Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised ... more Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding’s disease (or Harding’s syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding’s disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear.
Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched ... more Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). Results: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95...
Altered composition of gut bacteria and changes to the production of their bioactive metabolites,... more Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cel...
B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which t... more B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, ...
Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple s... more Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple sclerosis (MS). We evaluated the MRI features of clinically definite MS subjects with and without CSF-OCB. Relapsing MS subjects were recruited from a prospective registry in a university center. CSF-OCB were detected using isoelectric focusing and lgG-specific immunofixation. MRI metrics including brain volumes, lesion volumes and microstructural measures, were analyzed by FMRIB Software Library (FSL) and Statistical Parametric Mapping (SPM). Seventy-five subjects with relapsing MS were analyzed. Forty-four (59%) subjects had an interval MRI at around 1 year. CSF-OCB were detected in 46 (61%) subjects. The OCB-positive group had a higher proportion of cerebellar lesions than the OCB-negative group (23.9% vs. 3.4%, p = 0.057). Except for amygdala volumes which were lower in the OCB-positive group (p = 0.034), other regional brain volumes including the subcortical deep gray matter and corp...
Objective: Whether immunotherapy improves long-term disability in multiple sclerosis has not been... more Objective: Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis. Methods: We studied patients from MSBase followed for 1 year, with 3 visits, 1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with 15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity. Results: 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43- 0.82...
IntroductionLeber’s hereditary optic neuropathy is a mitochondrially-inherited disorder character... more IntroductionLeber’s hereditary optic neuropathy is a mitochondrially-inherited disorder characterized by bilateral, painless visual loss, which leads to severe optic atrophy.1 LHON can be associated with an MS-like illness referred to as Harding’s disease.2We report two siblings, who both harbour the 11778 mtDNA mutation, but manifest markedly different clinical phenotypes; a male with classical LHON and a female with Harding’s disease.Methods and ResultsA 61-year-old female, who was diagnosed with MS 22 years ago was referred to our service for a second opinion. She developed unilateral painless visual loss in her 20’s, was diagnosed with optic neuritis and treated with corticosteroids with some recovery. A second episode of more severe visual loss at age 39 left her with visual impairment to less than finger counting. 4 years later, she had an episode of dysarthria and gait ataxia. MRI showed multifocal white matter lesions involving the juxta-cortical and periventricular regions,...
IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently... more IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied.MethodsThis will be a multicentre, 6-year, phase IV, low interventional trial. Subjects considered for treatment with cladribine will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After year 3, patients will have the option for re-dosing, if clinically indicated or to switch to another disease modifying therapy. Throughout the duration of the study we will assess blood based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation and RNA analysis as well as...
Background: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and ... more Background: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription factor nuclear factor erythroid-derived 2 (E2)-related factor (Nrf2), which is involved in both immunomodulation and bone health. DMF has not previously been reported to cause bone marrow complications, though other fumarates including tenofovir have. The mechanism of fumarate-associated bone toxicity remains unclear with altered osteoblastic gene expression and function suggested. Methods: We present a case of a 54-year-old female with relapsing remitting multiple sclerosis (RRMS) treated for 30 months with DMF who developed relapsing atraumatic lower limb bone pain. Results: Serial imaging revealed multifocal areas of bone marrow oedema and trabecular fractures. The patient was diagnosed with transient bone marrow oedema syndrome. Management consisted of cessation of therapy and treatment with the pro-oste...
The Journal of Steroid Biochemistry and Molecular Biology
A proportion of circulating 25-hydroxy vitamin D (25(OH)D) undergoes epimerization to form C3-epi... more A proportion of circulating 25-hydroxy vitamin D (25(OH)D) undergoes epimerization to form C3-epi 25(OH)D and C3-epi 1,25(OH)D. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D 2000 IU/kg) or -deficient diets (no vitamin D) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D at week 7 (p &lt; 0.05) and week 9 (p &lt; 0.01). C3-epimer concentrations and %C3-epi 25(OH)D were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D and the %C3-epi 25(OH)D levels measured at 12 months after oral vitamin D supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D that undergoes epimerization is greater with oral vitamin D supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.
Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A... more Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l-tryptophan- and l-arginine-catabolising enzymes, indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly and in cells after culture for 4 h in the absence of regulatory factors in autologous serum. When measured directly , the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients ...
Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised ... more Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding’s disease (or Harding’s syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding’s disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear.
Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched ... more Background: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. Objective: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Methods: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). Results: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95...
Altered composition of gut bacteria and changes to the production of their bioactive metabolites,... more Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cel...
B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which t... more B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, ...
Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple s... more Oligoclonal IgG bands (OCB) in cerebrospinal fluid (CSF) are important in diagnosis of multiple sclerosis (MS). We evaluated the MRI features of clinically definite MS subjects with and without CSF-OCB. Relapsing MS subjects were recruited from a prospective registry in a university center. CSF-OCB were detected using isoelectric focusing and lgG-specific immunofixation. MRI metrics including brain volumes, lesion volumes and microstructural measures, were analyzed by FMRIB Software Library (FSL) and Statistical Parametric Mapping (SPM). Seventy-five subjects with relapsing MS were analyzed. Forty-four (59%) subjects had an interval MRI at around 1 year. CSF-OCB were detected in 46 (61%) subjects. The OCB-positive group had a higher proportion of cerebellar lesions than the OCB-negative group (23.9% vs. 3.4%, p = 0.057). Except for amygdala volumes which were lower in the OCB-positive group (p = 0.034), other regional brain volumes including the subcortical deep gray matter and corp...
Objective: Whether immunotherapy improves long-term disability in multiple sclerosis has not been... more Objective: Whether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis. Methods: We studied patients from MSBase followed for 1 year, with 3 visits, 1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with 15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity. Results: 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43- 0.82...
IntroductionLeber’s hereditary optic neuropathy is a mitochondrially-inherited disorder character... more IntroductionLeber’s hereditary optic neuropathy is a mitochondrially-inherited disorder characterized by bilateral, painless visual loss, which leads to severe optic atrophy.1 LHON can be associated with an MS-like illness referred to as Harding’s disease.2We report two siblings, who both harbour the 11778 mtDNA mutation, but manifest markedly different clinical phenotypes; a male with classical LHON and a female with Harding’s disease.Methods and ResultsA 61-year-old female, who was diagnosed with MS 22 years ago was referred to our service for a second opinion. She developed unilateral painless visual loss in her 20’s, was diagnosed with optic neuritis and treated with corticosteroids with some recovery. A second episode of more severe visual loss at age 39 left her with visual impairment to less than finger counting. 4 years later, she had an episode of dysarthria and gait ataxia. MRI showed multifocal white matter lesions involving the juxta-cortical and periventricular regions,...
IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently... more IntroductionCladribine tablets (marketed as Mavenclad®) is a new oral therapy, which has recently been listed on the pharmaceuticals benefit scheme (PBS) in Australia for treatment of relapsing MS. The current dosing schedule is for 2 courses given a year apart, which has been shown to be effective for treatment of MS up to 4 years in 75% of patients (based on annualised relapse rate). However, re-initiation of therapy after year 4 has not been studied.MethodsThis will be a multicentre, 6-year, phase IV, low interventional trial. Subjects considered for treatment with cladribine will receive an initial treatment course in year 1 and a continuing treatment course in year 2. After year 3, patients will have the option for re-dosing, if clinically indicated or to switch to another disease modifying therapy. Throughout the duration of the study we will assess blood based biomarkers including lymphocyte subsets, serum neurofilament light chain, DNA methylation and RNA analysis as well as...
Background: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and ... more Background: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription factor nuclear factor erythroid-derived 2 (E2)-related factor (Nrf2), which is involved in both immunomodulation and bone health. DMF has not previously been reported to cause bone marrow complications, though other fumarates including tenofovir have. The mechanism of fumarate-associated bone toxicity remains unclear with altered osteoblastic gene expression and function suggested. Methods: We present a case of a 54-year-old female with relapsing remitting multiple sclerosis (RRMS) treated for 30 months with DMF who developed relapsing atraumatic lower limb bone pain. Results: Serial imaging revealed multifocal areas of bone marrow oedema and trabecular fractures. The patient was diagnosed with transient bone marrow oedema syndrome. Management consisted of cessation of therapy and treatment with the pro-oste...
The Journal of Steroid Biochemistry and Molecular Biology
A proportion of circulating 25-hydroxy vitamin D (25(OH)D) undergoes epimerization to form C3-epi... more A proportion of circulating 25-hydroxy vitamin D (25(OH)D) undergoes epimerization to form C3-epi 25(OH)D and C3-epi 1,25(OH)D. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D 2000 IU/kg) or -deficient diets (no vitamin D) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D at week 7 (p &lt; 0.05) and week 9 (p &lt; 0.01). C3-epimer concentrations and %C3-epi 25(OH)D were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D and the %C3-epi 25(OH)D levels measured at 12 months after oral vitamin D supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D that undergoes epimerization is greater with oral vitamin D supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.
Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A... more Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l-tryptophan- and l-arginine-catabolising enzymes, indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly and in cells after culture for 4 h in the absence of regulatory factors in autologous serum. When measured directly , the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients ...
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Papers by A. Kermode