#primary progressive ms

[caregiversherry]

Josh (my husband) started using a walker recently. Before that he was using a cane. Our 10 year anniversary was this past weekend and we had pictures taken in NYC in front of a horse and carriage. Josh posted a picture with his walker in it for the first time on Facebook and an acquaintance of his commented something that needs to be discussed. He said that Josh needs to stop selling himself short by using assistance to walk and that he’s stronger than that. This is not only ignorant but hurtful. No one knows what someone else is going through and not everyone with MS has the same level of symptoms. It is not safe for him personally to walk without assistance, such as a cane or walker at this point due to falls and extremely poor balance. I could definitely go on forever about MS awareness but in a nutshell, no two people are alike. Don’t tell someone who is trying to better their quality of life to stop selling themself short. In fact, maybe ask why they’re using it instead if you (clearly) don’t know.

[atomsokc]

Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic

Wong et al. show that a single intrathecal injection of CSF from patients with primary progressive—but not relapsing-remitting or secondary

This is an interesting article about primary progressive MS. Thanks to Susan N.

[rituximabjourney]

Multiple Sclerosis Discovery Forum

I have found this site and I am sharing some edited down information.  I need to explore the site some more to see what the site has to offer. 

The more we know, the better we can participate in making decisions about our treatment.

After providing basic drug information, there is data on 10 different clinical trials. 3 against a placebo - 7 head to head studies.  4 trials look exclusively at Relapsing Remitting (RRMS), 1 trial looks exclusively at Primary Progressive (PPMS), 2 trials look at Secondary Progressive (SPMS) 

Just look for the "Status/Outcome" data if you are wanting to skip all the technical data.

Article:

Multiple Sclerosis Discovery Forum (Edited)

http://www.msdiscovery.org/research-resources/drug-pipeline/229-rituximab

(website has complete listing of footnote references on all data below)

Last updated: 6 Sep 2014

Rituximab

Summary

Trade name: 

Rituxan

MabThera

MabThera SC (subcutaneous version)

Mabtas (biosimilar version)

Class: 

Immunosuppressor (3) (6)

Target: 

B cells (3)

CD20 (3)

Status for MS: 

Results from Phase II trials for RRMS have been published (2009, 2010) (12) (13)

Used off-label to treat MS (15)

Administration: 

Intravenous infusion (8)

Example of frequency of intravenous infusions in clinical trials is two 1000 mg infusions every 24 weeks (12)

Results presented at a meeting indicate that subcutaneous administration is a non-inferior alternative to intravenous infusion, which would allow administration over 5 minutes rather than 2.5 hours (8 December 2012) (17)

Subcutaneous formulation is approved by the European Commission for treating non-Hodgkin lymphoma, allowing administration over 5 minutes (28 March 2014) (35)

Commercial: 

Discovered by Biogen Idec (16)

Co-marketed by Genentech and Biogen Idec in the US (16)

Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan (16)

Marketed by Roche as MabThera elsewhere in the world (16)

Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) (18)

Synonyms: 

HSDB 7455 (1)

IDEC-102 (1)

Immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer (1)

Mabtas (18)

Mab Thera (1)

MabThera (16)

Rituxan (1)

Rituximab (1)

UNII-4F4X42SYQ6 (1)

Systematic name: 

Immunoglobulin G1, anti-(human CD20 (antigen)(human-mouse monoclonal IDEC-C2B8 gamma1-chain), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer (1)

Physiology

Class: 

Immunosuppressor (3) (6)

Target: 

B cells (3)

CD20 (3)

Properties: 

Genetically engineered chimeric murine/human monoclonal antibody that binds to CD20, a B cell antigen (6) (7)

Contains murine anti-CD20 antibody complementarity-determining regions and human kappa and IgG1 heavy-chain constant regions (8)

Molecular weight: 145 kD (8)

Produced in Chinese hamster ovarian cells (8)

Binding affinity for CD20 is ~8 nM (8)

Mean half-life in serum in patients with B cell lymphoma receiving intravenous infusion is 59.8 hours, although range is wide (8)

Half life is 20 days in patients with rheumatoid arthritis (after receiving second dose) (8)

Serum levels generally increase as doses are repeated and levels of CD20 decrease (7)

Mechanisms/Effects

Human: 

Complete mechanism unknown (14)

Targets the antigen CD20, which is expressed on pre-B cells and mature B cells (6) (11), as well as on a small subset of T cells (42)

Rapidly eliminates mature circulating B cells for up to 6 to 9 months (3) (4) (8)

Decreases or eliminates B cells in the cerebrospinal fluid of MS patients (14)

Affects chemokine levels in the cerebrospinal fluid of MS patients, such that levels of CXCL13 and CCL19 are reduced (14)

Reduces T cell levels in the cerebrospinal fluid of many MS patients, possibly because B cells (depleted by drug) influence T cell trafficking into the central nervous system by affecting chemokine production (14)

