The conundrum of iron in multiple sclerosis – time for an individualised approach

Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome--some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.     

Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferonβ la

To alert clinicians to a potential novel adverse drug effect of interferonβ la, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferonβ la. Ulcerative colitis persisted despite discontinuation of interferonβ la treatment and switching the patient to glatiramer acetate. Tacrolimus （FK506）, 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease （IBD） and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.     

The role of children in their HIV-positive parents’ management of antiretroviral therapy in Uganda

Adjustment to life on antiretroviral therapy (ART) and living with HIV as a long-term chronic condition, pose significant medical, social and economic challenges. We investigated children’s role in supporting HIV-positive parents to self-manage life on ART. Between 2010 and 2012, we conducted a qualitative study using semi-structured interviews with 38 HIV-positive parents who had been on ART for over a year. They were randomly selected from people accessing ART from three delivery sites in Wakiso district, Uganda. Data were analysed thematically. Participants reported children between the ages of 1 and 47 years providing support. Children were a source of happiness, self-worth, encouragement, and comfort. Both younger and older children supported parents’ adherence to treatment through reminding them to take the drugs and honour clinic appointments. Older children provided money to buy medication, food and shelter. Parents reported that the encouragement they received after they disclosed to their children enhanced their survival. After HIV disclosure to their children many of their fears about the future were allayed. Thinking about their children’s future brought hope. However, looking after younger children while on ART could be burdensome since some parents could not work to their full capacity due to reduced physical health. Children are an important resource in their parents’ adjustment to living with HIV while taking ART. There is a need for children to be supported by appropriate policy and other social and health development structures.     

The role of Akt/GSK-3β signaling in familial hypertrophic cardiomyopathy

Mutations in cardiac troponin T (TnT) are a cause of familial hypertrophic cardiomyopathy (FHC). Transgenic mice expressing a missense mutation (R92Q) or a splice site donor mutation (Trunc) in the cardiac TnT gene have mutation-specific phenotypes but mice of both models have smaller hearts compared to wild type and exhibit hemodynamic dysfunction. Because growth-related signaling pathways in the hearts of mice expressing TnT mutations are not known, we evaluated the impact of increased Akt or glycogen synthase kinase-3β (GSK-3β) activity in both mutant TnT mice; molecules that increase heart size via physiologic pathways and block pathologic growth, respectively. Expression of activated Akt dramatically augments heart size in both R92Q and Trunc mice; however, this increase in heart size is not beneficial, since Akt also increases fibrosis in both TnT mutants and causes some pathologic gene expression shifts in the R92Q mice. Activated GSK-3β results in further decreases in left ventricular size in both R92Q and Trunc hearts, but this decrease is associated with significant mutation-specific phenotypes. Among many pathologic consequences, activating GSK-3β in R92Q hearts decreases phosphorylation of troponin I and results in early mortality. In contrast, increased GSK-3β activity in Trunc hearts does not significantly impact cardiac phenotypes. These findings demonstrate that increased Akt and its downstream target, GSK-3β can impact both cardiac size and phenotype in a mutation-specific manner. Moreover, increased activity of these molecules implicated in beneficial cardiac phenotypes exacerbates the progression of disease in the R92Q TnT mutant.     

Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis： A case reportDevelopment of autoimmune hepatitis type I after pulsed methylprednisolone therapy for multiple sclerosis： A case report

A 43-year-old woman with multiple sclerosis （MS） was treated with pulsed methylprednisolone and interferon 13 at a hospital. Four weeks after initiating treatment, liver dysfunction occurred and she was referred and admitted to our hospital. Clinical and laboratory findings were consistent with and fulfilled the criteria for drug-induced hepatitis, but not for autoimmune hepatitis （AIH）. She was successfully treated with corticosteroids. As ataxia developed after i year, she was treated with pulsed methylprednisolone for 3 days, then readmitted to our hospital when liver dysfunction occurred. Clinical and laboratory findings led to the diagnosis of AIH. To the best of our knowledge, this is the second case of AIH developed after pulsed methylprednisolone for MS.     

IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes

Aims/hypothesis  

Islet antibody-negative first-degree relatives of type 1 diabetes patients have a very low risk of developing diabetes. We studied the balance between IFN-γ (proinflammatory) and IL-10 (regulatory) T cell responses in these participants.     

The role of hypergastrinemia in the pathogenesis of intussusception in infants

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Stem cell transplantation for multiple sclerosis: what is the evidence?

Experimental and clinical observations have indicated that high-dose immunosuppression followed by autologous stem cell transplantation (ASCT) can induce remissions in severe, refractory, autoimmune diseases including multiple sclerosis (MS), a T cell-mediated autoimmune disorder against CNS myelin components, causing severe chronic disability. Control of the disease is unsatisfactory in most of the patients, especially those with rapidly evolving relapsing-remitting course and those with chronic progressive disease. The rationale for treating autoimmune diseases with ASCT is based on the immunosuppressive and immunomodulating effects of ASCT which may shift the immunological balance towards disease quiescence, a hypothesis supported by the results of ASCT in animal models of MS and by clinical observations in MS patients transplanted for concurrent malignancies. A number of phase I-II studies of ASCT in patients with active MS, conducted worldwide since 1995, and a comprehensive analysis of 85 patients, recently reported by the European Group for Blood and Marrow Transplantation (EBMT), have shown the feasibility of the method, a prominent anti-inflammatory effect on magnetic resonance imaging (MRI) disease, and a possible clinical benefit for active and refractory cases. The impact on MRI disease parameters appears superior with ASCT than with conventional therapies but the clinical results, in terms of stabilization of disease and prevention of disability, need to be validated in prospective, controlled trials. The procedure is also associated with a transplant-related mortality risk, of about 5% in high-risk cases, i.e., in older patients, those with high disability scores, those receiving strong myeloablative conditioning regimens and those undergoing intensive in vivo or ex vivo T cell-depletion. Therefore, it could be recommended for the treatment of a chronic, non-lethal, disease like MS only if it proved superior to standard therapies. A randomized trial is now launched by the EBMT to compare ASCT to mitoxantrone, currently regarded as one of the best available treatments, in properly selected patients having high chance of response at minimal mortality risk.     

The changing role of high dose melphalan with stem cell rescue in the treatment of newly diagnosed multiple myeloma in the era of modern therapies—back to the future!

State of the art treatment for myeloma involves using 3-drug combinations incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Clinical trials for 4-drug combinations incorporating monoclonal antibodies added to IMiD and PI based backbones are underway. Recent retrospective analyses show that patients who attain MRD negativity have similar long term outcomes regardless of early or delayed high dose melphalan with autologous stem cell support (HDM-ASCT). Given HDM-ASCT toxicity, not “overtreating” would be beneficial. Short of data from future prospective clinical trials addressing the question of the role of HDM-ASCT in MRD negative patients, varying expert opinions inherently arise. In this paper, we present the historical context of HDM-ASCT and data supporting 3-drug combinations. We then propose that a viable option for patients who reach MRD negativity is to transition to maintenance therapy directly without early HDM-ASCT, and reserving stem cell harvest to cases where HDM-ASCT is a possibility at relapse.     

The role of maintenance therapy in eosinophilic esophagitis: who,why, and how?

Journal of Gastroenterology - In patients with eosinophilic esophagitis (EoE) who do not respond to proton pump inhibitors, initial anti-inflammatory/anti-eosinophilic treatment is with either...