rheumatoid arthritis update...1/4/2016 4 clinical case #4 53 y.o. male with history of ra and nyha...

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Rheumatoid Arthritis Update

Beth Valashinas, DO, FACOI, FACR

Disclosures

Speaker for AbbVie Pharmaceuticals

Learning Objectives

Upon completion of this session, participants should be able to discuss:

The paradigm shift in treatment of RA

Recent changes in classification criteria for RA

Treat-to-target (T2T) Recommendations

2015 ACR recommendations for treatment of RA

DMARDs, Biologics, and other novel RA therapies

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Clinical Case #1

47 y.o. female with recently diagnosed RA is currently maintained on oral methotrexate at 20mg once weekly in addition to prednisone 5mg daily. Recent labs included an ESR of 12mm/hrand elevated CRP at 10mg/L. She has 2 tender joints and 2 swollen joints on exam, global health evaluation of 10/100, and DAS 28 score of 3.06 indicating moderate disease activity. Recent hand XR reveal marginal erosions on bilateral 2nd MCPs.

Clinical Case #1 Question

Which of the following would be the best treatment option at this time?

A.) Increase methotrexate to 25mg once weekly

B.) Increase prednisone to 10mg daily

C.) Add sulfasalazine or hydroxychloroquine

D.) Add a TNF inhibitor

E.) Change to parenteral methotrexate

Clinical Case #2

67 y.o. female with history of long-standing RA and HTN presents for a routine follow up and inquires about immunizations. Her RA has been well controlled on Enbrel, parenteral methotrexate 25mg once weekly, and prednisone 5mg daily.

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All of the following vaccines are appropriate to give as indicated EXCEPT:

A.) Pneumococcal

B.) Hepatitis B

C.) Herpes Zoster

D.) Influenza (IM)

Clinical Case #3

64 y.o. female presents with an inflamed left PIP joint as well as tenderness of all PIPs, DIPs, and bilateral knees. She relates long-standing joint discomfort and laboratory evaluation reveals a negative RF and anti-CCP Ab. Both ESR and CRP are normal.


Does she meet criteria for diagnosis of RA based on the 2010 ACR/EULAR Criteria?

A.) Yes

B.) No

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Clinical Case #4

53 y.o. male with history of RA and NYHA Class III CHF presents for routine follow up visit. He has been maintained on oral methotrexate 20mg once weekly for his RA and relates recurrent flare activity. He has multiple tender and swollen joints on exam and DAS28 score is 4.7, consistent with moderate disease activity.


All of the following would be potential treatment options EXCEPT:

A.) Change to parenteral methotrexate for better bioavailability

B.) Add Abatacept (Orencia)

C.) Add a TNF inhibitor

D.) Add sulfasalazine and hydroxychloroquine for triple therapy

Clinical Case #5

42 y.o. male who presents with a 4 week history of polyarticular joint pain. On exam, he has tenderness and synovitis involving bilateral 2nd-4th

MCPs. Laboratory evaluation reveals negative RF and anti-CCP Ab. ESR is normal, but CRP is elevated.

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Does he meet criteria for RA according to the 2010 ACR/EULAR Criteria?

A.) Yes

B.) No

Rheumatoid Arthritis

Affects 1% of population worldwide

Risk increases with age as affects ~6% of Caucasian population >65 years of age

Higher prevalence in women

3.6% female vs. 1.7% male lifetime risk

Morbidity/Mortality associated with RA

>1/3 of patients with RA experience work disability due to their disease

RA is associated with a 50% increased risk for MI and >2-fold increased risk for CHF

RA shortens life expectancy by 3-5 years

Includes extra-articular disease as well as treatment-related adverse effects

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Evidence of early radiographic progression contributes to paradigm shift

Studies in very early RA indicate early radiographic progression

63.6% of patients developed erosive disease within 3 years

74.3% in first year

97.2% by second year

Strongly associated with positive ACPA, RF, and high long-term disease activity

K.P. Machold, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of the disease. Rheumatology. 2007; 46:342-349.

