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Journal: Expert review of clinical immunology

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Juvenile dermatomyositis (JDM) is a rare, chronic autoimmune illness with primary features of symmetric, proximal muscle weakness and involvement of the skin with a number of identifiable rashes. Evidence to support treatment decisions is limited, given the paucity of clinical trials. Consensus based methods, informed by available data, play an important role in treatment recommendations. Areas covered: This review focuses on evidence and consensus opinion regarding therapeutic options in JDM and identifies gaps where future research is needed. Expert commentary: The combination of trial evidence (as limited as it is) and consensus opinion support standard initial management for children with JDM to consist of high dose corticosteroids, either intravenous or oral, and methotrexate. Several other agents have preliminary support, either through clinical trials or case series for their use in patients who either fail to respond adequately, have severe disease or have contraindications to standard initial therapy. One of the important goals of management in JDM will be to reduce the corticosteroid exposure experienced by patients. To meet this goal, progress in a number of key areas is needed: increased international collaboration, advances in study design and increased translational research.

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Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder typically characterised by fever, arthritis and hyperferritinemia. Concerning AOSD pathogenesis, it is categorised as a multigenic autoinflammatory disease, at the “crossroads” of autoinflammatory and autoimmune diseases, because of the involvement of both arms of immune system. Areas covered: This work is conceived as narrative overview assessing the pathogenesis of AOSD. We performed a narrative synthesis of published information, summarising the contents of previous studies and providing a possible rationale for future researches. MedLine database was searched for identification of suitable studies. In reporting the available evidence, we described the results according to distinct pathogenic steps associated with different clinical features of the disease. Expert commentary: AOSD is a systemic severe inflammatory disorder of unknown aetiology affecting young adults. Although pathogenesis of the disease is not fully clarified, the role of the pro-inflammatory cytokines is well-recognised and biologic drugs, blocking these molecules, are routinely used in clinical practice. Finally, given that multiple recent lines of evidence have suggested new insights in AOSD pathogenesis, new therapeutic targets have been highlighted and the results of studies with new drugs could further improve the management of these patients.

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Poor adherence in children with asthma is a major cause of asthma attacks and poor control, leads to large healthcare costs and has been identified as a factor in asthma deaths. However, it is difficult to detect and frequently overlooked leading to inappropriate escalation of asthma treatment. There is a need for cost effective ways to monitor adherence in order to intervene to change this modifiable behaviour. Areas Covered: Several measurement tools have been developed to assess adherence in adults and children with asthma. The current methods for measuring adherence, both subjective and objective, have several flaws and even the current gold standard, electronic monitoring devices (EMDs), has limitations. This review will outline and critique the adherence monitoring tools and highlight ways in which they have been used for the purpose of intervention. Expert Commentary: Although advances have been made in adherence monitoring we still have some way to go in creating the ideal monitoring tool. There are no validated tailored self-monitoring questionnaires for children with asthma and most objective measures, such as prescription refill rate and weighing canisters, over-estimate adherence. Current electronic monitoring devices, although useful, need improved accuracy to ensure that both actuation and inhalation are measured, and the devices need to be affordable for use in routine health care practice.

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A new generations of small molecules are being developed for the treatment of ulcerative colitis. Among them, tofatinib (a Janus kinase (JAK) inhibitor) has demonstrated efficacy for inducing and maintaining remission and achieving mucosal healing with a reasonable safety profile. Oral administration is attractive for patients and lack of immunogenicity represents an advantage over biologic drugs. Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway; the mechanism of action of tofacinitib pertinent to ulcerative colitis and the evidence on the efficacy of tofacitinib for achieving clinically relevant outcomes, including clinical remission, mucosal healing, and normalization of quality of life, as well as safety aspects with special attention to adverse events related to the mode of action of the drug. Expert commentary: Tofacitinib will be the first drug on the class of JAK inhibitors to be available for treatment of ulcerative colitis. The efficacy of the drug, with a rapid onset of action even in cases of severe colitis, oral administration, and possibility to use the drug intermittently without generating immunogenicity, will bring about a redesign of current treatment paradigms for ulcerative colitis.

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The transcription factors signal transducer and activator of transcription (STAT) 1 and STAT3 fulfill fundamental functions in non-immune and immune cells. The description and follow-up of patients with germline mutations that result in either loss-of-function (LOF) or gain-of-function (GOF) have contributed to our understanding of the pathophysiology of these regulators. Depending on the type of mutations, clinical symptoms are complex and can include infection susceptibility, immune dysregulation as well as characteristic non-immune features. Areas covered: In this review we provide an overview about mechanistic concepts, clinical manifestations, diagnostic process and traditional as well as innovative treatment options aiming to help the clinical immunologist to better understand and manage these complex and rare diseases. Clinical and research papers were identified and summarized through PubMed internet searches, and expert opinions are provided. Expert Commentary: The last several years have seen an explosion in the clinical descriptions and pathogenesis knowledge of the diseases caused by GOF and LOF mutations in STAT1 and STAT3. However, harmonization of laboratory testing and follow-up in international cohorts is needed to increase our knowledge about the natural history of these disorders as well as the development of curative or supportive targeted therapies.

