MS Lecture PDF

Lecture 19 Clinical applications: Auto-immunity - Multiple Sclerosis with special guest: Ms. Sarit Klein MIMM 214 – Introductory Immunology: Elements of Immunity Wednesday February 21st, 2024 Dr. Jasmin Chahal 1 Multiple sclerosis Chronic autoimmune disease of the central nervous system Destruction...

Lecture 19 Clinical applications: Auto-immunity - Multiple Sclerosis with special guest: Ms. Sarit Klein MIMM 214 – Introductory Immunology: Elements of Immunity Wednesday February 21st, 2024 Dr. Jasmin Chahal 1 Multiple sclerosis Chronic autoimmune disease of the central nervous system Destruction of myelin sheath around neurons à lesions can be seen by MRI Nerves cannot properly pass along their signals (sclerosis = scar tissue) Range of symptoms: pain, fatigue, tingling, impaired gait (pattern of walking), vision problems, bladder problems, dizziness, cognitive and mood problems 2 MS & the immune system Inflammation causes increased recruitment of other immune cells Lymphocytes cross the blood-brain barrier and autoreactive CD4+ T cells reencounter their specific autoantigen presented by MHC II on macrophages Treg cells can regulate the Autoreactive T cells, B cells and innate cells lead to demyelination inflammation for a bit Produce myelin and support neurons 3 Types of MS ~ 85% of patients suffer from relapsing-remitting MS: experience periods when symptoms get better (remission) followed by attacks (relapse) Relapsing-remitting MS: Episodes of relapses (attacks) which may or may not leave permanent disability followed by periods of remission Primary progressive MS: Steady increase in disability with no relapse or remissions Progressive-relapsing MS: steady increase in disability with subsequent relapses and no remissions Secondary progressive MS: Initial relapsing-remitting MS that begins to steadily increase in disability without periods of remission 4 Abigail Burrus (2017); national Multiple Sclerosis Society Clinically isolated syndrome Radiologically isolated syndrome EDSS: Expanded disability Status Scale Wingerchuk, D.M. and Weinshenker, B.G., 2016 BMJ, 354, p.i3518. Relapsing-remitting MS Secondary progressive MS Diagnosing MS MRI Vision, coordination, sense of balance Spinal Tap or Lumbar puncture (collecting cerebral fluid to determine how much inflammation is in your CNS) 6 Timeline of developments in the treatment of PERSPECTIVES multiple sclerosis DO NOT MEMORIZE Subcutaneous IFNβ-1b is the first drug to be approved for treatment of RRMS 1993 The first drug for treating SPMS is approved 1996 Subcutaneous IFNβ-1b Subcutaneous glatiramer acetate Intramuscular IFNβ-1a 2000 Targeting of B cells is confirmed as an effective therapy for RRMS Ocrelizumab becomes the first drug to be approved for treatment of PPMS First reports of progressive multifocal leukoencephalopathy with natalizumab treatment Natalizumab is the first monoclonal antibody and high-efficacy drug to be approved for treatment of RRMS 2002 Intravenous mitoxantrone Subcutaneous IFNβ-1b for SPMS 2004 Intravenous natalizumab Subcutaneous IFNβ-1a Fingolimod is the first oral drug to be approved for treatment of RRMS 2005 2010 Oral dimethyl fumarate 2012 Oral fingolimod 2013 For the first time, a generic drug — a generic version of glatiramer acetate — is approved for the treatment of RRMS 2014 Oral dimethyl fumarate Oral teriflunomide Intravenous alemtuzumab Subcutaneous PEG-IFNβ-1b Tintore et al., Nature (2019). Oral fingolimod is the first diseasemodifying therapy to be approved for treatment of RRMS in paediatric patients 2015 2016 Subcutaneous daclizumab Generic glatiramer acetate 2017 2018 Oral fingolimod for RRMS in paediatric patients Oral cladribine Intravenous ocrelizumab for RRMS Intravenous ocrelizumab for PPMS 7 IFNb therapy and Corticosteroids used to treat MS Reduces relapses by ~30% Weekly injection Potential mechanisms - Control the secretion of pro and anti-inflammatory cytokines - Reducing the ability of lymphocytes to cross blood-brain barrier - Affecting APC function - May inhibit some T cell differentiation & increase T cell apoptosis Corticosteriod therapy: immunosuppressant à reduces inflammation caused by pro-inflammatory cytokines, increases induction of apoptosis in lymphocytes, reduces migration of leukocytes to the brain Dhib-Jalbut, S. and Marks, S., 2010. Interferon-β mechanisms of action in multiple sclerosis. Neurology, 74(1 Supplement 1), pp.S17-S24; Tintore et al., Nature (2019); Hojati, Zohreh et al, Mechanism of Action of Interferon Beta in Treatment of Multiple Sclerosis, Multiple Sclerosis Academic Press (2016). 8 Timeline of developments in the treatment of PERSPECTIVES multiple sclerosis DO NOT MEMORIZE Subcutaneous IFNβ-1b is the first drug to be approved for treatment of RRMS 1993 The first drug for treating SPMS is approved 1996 Subcutaneous IFNβ-1b Subcutaneous glatiramer acetate Intramuscular IFNβ-1a 2000 Targeting of B cells is confirmed as an effective therapy for RRMS Ocrelizumab becomes the first drug to be approved for treatment of PPMS First reports of progressive multifocal leukoencephalopathy with natalizumab treatment Natalizumab is the first monoclonal antibody and high-efficacy drug to be approved for treatment of RRMS 2002 Intravenous mitoxantrone Subcutaneous IFNβ-1b for SPMS 2004 Intravenous natalizumab Subcutaneous IFNβ-1a Fingolimod is the first oral drug to be approved for treatment of RRMS 2005 2010 Oral dimethyl fumarate 2012 Oral fingolimod 2013 For the first time, a generic drug — a generic version of glatiramer acetate — is approved for the treatment of RRMS 2014 Oral dimethyl fumarate Oral teriflunomide Intravenous alemtuzumab Subcutaneous PEG-IFNβ-1b Tintore et al., Nature (2019). Oral fingolimod is the first diseasemodifying therapy to be approved for treatment of RRMS in paediatric patients 2015 2016 Subcutaneous daclizumab Generic glatiramer acetate 2017 2018 Oral fingolimod for RRMS in paediatric patients Oral cladribine Intravenous ocrelizumab for RRMS Intravenous ocrelizumab for PPMS 9 Dimethyl fumarate therapy in MS Reduces relapses by 50% Oral pills More recent therapy (approved for MS in 2013) Fewer side effects Potential Mechanism: - Anti-inflammatory effects: can suppress the production of pro-inflammatory cytokines - Stimulate Tregs - Induce changes in maturation, availability and antigen-presenting capacity of APCs Fox RJ et al. N Engl J Med 2012; Tintore et al., Nature (2019); Mills, Elizabeth, Front Neurol (2018). 10