Treatments for Rheumatoid Arthritis

By: Brandon Trieu, Hamed Darabi, Alex Jun-Feng Pan, & Sean Zhang

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

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 Hydroxychloroquine

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=2817

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=10440

http://study.com/academy/lesson/what-is-methotrexate-uses-side-effects.html

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): 2130-2139

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-diabetes-pathogenesis-genetics-and-immunotherapy/innate-immunity-in-the-recognition-of-cell-antigens-in-type-1-diabetes

Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:704-712

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.

Protein-Ligand Complex

P

L

PL

k1

k2

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

antibodyCombination therapy with MTX

Subcutaneous injection

KD=127-150 pmol/L

Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:704-712Shealy DJ, Cai A et al., MAbs (2010), 2(4):428-439

GolimumabRecombinant human IgG1 monoclonal

antibodyCombination therapy with MTX

KD=18 pmol/L

KD determined by Surface Plasmon Resonance

CertolizumabFab fragment onlyCombination therapy with MTXSubcutaneous 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

● KD = 11 pM/L

● Advantages over standard DMARDs

http://img.medscape.com/article/726/181/Slide20.png

http://www.drugsdb.com/images/2012/03/Enbrel-Side-Effects-252x300.jpg

Alldred, A. Expert Opin Pharmacother (2001), 7: 1137-1148.

Infliximab (Remicade)● 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

http://img.medscape.com/article/726/181/Slide20.png

http://www.oncologynewjersey.com/wp-content/uploads/2013/08/remicade.jpeg

Blumenauer, B., et al. Cochrane Database Syst Rev (2002), 3: CD003785.

Rituximab (Rituxan)● 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

http://www.nature.com/onc/journal/v22/n47/images/1206939f1.jpg

http://www.biosimilarnews.com/wp-content/uploads/2012/10/rituxan-mabthera.png Nicholls, D., et al. Int J Rheum Dis (2014), 17: 755-761

Prevention of Rheumatoid Arthritis● Current focus on pre-

emptive 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_pone.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: 1137-

1148.

● 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