1. Rheumatoid Arthritis: Treatment options in 2017
Chacko J. Alappatt, M.D., F.A.C.P., F.A.C.R

2. Rheumatoid Arthritis (RA) Fast facts
PREVALENCE : An estimated 1.5 million adults in the United States have rheumatoid arthritis. Affects % of population
Women are two to three times as likely to be affected as men.
Rheumatoid arthritis (RA) is an inflammatory systemic disease, with the hallmark of symmetric peripheral polyarthritis.

3. What is Rheumatoid Arthritis (RA)?
A chronic systemic autoimmune inflammatory disease that causes aggressive inflammatory changes in the synovium which causes joint pain/stiffness/swelling and ultimately leads to joint damage and functional debility

4. Rheumatoid Arthritis (RA)

5. Rheumatoid Arthritis- Joint Distribution

6. Rheumatoid Factor
AUTOANTIBODIES (OFTEN IgM) WITH SPECIFICITY FOR THE Fc PORTION OF THE IgG MOLECULE
MAJOR LABORATORY HALLMARK OF RA
ASSOCIATED WITH MORE SEVERE DISEASE,
EXTRAARTICULAR MANIFESTATIONS
NOT SPECIFIC FOR RA

7. Cyclic Citrullinated Peptide (CCP) Ab
Sensitivity/Specificity for RA: 80%/96-98%
Can be detected up to 10 years prior to onset of symptoms
Marker for more aggressive disease
Readily available (yet not part of ‘arthritis panels’??)
Citrullination or deimination is the term used for the post-translational modification of the amino acid arginine in a protein into the amino acid citrulline. This reaction, shown below, is performed by enzymes called peptidylarginine deiminases (PADs). Note that citrullination of proteins is distinct from the formation of the free amino acid citrulline as part of the urea cycle or as a byproduct of enzymes of the nitric oxide synthase family.
The conversion of arginine into citrulline can have important consequences for the structure and function of proteins, since arginine is positively charged at a neutral pH, whereas citrulline is uncharged. This increases the hydrophobicity of the protein, leading to protein unfolding.
Proteins that normally contain citrulline residues include MBP, fillagrin and several histone proteins, while other proteins, like fibrin and vimentin can get citrullinated during cell-death and tissue inflammation. Fibrin and fibrinogen may be favored sites for arginine deimination within rheumatoid joints. Test for presence of anti-citrullinated protein (ACP) antibodies are highly specific (88-96%) for rheumatoid arthritis (RA), about as sensitive as Rheumatoid factor (70-78%) for diagnosis of RA, and are detectable from even before the onset of clinical disease.[1]
In the reaction from arginine to citrulline, one of the terminal nitrogen atoms of the arginine sidechain is replaced by an oxygen. The reaction uses one water molecule and yields ammonia as a side product

8. Rheumatoid Arthritis –ACR Criteria (1987)
 4 OF THE FOLLOWING CRITERIA MUST BE PRESENT IN ORDER TO CLASSIFY AS RA:
AM STIFFNESS > 1 HR (≥6 weeks)
ARTHRITIS IN > 3 JOINTS (≥6 weeks)
ARTHRITIS IN PIPS, MCP, WRISTS (≥6 weeks)
SYMMETRIC ARTHRITIS (≥6 weeks)
POSITIVE RHEUMATOID FACTOR
RHEUMATOID NODULES
RADIOGRAPHIC CHANGES:
PERIARTICULAR OSTEOPENIA
EROSIONS
Criteria have sensitivity and specificity of approximately 90%

9. RA 2010 Diagnostic Criteria

10. Etiology of Rheumatoid Arthritis (RA)

11. Joint Destruction Hereditary predisposition/environmental trigger
Autoimmunity
Release inflammatory mediators/cytokines
Chronic inflammation of the synovial tissue lining joint capsule
Proliferation of the synovium into Pannus
Pannus invades cartilage and bone surface producing bone erosion
Joint Destruction

