokines. Dysregulated NETs formation is associated with severe asthma. Most patients with neutrophilic asthma are unresponsive to the standard of care, including high dose inhaled corticosteroids, and to targeted biologics, such as mepolizumab, and dupilumab, which are very effective in treating eosinophilic asthma. There is unmet need to explore for novel biologics for the treatment of neutrophilic asthma, and in refining therapies, such as bronchial thermoplasty.

P025 The Impact of Non-Remission on Costs and Resource Use In Patients With Crohn's Disease: Targeted Literature Review.

The incidence of Crohn's disease (CD) has been rising globally. Patients with CD are at an increased risk of mortality compared to general population. The goal of treatment for CD is clinical remission based on clinical, endoscopic, and biological parameters. There has been introduction of new treatments in recent years. A review was conducted to assess the impact of non-remission on cost and resource use in patients with CD. Literature search of English language publications from 2015-2021 was conducted in Embase® and MEDLINE®. Real world studies meeting predefined review criteria were included and data were extracted in pre-defined extraction form. The review retrieved 1384 records; 24 fulfilled eligibility criteria. The definition of remission varied across the included studies. In most studies (66.67%), remission was defined using Crohn's disease activity index and/or Harvey-Bradshaw Index. Among included evidence, 21 studies reported proportion of non-remitters undergoing surgery, 11 studies reported the data for hospitalizations and 2 studies reported cost of treatment for non-remitters. Proportion of non-remitters requiring hospitalizations ranged from 6.7% to 30.6%. Univariate analysis suggested that deep remission was significantly associated with lower hazards for being hospitalized (HR: 0.18 [95%CI: 0.08, 0.25]); suggesting a significantly higher risk of hospitalization in non-remitters. In a study, the mean duration of cumulative hospital stays was significantly higher in patients with a pathological MRI (19.7 ± 7.4 days) compared to patients in deep remission (0.75 ± 0.52 days, p < 0.05). The proportion of non-remitters undergoing surgery ranged from 1.5% to 57%. The proportion of patients undergoing surgery were high in non-remitters compared to remitters. Hematopoietic stem cell transplantation was needed in 4.1% non-remitters and repeat surgery in 3.5% non-remitters. In a study, surgery was required by 11.6% patients with no healing (due to refractory strictures, penetrating complications, and severe refractory disease) and 11.5% patients presenting with mucosal healing (due to structuring and penetrating complications), while no patient with transmural healing required surgery. Non-remission led to higher total costs, especially in patients undergoing surgery or dependent on in-hospital administrated drugs. The costs were 4 to 6 times higher in patients in an active period and 19 times higher for patients requiring surgery compared to patients in remission. Adjusted total indirect cost among participants with disease remission was reduced by 60% compared to patients with active disease (€243.44 per patient per month, p < 0.001). The number of consultations in the last month, monthly consultation cost, current treatment cost, amount of benefits from public organisations, and self-reported expenses on all categories were significantly higher in non-remitters compared to patients in remission. This targeted review found in general that not being able to achieve/maintain remission has an impact on the economic outcomes of patients with CD. Non-remission in patients with CD was associated with an increased number of hospitalizations and surgeries. The cost of treatment for non-remitters was significantly higher than patients in remission. None of the studies presented data for patients who respond to treatment but are not able to achieve remission. Further research is warranted in these patients.

Severe refractory Hailey-Hailey disease Treated with electron beam radiotherapy and low-level laser therapy.

Severe refractory Hailey-Hailey disease Treated with electron beam radiotherapy and low-level laser therapy.

Bronchial Thermoplasty in the Treatment of Severe Asthma

Asthma is a chronic inflammatory airway disease with several distinct phenotypes, characterized by different immunopathological pathways, clinical presentation, severity of the disease, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed granulocytic, and paucigranulocytic asthma. Approximately 3.6-10% of patients with asthma have severe refractory disease, which is unresponsive to high dose inhaled corticosteroids (ICS), and long-acting β2-agonists (LABA). Most patients with eosinophilic asthma are responsive to corticosteroids, and interleukintargeted biologics, whereas, patients from other phenotypes, such as neutrophillic and paucigranullocytic asthma are resistant to treatment with ICS and biotherapeutics. The hallmark of severe refractory asthma is airway hyperresponsiveness, and remodeling. Histopathologically, patients with severe asthma have airway smooth muscle (ASM) hyperplasia and hypertrophy; subepithelial basement membrane thickening and fibrosis; all which contribute to fixed airflow limitation. Severe refractory asthma is very difficult to treat pharmacologically. It requires innovative therapies, such as bronchial thermoplasty which reduces the hypertrophied ASM mass and relieves the AHR, and broncoconstriction. Bronchial thermoplasty has been shown to improve asthma control, reduce severe exacerbations, hospitalizations, emergency room visits, and improve the quality of life, which persist up to 5 years following the procedure

Severe refractory Kawasaki disease in seven infants in the COVID-19 era.

A cohort of seven infants (aged ≤1 year) with severe Kawasaki-like disease were diagnosed and treated at five hospitals in the UK between February and March, 2020 (appendix p 1). All of the infants received prompt intravenous immunoglobulins and steroid treatment, but none responded and all required the addition of a biological agent because of continued inflammation, recurring fever, and progressive changes on echocardiography. Six patients (86%) developed coronary artery aneurisms (Z score >2·5) and one infant died as a result of a ruptured aneurysm, despite early aggressive treatment.

Role of IL-17 and IL-23 in the Pathogenesis of Neutrophilic Asthma

Asthma is a complex chronic airway disease with several distinct phenotypes characterized by different immunopathological pathways, clinical presentation, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids and other modifiers. About 50% of these individuals suffer from neutrophilic asthma.

Efficacy and Safety of Dor Fundoplication in Patients with Severe Gastroparesis and Refractory Gastroesophageal Reflux Disease

Poor quality of life is a major problem in patients with gastroesophageal reflux disease (GERD). Delayed gastric emptying in patients with severe gastroparesis (GP) worsens GERD symptoms and particularly nocturnal heartburn and regurgitation refractory to medical therapy. With limited therapeutic options, a Nissen fundoplication may be considered but concerns for this surgery are inability to wretch and vomit post-op, increasing the risk of wrap rupture. Dor fundoplication, a 180–200 degree anterior wrap, may improve sphincter competency and provide symptom relieve while minimizing these concerns and avoiding vagal nerve damage.