Depletes CD3+ CD20(dim) T cells (a subset of cells that is increased in MS) from individuals with MS (42)

May induce cell death through apoptotic pathways involving caspase-3 activation, as shown by studies of chronic lymphocytic leukemia patients (7)

Can cause complement activation, resulting in cell lysis (complement-dependent cytotoxicity), but the strength of the effect varies depending on the B-cell lymphoma cell line studied and does not correlate with clinical responses to the drug (7)

May act through antibody-dependent cellular cytotoxicity (in which cells are killed by effector cells that have been activated by the Fc portion of rituximab bound to the lymphoma cell) (7)

Binding to CD20 induces intracellular signaling pathways, and if crosslinked, the degree of signaling increases, as shown with studies of malignant B cells (7)

Binding to CD20 induces intracellular signaling, and the result of such signaling (such as apoptosis or cell cycle arrest) appears to depend on the cell line studied (7)

Appears to reduce axonal damage (as determined by measuring levels of the axonal damage biomarker neurofilament light protein in cerebrospinal fluid) in progressive MS (after 12 to 24 months of treatment) (19)

Intrathecal treatment depletes B cells in the central nervous system, which leads to a strong reduction in the increased levels of tumor necrosis factor-alpha (which can cause excitotoxic damage) and neurofilament light protein (a marker of axonal damage) in the cerebrospinal fluid, based on analysis of an individual with progressive MS (24)

Generally appeared safe and effective in a study involving 3 pediatric patients (2 with RRMS and 1 with SPMS) (39)

Repeated intrathecal doses (to target compartmentalized inflammation) reduced (i) peripheral CDC20+ B cells, (ii) several central proinflammatory cytokines, and (iii) neurodegeration markers, but did not affect oligoclonal bands, in an individual with severe progressive MS (43)

Negative effects: 

Angina (16)

Anthralgia (16)

Bronchospasm (4)

Cardiac arrhythmias (16)

Hypertension (16)

Hypotension (4)

Hypoxia (4)

Infections (16)

Infusion-related reactions (15)

Nausea (16)

Pyrexia (16)

Progressive multifocal leukoencephalopathy (3)

Strongly reduces antibody response to pandemic H1N1 influenza vaccine in individuals with arthritis (32)

Viral reactivation (16)

May lead to immunosuppression-related reactivation of the hepatitis B virus in previously-infected individuals; the US Food and Drug Administration requires this information to be displayed in a boxed warning (25 September 2013) (27)

Commercial: 

Discovered by Biogen Idec (16)

Co-marketed by Genentech and Biogen Idec in the US (16)

Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan (16)

Marketed by Roche as MabThera elsewhere in the world (16)

Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) (18)

Key Clinical Trials

Placebo-controlled Trials: 

Trial name: 

Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe) (recruiting as of January 2014) (33)

Phase I/Phase II trial (33)

Study Design: 

Government institute-sponsored, double-blind, placebo-controlled trial to examine the effects of combined systemic and intrathecal rituximab (to ensure that the drug reaches the central nervous system) on brain atrophy (primary outcome measure) (33)

Disease Stage: 

SPMS (33)

Enrollment/Number of Patients: 

80 (estimated) (33)

Duration: 

3 years (1 year of pretreatment visits followed by 2 years of treatment) (33)

Status/Outcome: 

Recruiting as of January 2014, estimated completion date, September 2016 (33)

Trial name:

Hawker et al., Ann. Neurol., Oct 2009 trial (12)

Phase: 

Phase II/III trial (12)

Study Design: 

Randomized, double-blind, placebo-controlled, multicenter trial to evaluate the effects of rituximab (two 1000 mg infusions or placebo every 24 weeks) on time to confirmed disease progression (primary endpoint) and T2 lesion volume and total brain volume (secondary endpoints) (12)

Disease Stage: 

PPMS (12)

Enrollment/Number of Patients: 

439 (12)

Duration: 

96 weeks (12)

Status/Outcome: 

Drug was not associated with a decrease in time to confirmed disease progression (but there was a suggestion of a potential decrease in younger patients, especially those with inflammatory lesions) (12) (16)

Trial name: 

Hauser et al., N. Engl. Med., Feb 2008 trial (5)

Phase: 

Phase II trial (5)

Study Design: 

Double-blind, placebo-controlled trial to evaluate the effects of intravenous rituximab (1000 mg or placebo on weeks 1 and 15) on the total count of gadolinium-enhancing lesions (primary endpoint) and on the proportion of patients with relapses (5)

Disease Stage: 

RRMS (5)

Enrollment/Number of Patients: 

104 (5)

Duration: 

48 weeks (5)

Status/Outcome: 

Drug was associated with a reduced number of inflammatory brain lesions and a reduced number of relapses (14.5% vs 34.3% at week 24 and 20.3% vs 40% at week 48) (5)