12. Rheumatoid Arthritis Treatment Goals
RELIEVE PAIN, SWELLING, FATIGUE
IMPROVE JOINT FUNCTION
STOP JOINT DAMAGE
PREVENT DISABILITY AND DISEASE- RELATED MORBIDITY
MINIMIZE/AVOID ADVERSE EVENTS
(MONITOR FOR TOXICITY)

13. DMARD:
Disease Modifying
Anti-Rheumatic
Drug

14. RA Management in 2017 Goal Processes Tools Zero Disease Activity
Remission
Processes
Tools
Early Treatment
Aggressive Treatment
Monitor Disease Activity
Traditional DMARDs
Biologic DMARDs
Combination Therapy

15. Non Biologic small molecule DMARDs
Hydroxychloroquine
Sulfasalazine
Leflunomide
Methotrexate
(Prednisone/Corticosteroid)

16. Biologic Response Modifier Drugs

17. Important information: Biologics
Typically given by SC injection or infusion
Complex molecules made in living cells
All modify the immune system; can predispose to infection
? Associated with Malignancy
Before initiation, screen for latent infections: Tuburculosis, Hepatitis, HIV
live vaccines (Zoster) contraindicated; vaccinate prior to initiation

18. Important information: Biologics
Most common adverse events: injection site reactions, “nasopharyngitis”, headache
Abatacept (Orencia) : caution in COPD
Combining two biologics: Not recommended
Tofacitinib citrate (Xeljanz): watch Lipids
Rituximab (Rituxan): PML and use in malignancy
Other: CHF, Bowel perforations, Demyelination, “Lupus like Syndrome”

19. Tumor Necrosis Factor Antagonists
Infliximab (Remicade)
Etanercept (Enbrel)
Certolizumab (Cimzia)
Golimumab (Simponi)
Adalimumab (Humira)

20. B-Cell Depletion: Rituximab

21. Co-stimulation Inhibitor: Abatacept

22. Tocilizumab (Actemra): IL-6 (-)

23. Jak inhibition: Tofacitinib (Xeljanz)

24. Biosimilars: the new Horizon
Properties
Generics
Biosimilars
Size
Small
Large
Molecular Weight
< Daltons
4000- >140,000 Daltons
Structure
Simple / well defined
Complex
Manufacturing
Predictable Chemical process: identical copy
Specialized process to make similar copy
Complexity
Easy to fully characterize
Difficult to characterize
Stability
Relatively stable
Sensitive to storage
Adverse immune react
Lower potential
Higher potential
Manufact. Quality
<50
> 250
Approval requirements
Small Clinical Trials
Large Clinical Trials

25. The new Horizon: Biosimilars
4/2016: FDA approves Inflectra (Pfizer), biosimilar for Infliximab (Remicade-Jansen)
8/2016: FDA approves Erelzi (Sandoz), biosimilar for Etanercept (Enbrel-Amgen)
9/2016: FDA approves Amjevita (Amgen), biosimilar for Adalimumab (Humira-Abbvie)

26. Your patient John, a 51 year old male, who takes Enbrel for his RA is interested in the Zoster vaccination. You advise
Good idea, arrange for vaccination
He is not a candidate for vaccination
Can get vaccination but has to be off Enbrel for a month before and after vaccination
Good idea but he will need to wait until age 60 10

27. Treat with Bactrim; continue MTX; hold Enbrel
Your patient Alexandra, a 58 year old female with Rheumatoid Arthritis who takes Methotrexate (MTX) and Enbrel develops a culture positive (E. Coli) urinary tract infection. You advise
Treat with Bactrim; continue MTX; hold Enbrel
Treat with Cipro; hold Enbrel
Treat with Cipro; continue MTX and Enbrel 10

28. Tofacitinib (Xeljanz) Tolcilizumab (Actemra) Rituximab (Rituxan)
Which of the following Rheumatoid Arthritis medications can increase serum cholesterol?
Etanercept (Enbrel)
Tofacitinib (Xeljanz)
Tolcilizumab (Actemra)
Rituximab (Rituxan) 10