Dermatomyositis (DM)

Dermatomyositis (DM)

• Dermatomyositis (DM)

• Polymyositis (PM)

• Autoimmune Necrotizing Myopathy

• Inclusion Body Myositis (IBM)

1st Line

• 1st Line

• Prednisone
• IV methylprednisolone

• 2nd Line

• Methotrexate
• Azathioprine*
• IVIG*
• Mycophenolate mofetil

Etanercept = tumor necrosis factor α inhibitor

• Etanercept = tumor necrosis factor α inhibitor

• NIH funded; 16 subjects: 11 ETAN/5 PLAC

• ETAN 50 mg subQ weekly x 52 weeks

• All on PRED at least 2 mo

• After ETAN vs. PLAC, PRED taper

• Results: All 5 PLAC relapsed (med 148 days)

• 5/11 ETAN tapered off PRED
• 6/11 ETAN failures (med 358 days)

Avg PREDdose after week 24:

• Avg PREDdose after week 24:

• PLAC – 29.2 mg/day
• ETAN – 1.2 mg/day

• Other outcome measures: no diff

• MMT, MVIC, IMACS, MITAX, MYOACT, HAQ, SF36, INQOL, CK

• No AE/SAE diffs

• Conc: ETAN may have steroid sparing in DM

• Needs further study

• Lessons: PRED taper & dose good for endpoint

• Small, underpowered trial can be positive – if lucky!

NIH funded

• NIH funded

• Rituximab – B cell depleting agent

• 195 pts (76 PM, 76 DM, 48 JDM)

• Refractory to PRED and other oral IS

• 2 groups:

• RITUX early – RITUX wks 0/1; PLAC wks 8/9
• RITUX late – PLAC wks 0/1; RITUX wks 8/9

• Primary endpoint: time to DOI

• DOI = >20% improv in 3/6 core measures & no >2 CSMS worsening by >25%

• Secondary - time to 20% imp MMT

• - % DOI week 8

Dose – adults 1.5 gm/m2; child 575 mg/m2

• Dose – adults 1.5 gm/m2; child 575 mg/m2

• Core set measures – MMT; patient & MD VAS; HAQ; CK; extraneuromuscular disease/activity score

• Results: DOI time: 20.0 wks early group; 20.2 wks late group

• Time to 20% imp MMT: no diff

• % meeting DOI @ 8 wks: Ritux 15%; Plac 20.6%

• AE inf reactions – Ritux 15%; Plac 5.3%

• Lessons: Trial design – overestimated how fast Ritux worked

• Placebo effect – underestimated
• ? instruments

DEF: NM after statin use, but weakness progressing >2 months

• DEF: NM after statin use, but weakness progressing >2 months

• Retrospective chart review over the last 10 years at U. Kansas Medical Center

• 138 with idiopathic inflammatory myopathy

• 30 with biopsy proven NM:

• 18 (60%) had history of statin intake
• 2 (6.7%) had associated malignancy
• 10 (33.3%) had idiopathic NM

• Out of the 18 patients on statins :

• 7 toxic NM
• 11 SANM

Clinical Features

• Clinical Features

• frequently misdiagnosed as PM
• insidious onset and slowly progressive (average duration of symptoms prior to dx is 6 yrs)
• males affected more than females
• usually develops over the age of 50 to 60 years (most common myositis in patients presenting over the age of 50 years)
• Typical phenotype:
• wrist/finger flexors
• Knee extensors

SUMMARY

• SUMMARY

• No convincing evidence drug Rx significantly improves IBM

• A small number of patients may have transient improvement or stabilization

• However, all patients ultimately deteriorate over time

• Empiric trial can be offered if patient is aware of realistic results and side effects

• Other option - No drug Rx

• Other option – Investigational Rx trials

Derivative of Bimoclomol, developed by CytRx, a potent co-inducer of Heat Shock Proteins

• Derivative of Bimoclomol, developed by CytRx, a potent co-inducer of Heat Shock Proteins

• Stabilizes Heat Shock Transcription Factor-1 (HSF-1)

• This increases levels of HSP70 and HSP90

• Interacts with acidic membrane lipids to stabilize plasma membranes

• Interacts with cardiolipin in mitochondria

• May stabilize membrane
• May inhibit apoptosis

• Safe in 3 month ALS trial

To assess the safety and tolerability of arimoclomol 100 mg PO TID administered for 4 months in subjects with IBM

• To assess the safety and tolerability of arimoclomol 100 mg PO TID administered for 4 months in subjects with IBM

• 2 sites: KUMC & UCL-ION MRC

• Each site enrolled 12 subjects, n=24

• Randomization 2/1

• Provide data for future multi-center, randomized, placebo-controlled efficacy study

• Problem – unclear if small biotech company will move drug forward

Corticosteroid therapy

• Corticosteroid therapy

• Treatment of boys with nonsense stop-codon mutations

• Gentamicin
• PTC 124 (Ataluren)

• Exon skipping therapy

Mendell and CIDD group – 1989

• Mendell and CIDD group – 1989

• Prednisone delayed wheelchair use

• Boys placed on prednisone 0.75 mg/kg/day

• 30 lb / 15 kg boy = approx. 10 mg/day

• We recommended prednisone to most families when boys are ambulatory and beginning to fall

• Potential side effects:

