PHM142 Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Treatments for
Rheumatoid Arthritis
By: Brandon Trieu, Hamed Darabi, Alex Jun-Feng Pan, & Sean Zhang
Current Therapeutic Strategy
●
Start with conventional DMARDs
(disease-modifying antirheumatic
drugs) monotherapy:
methotrexate.
●
Conventional DMARDs
combinations
●
Conventional DMARDs plus
biologics
Radner and Aletaha. Wien Med Wochenschr. 2015. 165:3-9
Challenges
●
Rheumatoid arthritis is a
progressive disease
●
Conventional DMARDs (e.g.
methotrexate) have a variety of
side effects
●
Cost of treatments
Can and Ginsburg Annu. Rev. Genomics Hum. Genet. 2011
12:217-44.
New Strategies
●
“Treat-to-target” approach
●
Induction-maintenance therapy
●
Dosing down of biologics
Combination Therapy
● Research has shown that combinations of different kinds of drugs to be more effective
than monotherapies
● Focus on aggressive treatment early on
Methotrexate
Sulfasalazine
http://study.com/academy/le http://dailymed.nlm.nih.gov/dai
sson/what-is-methotrexate- lymed/archives/fdaDrugInfo.cf
uses-side-effects.html
m?archiveid=10440
Hydroxychloroquine
http://dailymed.nlm.nih.gov/da
ilymed/archives/fdaDrugInfo.c
fm?archiveid=2817
Action of Methotrexate
● Cutolo M, Sulli A, Pizzorni C, Seriolo B. 2001. Anti-inflammatory mechanisms
of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 60(1): 729-735
Action of Sulfasalazine
● Jansen G, Heijden JVD, Oerlemans R, Lems WF, Ifergan I, Scheper RJ,
Assaraf YG, Dijkmans BAC. 2004. Sulfasalazine is a potent inhibitor of the
reduced folate carrier: Implications for combination therapies with
methotrexate in rheumatoid arthritis. Arthritis Rheumatol. 50(7): 21302139
Action of Hydroxychloroquine
● Works on the major histocompatibility complex class 2 protein
● Increases the pH of vesicles
● Leads to improper processing of alpha and beta chains
http://www.intechopen.com/books/type-1-diabetespathogenesis-genetics-and-immunotherapy/innate-immunity-inthe-recognition-of-cell-antigens-in-type-1-diabetes
TNFα inhibitors:
-Adalimumab
-Entanercept
-Infliximab
-Certolizumab
-Golimumab
TNFα cytokine interacts with p55 and p75 TNFα
receptor on target cell of synovial tissue.
Signaling Ca2+ release in cells, triggering cell
apoptosis.
Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:704-712
Protein-Ligand Complex
L
k1
k2
P
P
L
Why target TNFα?
High concentration of TNFα in
synovial joints of rheumatoid arthritis
patients
Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:704-712
Adalimumab
(Humira Abbott)
Recombinant human IgG1 monoclonal
antibody
Combination therapy with MTX
Subcutaneous injection
Golimumab
Recombinant human IgG1 monoclonal
antibody
Combination therapy with MTX
KD=18 pmol/L
KD=127-150 pmol/L
KD determined by Surface Plasmon
Resonance
Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:704-712
Shealy DJ, Cai A et al., MAbs (2010), 2(4):428-439
Certolizumab
Fab fragment only
Combination therapy with MTX
Subcutaneous injection
KD=90 pmol/L
Doesn’t have the Fc fragment of IgG
Less compliment-dependent cytotoxicity and
antibody-dependent cellular cytotoxicity. Key for
lysis of target cell.
PEGylated
Inhibits mast cell degranulation process at injection
site. Common minor side effect of other inhibitors
Deeks E. D., Drugs (2013), 73:75-97
Etanercept (Enbrel)
●
Recombinant Human Soluble TNF Receptor
●
Mono-therapy and combination therapy
with methotrexate
●
25 mg x 2/ week or 50 mg / week
http://img.medscape.com/article/726/1
81/Slide20.png
●
KD = 11 pM/L
●
Advantages over standard DMARDs
Alldred, A. Expert Opin Pharmacother (2001), 7: 1137-1148.
http://www.drugsdb.com/images/2012/0
3/Enbrel-Side-Effects-252x300.jpg
Infliximab (Remicade)
http://img.medscape.com/art
icle/726/181/Slide20.png
http://www.oncologyne
wjersey.com/wpcontent/uploads/2013/0
8/remicade.jpeg
●
Chimeric anti-TNF alpha
monoclonal antibody
●
Combination therapy with
methotrexate only
●
3 mg/kg 0, 2, 6 weeks, every 8
weeks afterwards
●
KD = 44 pM/L
Blumenauer, B., et al. Cochrane Database Syst Rev (2002),
3: CD003785.