Head-to-Head Trials: 

Other Trials: 

Trial name: 

He et al., Cochrane Database Syst. Rev., December 2013 study (31)

Phase: 

Retrospective clinical trial review (31)

Study Design: 

Review of all randomized, double-blind, controlled parallel group clinical trials that evaluated the effects of rituximab (versus placebo or another approved disease-modifying therapy) on MS, with a followup of at least 1 year; 1 trial (5) was included in this analysis (31)

Disease Stage: 

RRMS (31)

Enrollment/Number of Patients: 

104 (31)

Duration: 

1 year (31)

Status/Outcome: 

Analysis did not support the use of rituximab in MS because only 1 trial was included; a significant attrition bias at week 48 (24%), a small number of participants, and short duration meant that the quality of the study was limited (31)

Trial name: 

Evdoshenko et al., ISRN Neurol., September 2013 study (28)

Phase: 

Observational/open-label study (28)

Study Design: 

Prospective, observational pilot study to examine the effects of combined rituximab and mitoxantrone therapy (consisting of an intravenous infusion of 1000 mg methylprednisolone, 1000 mg rituximab, and 20 mg mitoxantrone on day 1 and 1000 mg methylprednisolone and 1000 mg rituximab on day 14) (28)

Disease Stage: 

Active MS (28)

Enrollment/Number of Patients: 

28 (28)

Duration: 

12 to 48 month observation period (28)

Status/Outcome: 

No relapses occurred during the observation period; CD19+ and CD19+/CD27+ B cells were depleted in all individuals in the peripheral blood and cerebrospinal fluid at 6 months; the CD19+/CD27+ memory B cell subset was depressed over longer time periods than the CD19+ cells (28)

Trial name: 

Castillo-Trivino et al., PLoS One, July 2013 study (21)

Phase: 

Retrospective trial review (21)

Study Design: 

Review of 4 clinical trials to evaluate the safety and efficacy of rituximab for treating MS (21)

Disease Stage: 

PPMS and RRMS (21)

Enrollment/Number of Patients: 

599 (21)

Duration: 

N/A (21)

Status/Outcome: 

The drug was associated with frequent mild or moderate adverse events, but generally appears safe for up to 2 years of treatment; it substantially reduces inflammatory disease activity (the annualized relapse rate and gadolinium-enhancing lesions seen on brain MRI scans) in RRMS, but only marginally delays disease progression in PPMS (21)

Trial name: 

Rituximab in Secondary Progressive MS (conference report, June 2013) (20)

Phase: 

Retrospective medical record review (20)

Study Design: 

Retrospective study to examine the effects of rituximab (at least 3 cycles of 1 g intravenous infusions 2 weeks apart, given every 6 months) in patients for whom conventional therapy had failed; the functional ability of these patients had declined significantly in the two previous years, such that their Expanded Disability Status Scale (EDSS) scores increased about 0.5 points per year (20)

Disease Stage: 

SPMS (20)

Enrollment/Number of Patients: 

25 (20)

Duration: 

At least 18 months (20)

Status/Outcome: 

Rituximab treatment was associated with reduced disease progression, such that mean EDSS scores after the third cycle of treatment were very similar to the mean scores one year before treatment began (20)

Trial name: 

Naismith et al., Neurology, Jun 2010 trial (13)

Phase: 

Phase II, open-label study (13)

Study Design: 

MRI-blinded, single-center study to evaluate the effects of rituximab (375 mg/m2 weekly for four weeks) on gadolinium-enhancing lesions (primary objective) in patients who had been treated with a standard injectable disease-modifying agent in the past 18 months but had shown an inadequate response and were then given rituximab as add-on therapy (13)

Disease Stage: 

RRMS (13)

Enrollment/Number of Patients: 

30 (13)

Duration: 

52 weeks, such that the drug was given for the first four weeks and MRI scans were performed monthly beginning 12 weeks after the first drug treatment (13)

Status/Outcome: 

Drug was associated with a reduction in the number of gadolinium-enhancing lesions, such that 74% of posttreatment MRI scans were free of gadolinium-enhancing activity versus 26% of baseline MRI scans (13)

Trial name: 

Bar-Or et al., Ann. Neurol., Mar 2008 trial (10)

Phase: 

Phase I trial (10)

Study Design: 

Open-label trial to evaluate the safety, tolerability, pharmacodynamics, and activity of two courses of rituximab (total dose, 4000 mg), six months apart, in MS (10)

Disease Stage: 

RRMS (10)

Enrollment/Number of Patients: 

26, with 22 completing the trial (10)

Duration: 

72 weeks (10)

Status/Outcome: 

The drug was not associated with any serious adverse effects, although mild and moderate infusion-associated events were seen; furthermore, the drug was associated with fewer new gadolinium-enhancing or T2 lesions (10)