• Weight gain
• Mood changes/insomnia
• Osteoporosis
• Less often: diabetes, high blood pressure, cataracts

Deflazacort

• Deflazacort

• Intermittent prednisone dosing

• Blinded Trial to Find Optimum Steroid Regimen for DMD

• New trial just funded by NIH – Drs. Griggs & Bushby

• Boys randomized to 3 groups

• Pred 0.75 mg/kg/d
• Pred 0.75 mg/kg/d: 10 days on/10 days off
• Deflazacort 0.9 mg/kg/day

• KUMC/CMH is a site

Molecular genetic testing

• Molecular genetic testing

• 70% deletions
• 10% duplications
• By PCR
• 20% point mutation/splicing errors
• Require gene sequencing

• Muscle biopsy for immunostaining and/or Western blot

• Conclusion: 1st do deletion/duplication testing. If neg, do biopsy or sequencing

Duchenne

• Duchenne

• Disruption of amino acid reading frame

• Out-of-frame mutation

• No dystrophin

• Becker’s

• Preservation of amino acid reading frame

• In-frame mutation

• Dystrophin abnormal but present

THE BIG RED DOG RAN AND SAT

• THE BIG RED DOG RAN AND SAT

• THE BIR EDD OGR ANA NDS AT

• = Duchenne (more severe) Muscular Dystrophy

• THE DOG RAN AND SAT

• = Becker (less severe) Muscular Dystrophy

Pompe disease

• Pompe disease

• A genetic lysosomal storage disorder characterized by the absence or marked deficiency of the lysosomal enzyme acid a-glucosidase (GAA)1:
• Glycogen accumulates in muscle cells;
• Which in turn causes progressive degeneration of skeletal, including respiratory, and cardiac muscle, depending on patient age
• Classified as infantile-onset or late-onset, although disease onset presents as a continuous spectrum2

van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA.

• van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, Herson S, Kishnani PS, Laforet P, Lake SL, Lange DJ, Leshner RT, Mayhew JE, Morgan C, Nozaki K, Park DJ, Pestronk A, Rosenbloom B, Skrinar A, van Capelle CI, van der Beek NA, Wasserstein M, Zivkovic SA.

• N Engl J Med. 2010 Apr 15;362(15):1396-406.

Randomized, double-blind, placebo-controlled, 12-month trial; (extended to 18 mo)

• Randomized, double-blind, placebo-controlled, 12-month trial; (extended to 18 mo)

• 20 mg/kg every other week

• 90 patient planned enrollment
• 2:1 drug to placebo assignment

• Co-primary end points

• 6MWT
• FVC upright

• Secondary end points

• QMT leg score
• Short Form-36 physical component summary (SF-36 PCS) score
• 6-month FVC analysis
• 6-month walk test analysis

• All patients begin active treatment after 26th infusion prior to unblinding

Primary Outcome:

• Primary Outcome:

• Stiffness: self-reported using an Interactive Voice Response Diary (IVR)
• Telephone call in daily
• Rate stiffness, weakness, fatigue and pain on 0-9 scale

• Secondary Outcome:

• Pain, Weakness, and Fatigue– IVR
• Clinical Myotonia Assessment
• Quality of life as measured by INQoL, SF36
• Quantitative measure of hand grip myotonia
• Measurement of CMAP after short and long exercise
• Grading of Myotonia on Needle EMG

Enrollment N = 62

• Enrollment N = 62

• Ineligible N = 3
• Prolonged QT:1
• Elevated ALT:1
• No myotonia seen on clinical exam:1

• Randomized N = 59 (December 23, 2008 to January 25, 2011)

• Received Mexiletine followed by Placebo N = 29
• Received Placebo followed by Mexiletine N = 30
• Dropouts:4
• Migraines:1
• Gastric discomfort:1
• Noncompliance: 2

• Genotype

• Na – 21 (35.6%)
• Cl – 34 (57.6%)
• ? - 4 (6.8%)

Primary outcome:

• Primary outcome:

• Mexiletine significantly improved stiffness on the IVR

• Secondary measures

• Mexiletine also significantly improved pain, weakness, and tiredness on the IVR

Mexiletine improved stiffness, pain, weakness and fatigue in NDM patients measured by IVR and quality of life measured by SF-36

• Mexiletine improved stiffness, pain, weakness and fatigue in NDM patients measured by IVR and quality of life measured by SF-36

• Stiffness scores: the largest treatment mean difference

• Most frequent side effect

• GI: 9/59 (15%) reported

• Other outcome measures currently being analyzed

• Lessons:

• Investigator-initiated rare disease research can be done in multi-site consortium
• Patient reported outcome measures can be primary endpoint
• Generic drug availability can be problematic

Cardiology rarely uses now

• Cardiology rarely uses now

• 2 generic companies

• TEVA (US)
• Boehringer (Europe)

• Pharmacies find it hard to keep in stock

• We applied for orphan drug status 7/2010

• ? Possibility of getting current generic companies or new companies interested in labeling indication

• ? Re-purposing mexiletine

KUMC involved in numerous cutting edge clinical trials

• KUMC involved in numerous cutting edge clinical trials

• Novel drugs
• Re-purposed drugs

• Fertile research field for students, residents, fellows, faculty

• Utilize infrastructure of Frontiers/CTSA

• Requires a large TEAM!