Rituximab (Rituxan)
http://www.nature.com/onc/journal/v22/n47/images/1206939f1.jpg
http://www.biosimilarnews.com/wp-content/uploads/2012/10/rituxan-mabthera.png
●
Chimeric anti-CD20 human
monoclonal antibody
●
B-cell therapy (not TNF-a
inhibitor)
●
Only for use after anti-TNF
alpha therapy
●
Two 1000 mg infusions, 2
weeks apart
Nicholls, D., et al. Int J Rheum Dis (2014), 17: 755-761
Prevention of Rheumatoid Arthritis
●
Current focus on preemptive use for
prevention of RA
●
Case study aims to
reduce 75% of RA
development with
treatment
http://openi.nlm.nih.gov/imgs/512/226/3184166/3184166_pon
e.0025789.g001.png
Gerlag, D.M., et al. Rheumatology (2015)m, pii: kev347.
Summary
● Currently, Rheumatoid Arthritis patients will be treated first with conventional DMARDs
monotherapy, and methotrexate is frequently used. Then, DMARs combinational therapy is
used, and then DMARDs will be combined with biologics.
● Conventional Combination of DMARDs is Methotrexate, Sulfasalazine, Hydroxychloroquine
● Methotrexate is a competitive inhibitor of dihydrofolate reductase
● Sulfasalazine is a noncompetitive inhibitor of reduced folate carrier
● Hydroxychloroquine inhibits correct processing of MRC class 2 protein
● New strategies include the “treat-to-target” approach, induction-maintenance therapy (treat
patients with conventional DMARDs plus biologics right away), and dosing down of biologics.
● Tnf-α inhibitors prevent the Tnf-α cytokine from binding the p75 Tnf-α receptor on target
cell. Includes adalimumab, golimumab, certolizumab, etanercept, and infliximab which have
similar Kd values.
● New treatments such as rituximab are focused on prevention of rhuematoid arthritis
Sources
● Alldred, A. “Etanercept in rheumatoid arthritis.” Expert Opinion of Pharmacotherapy. 2001. 7: 11371148.
● Blumenauer, B., et al. “Infliximab for the treatment of rheumatoid arthritis.” The Cochrane Database of
Systematic Reviews. 2002. 3: CD003785.
● Cutolo M, Sulli A, Pizzorni C, Seriolo B. 2001. Anti-inflammatory mechanisms of methotrexate in
rheumatoid arthritis. Ann Rheum Dis. 60(1): 729-735
● Fox RI, Kang H. 1993. Mechanism of Action of Antimalarial Drugs: Inhibition of Antigen Processing and
Presentation. Lupus. Suppl 1: S9-12
● Gerlag, D.M., et al. “RA: from risk factors and pathogenesis to prevention: Towards prevention of
autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment.”
Rheumatology. 2015. pii: kev347.
● Jansen G, Heijden JVD, Oerlemans R, Lems WF, Ifergan I, Scheper RJ, Assaraf YG, Dijkmans BAC.
2004. Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination
therapies with methotrexate in rheumatoid arthritis. Arthritis Rheumatol. 50(7): 2130-2139
Sources cont’d
● Lipsky, P.E., et al. “Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis.” The New England Journal
Medicine. 2000. 343:1594-1602.
● Nicholls, D., et al. “A retrospective chart review of the use of rituximab for the treatment of rheumatoid arthritis in
Australian rheumatology practice.” International Journal of Rheumatic Diseases. 2014. 17: 755-761.
● O’Dell JR, Leff R, Paulsen Gail, Haire C, Mallek J, Eckhoff PJ, Fernandez A, Blakely K, Wees S, Stoner J, Hadley S,
Felt J, Palmer W, Waytz P, Churchil M, Klassen L, Moore G. 2002. Treatment of Rheumatoid Arthritis With
Methotrexate and Hydroxychloroquine, Methotrexate and Sulfasalazine, or a Combination of the Three Medications.
Arthritis Rheumatol. 46(5): 1164-1170
● Shealy, D., et al. “Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis
factor α.” mAbs. 2010. 2: 428-439.
● Smolen, J., et al. “New Therapies for treatment of rheumatoid arthritis.” Lance. 2007. 370:1861-74.
● Vollenhoven, R.F. “Two New Approaches to Treating Rheumatoid Arthritis”. Medscape. 2014. Web.
http://www.medscape.com/viewarticle/819620