1. Treatments for Rheumatoid Arthritis
PHM 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

2. Current Therapeutic Strategy
Start with conventional DMARDs (disease-modifying antirheumatic drugs) monotherapy: methotrexate.
Conventional DMARDs combinations
Conventional DMARDs plus biologics
bioglocis: obtained from biological sources (ie not chemically synthesized)
goal is remission
Radner and Aletaha. Wien Med Wochenschr :3-9

3. Challenges Rheumatoid arthritis is a progressive disease
Conventional DMARDs (e.g. methotrexate) have a variety of side effects
Cost of treatments
methotrexate is also used in chemotherapy. common side effects include hepatoxocity, low WBC count thus higher risk for infection. terotogenic
Can and Ginsburg Annu. Rev. Genomics Hum. Genet :

4. New Strategies “Treat-to-target” approach
Induction-maintenance therapy
Dosing down of biologics

5. 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

6. Action of Methotrexate
Cutolo M, Sulli A, Pizzorni C, Seriolo B Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 60(1):

7. Action of Sulfasalazine
Jansen G, Heijden JVD, Oerlemans R, Lems WF, Ifergan I, Scheper RJ, Assaraf YG, Dijkmans BAC Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheumatol. 50(7):

8. 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

9. 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:

10. Protein-Ligand Complexk1 PL k2 P

11. 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:

12. Adalimumab (Humira Abbott)
Recombinant human IgG1 monoclonal antibody
Combination therapy with MTX
Subcutaneous injection
KD= pmol/L
Golimumab
Recombinant human IgG1 monoclonal antibody
Combination therapy with MTX
KD=18 pmol/L
KD determined by Surface Plasmon Resonance
Scott D. L. and Kingsley G. H., N Eng J Med (2006), 355:
Shealy DJ, Cai A et al., MAbs (2010), 2(4):

13. 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

14. 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
Etanercept, sold under the brand name of Enbrel, is classified as a recombinant human soluble TNF receptor, which means that it consists of the human antibody, IgG1, combined with a TNF receptor. Entanercept’s ability to alleviate RA symptoms arises from the fact that its presence allows for the competitive inhibition of TNF-a inflammatory mediators in the synovial membrane, as the TNF-a cytokines will bind to the TNF receptor of the etanercept drug, and become unavailable to bind to the natural TNF receptors found on neutrophils, vascular endothelial cells, and also fibroblasts. This ultimately results in the prevention of activation of inflammatory responses responsible for joint tissue destruction caused by TNF-a binding.
The drug is administered subcutaneously, in doses of 25mg twice weekly, or a single 50mg dose once weekly. In early stages of RA, administration of Etanercept has shown reduction in the rates of joint space narrowing caused by RA similar to those of MTX (ACR 20/50 of 64/40 vs 55/30 = 6 months), while proving to be more effective than MTX during the later stages of RA (ACR 20/50 of 72/47 vs 65/43 = 12 months). Additionally, etanercept exhibits a faster rate of onset for its drug mechanism and therapeutic effect compared to traditionally used DMARDs.
However, side effects of the drug include headache, pain, redness, itching, swelling, or in some cases severe allergic reactions.
Alldred, A. Expert Opin Pharmacother (2001), 7:

15. 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
Infliximab is another TNF-a inhibitor, and is classified as a chimeric anti-TNF alpha monoclonal antibody. This means that the drug is an antibody comprising of both human and mouse components through the use of recombinant DNA technology, of which is specific for the TNF-a cytokine. Application of this drug to RA patients allows for the high affinity binding of the drug to available TNF-a cytokines, thus shutting down the biological activity of TNF-a in eliciting inflammatory reponses in RA.
Infliximab is only authorized for treatment of RA in conjunction with methotrexate, and cannot be used as a mono-therapy treatment, in order to reduce the body’s inherent immune response against the antibody itself. The drug is administered via an IV infusion at a dose of 3 mg/kg at 0, 2, and 6 weeks, followed by another regimen consisting of a dose of 3mg/kg every 8 weeks after. In instances where the patient exhibits an incomplete response following this dosing regimen, it may be necessary to increase the dose to 10 mg/kg up to every 4 weeks. Administration of the drug concurrently with methotrexate exhibited greater reductions in joint deterioration compared to only methotrexate treatment in throughout the early and late phases of RA. However, it’s interesting to note that these values were still less than those demonstrated by etanercept.
Common side effects of the drug include stomach pain, chest pain, chills, cough, dizziness, and nausea.
Blumenauer, B., et al. Cochrane Database Syst Rev (2002), 3: CD

16. 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
Similarly, rituximab is also a chimeric human monoclonal antibody, however it is specific against the CD20 protein found on the surfaces of B-cells. CD20 antigens are responsible for the optimal functioning and activation of B-cells (lymphocytes). The binding of rituximab to these antigens effectively results in the removal of memory B-cells from the inflammatory region of RA, and alleviates the symptoms of the disease due to the result immunosuppression.
Rituximab acts on B-cells found in the synovium inflammation area, by binding to the CD20 receptors found upon B-cells, and effectively preventing the B-cell from triggering an inflammatory immune response within the synovial joint. The lack of B-cell activation within the synovial membrane allows for effective treatment of RA symptoms in the late stages of the disease development. However, given the importance of B-cells in the proper functioning of the immune system, the side effects associated with the drug are highly undesirable, and the drug is only authorized for administration following ineffective therapeutic treatment with TNFa inhbitors.
The drug is administered as an IV infusion, consisting of 1000 mg infusions separated by 2 weeks. Rituximab can also be administered concomitantly with methothrexate for increased efficacy.
Nicholls, D., et al. Int J Rheum Dis (2014), 17:

17. 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
An important application of Rituximab as a treatment method for RA lies in its potential use for the prevention of the disease state. Traditionally, all of the RA treatments have been represented by drugs serving as chronic immune-suppressants to alleviate RA symptoms, but current research is now focusing on a more preventative approach to addressing the onset of RA. Rituximab represents such a drug spearheading this new paradigm shift in RA treatment research, and current case studies are using the drug for high-risk individuals for RA, with a desired reduction of 75% in RA development among treated individuals.
Gerlag, D.M., et al. Rheumatology (2015)m, pii: kev347.

18. 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

19. Sources
Alldred, A. “Etanercept in rheumatoid arthritis.” Expert Opinion of Pharmacotherapy :
Blumenauer, B., et al. “Infliximab for the treatment of rheumatoid arthritis.” The Cochrane Database of Systematic Reviews : CD
Cutolo M, Sulli A, Pizzorni C, Seriolo B Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 60(1):
Fox RI, Kang H 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 pii: kev347.
Jansen G, Heijden JVD, Oerlemans R, Lems WF, Ifergan I, Scheper RJ, Assaraf YG, Dijkmans BAC Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheumatol. 50(7):

20. Sources cont’d
Lipsky, P.E., et al. “Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis.” The New England Journal Medicine :
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 :
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 Treatment of Rheumatoid Arthritis With Methotrexate and Hydroxychloroquine, Methotrexate and Sulfasalazine, or a Combination of the Three Medications. Arthritis Rheumatol. 46(5):
Shealy, D., et al. “Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.” mAbs :
Smolen, J., et al. “New Therapies for treatment of rheumatoid arthritis.” Lance :
Vollenhoven, R.F. “Two New Approaches to Treating Rheumatoid Arthritis”. Medscape Web.