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Juvenile idiopathic arthritis (JIA) comprises systemic and non-systemic forms of chronic childhood arthritis diagnosed prior to age 16. Significant improvement in treatment outcomes has been witnessed since the introduction of biologics. Advances in research, in particular, in the area of multi-dimensional interrogation and network analysis, have facilitated understanding of the complex cacophony of components orchestrating disease immuno-pathogenesis. Areas covered: In this review, we will examine the scientific advances that have augmented our understanding of JIA pathogenesis, focusing on the progress made in systemic, poly and oligo JIA in four major aspects: (a) unraveling the pathogenic mechanisms, (b) disease classification, © therapeutic selection and (d) decision for withdrawal of medications after achieving remission. Expert commentary: Dysregulation of innate immune cell physiology and function in sJIA will be highlighted. MicroRNAs contribute to monocyte/macrophage polarization with resulting consequences on MAS development. The involvement of neutrophils, a major source of S100A8/9/12, in the active inflammatory phase of sJIA is compelling. In non-sJIA, circulating CD4 subsets in T effector and regulatory compartments possessing a strong synovial T cell receptor coverage and disease activity correlation, acted as an accessible reservoir of pathogenic cells exploitable for clinical management.

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Patients with systemic lupus erythematosus (SLE) have a better survival than decades ago; nevertheless, they still experience a low health-related (HR) quality of life (QoL). Areas covered: After defining QoL and HRQoL we review the need to assess it, its elements, how to measure it, its predictors and its impact and potential interventions to improve it. Expert commentary: Physicians assessments of disease activity and damage do not capture the patients' perspective of their health, and these differences could lead to nonadherence to therapy. Based on that, a comprehensive evaluation of SLE should include the assessment of HRQoL or the sum of the physical, psychological and social perception of wellbeing, influenced by the patient’s illness. The most consistent predictors of low HRQoL are older age, poverty, lower educational level, behavioral issues, some clinical manifestations and comorbidities. HRQoL impacts negatively on dealing with stress, intimal relationship, home and job-related activities and treatment adherence. At the present, there are no successful specific therapeutic strategies aimed at improving it.

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Allergic rhinitis (AR) is a disorder with high prevalence worldwide. Identification of clinically relevant allergens is the key step for the diagnosis, allergen avoidance and allergen specific immunotherapy for AR. Areas covered: With the new findings of mechanisms of AR and the development of technology, much progress has been achieved in the diagnosis of AR recently. We review the recent advances about local IgE, in vivo and in vitro tests, cytological diagnosis and nitric oxide (NO) in the diagnosis of AR. Expert commentary: AR is traditionally diagnosed with the combined evaluation of history and allergen sensitization by in vivo skin prick tests and in vitro allergen specific IgE in serum, to confirm the correlation between clinical history and potential allergens. Nasal provocation test and local IgE measurement can be used to diagnose local AR (LAR). Allergen microarray has the ability to detect more potential allergens. Basophil activation and mast cell activation tests can be used in allergen diagnosis and to modify the response to immunotherapy, while cytological diagnosis is useful in the differential diagnosis of AR and non-AR. Nasal NO has been confirmed to be an optimal biomarker to discriminate between AR and non-AR.

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Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the presence of psoriasis, arthritis and enthesitis, with the association of other musculoskeletal and extra-articular manifestations. Current treatment of PsA is mainly based on the use of conventional, biological and targeted synthetic DMARDs; however, patients may not respond or have a loss of response to these agents. Recently, a deeper understanding of the pathogenetic mechanisms has made possible the development of new drugs that actively interact with the activation of immune system, inhibiting the co-stimulation between antigen presenting cells and lymphocytes. Areas Covered: The aim of this paper is to review the role of the activation of the immune system in the pathogenesis and treatment of PsA, with a discussion on the emerging CTLA4Ig drugs (abatacept) for PsA. A search in PubMed and EMBASE was performed with the keywords: “abatacept”, “CTLA4” and “Psoriatic Arthritis”. We considered preclinical studies, phase I, II and III clinical trials. Expert Commentary: The inhibitors of co-stimulation may represent an effective treatment strategy by acting on the very early phase of the immunological process that brought about the development of inflammation and activation of the immune system, mainly for patients with peripheral joint involvement and mild psoriasis.

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Functional dyspepsia (FD) is widespread with 20% prevalence worldwide and a significant economic burden due to health care cost and constraints on daily activities of patients. Despite extensive investigation, the underlying causes of dyspepsia in a majority of patients remain unknown. Common complaints include abdominal discomfort, pain, burning, nausea, early satiety, and bloating. Motor dysfunction of the gut was long considered a major cause, but recent investigations suggest immune-based pathophysiological and molecular events in the duodenum are more probable contributing factors. Areas Covered: Inflammatory mediators and immune cells including duodenal eosinophils, intraepithelial lymphocytes, and T-cells have been implicated in the underlying cause of disease process, as have genetic factors. In this article, we critically reviewed findings, identified gaps in knowledge and suggested future directions for further investigation to identify targets and develop better therapeutic approaches. Expert Commentary: Impaired gastric accommodation, slow gastric emptying, and increased visceral sensitivity have long been thought of as main causal factors of FD. However, more recent identification of eosinophilic degranulation and recruitment of T cells that induce mild duodenal inflammation are giving rise to new insights into immune-mediated pathophysiology. These insights offer promising avenues to explore for immune-mediated therapy in the future.