2010 ACR/EULAR Classification Criteria for RA

Established by an international task force

Designed to be used in patients with clinical synovitis in at least one joint

Classification criteria, not diagnostic criteria

Serves as a guide

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Treating RA to target: The T2T International Task Force 2014 Update

PrinciplesTreatment must be based on shared decision

between patient and rheumatologist

Primary goal is to maximize long-term health-related quality of life

Abrogation of inflammation most important way to achieve goal

T2T by measuring disease activity and adjusting therapy to optimize outcomes in RA

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10 recommendations of T2T committee

1. Primary target in treatment of RA should be state of clinical remission

2. Clinical remission is defined by absence of signs and symptoms of significant inflammatory disease activity

3. While remission is goal, low disease activity may be acceptable alternative, especially in long-standing disease


4. Until desired target met, drug therapy should be adjusted at least every 3 months

5. Measures of disease activity must be obtained frequently (monthly for moderate/high disease activity or every 3-6 months for low disease activity/clinical remission)

6. Use of validated composite measures of disease activity, including joint assessment, needed to guide treatment decisions


7. Structural changes and functional impairment should be considered in treatment decisions

8. Desired treatment target should be maintained throughout course of disease

9. Choice of composite measure of disease activity and level of target value may be influenced by co-morbidities, patient factors, and drug-related risks

10. Patient should be informed of target and strategy planned to reach target under supervision of rheumatologist

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Composite Disease Activity Measurement

Disease activity score(DAS 28)

Simplified disease activity index (SDAI)

Clinical disease activity index (CDAI)

Tender joint count (0-28)Swollen joint count (0-28)ESR or CRPPatient’s global assessment on VAS(0-100)

Tender joint count (0-28)Swollen joint count (0-28)CRPPatient’s global assessment on VAS(0-100)Physician’s global assessment on VAS(0-100)

Tender joint count (0-28)Swollen joint count (0-28)Patient’s global assessment on VAS(0-100)Physician’s global assessment on VAS(0-100)

Remission score <2.6 Remission score </= 3.3 Remission score </= 2.8

Novel measure of disease activity

Vectra DA

Blood test which measures 12 biomarkers linked to RA inflammation and produces a composite score between 1-100 indicating low, moderate, or high disease activity

Clinical validation in both RF, ACPA positive and seronegative RA patients

DMARDs (Disease modifying anti-rheumatic drugs)

Methotrexate Approved in 1988 Remains cornerstone of RA therapy Often used in combination with other DMARDs, biologic

therapies

Leflunomide (Arava) Hydroxychloroquine (Plaquenil) Sulfasalazine Triple therapy (methotrexate, hydroxychloroquine, and

sulfasalazine)

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Potential side effects/adverse effects of DMARDs

MethotrexateNausea, fatigue, alopecia, hepatotoxicity, lowered

blood counts, pneumonitis, immunosuppression Hydroxychloroquine

Rash, increased sun sensitivity, skin discoloration, rare eye toxicity

Leflunomide (Arava)Nausea, diarrhea, alopecia, hepatotoxicity, lowered

blood counts, immunosuppression Sulfasalazine

Nausea, vomiting, lowered blood counts, rash

Triple therapy vs. Etanercept+MTX

Biologic therapy for RA

Tumor necrosis factor (TNF) inhibitorsEtanercept (Enbrel)

Approved in 1998

Soluble TNF receptor fusion protein

Infliximab (Remicade)Chimeric monoclonal antibody

Adalimumab (Humira)Fully monoclonal antibody

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Tumor necrosis factor (TNF) inhibitors

Golimumab (Simponi)

Human monoclonal antibody

Certolizumab pegol (Cimzia)

Pegylated Fab’ fragment of a humanized monoclonal antibody

Mechanism of action in anti-TNF therapy

Potential side effects/adverse effects of TNF inhibitors

Injection site reactions, upper respiratory tract infections, immunosuppression, reactivation of TB/latent fungal infections, malignancy, infusion reactions (Remicade)

Avoid in CHF (especially NYHA Class III-IV), previously treated or untreated skin cancer (non-melanoma or melanoma), and previously treated lymphoproliferative disorders

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Abatacept (Orencia) Selective T cell costimulation modulator which

inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28

Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. Orencia decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2.


Abatacept (Orencia)

Potential adverse effects

Headache, immunosuppression, serious infections, infusion reactions, malignancy, COPD exacerbations


Tocilizumab (Actemra)Humanized monoclonal antibody that binds to

interleukin-6 (IL-6) receptors and inhibits IL-6 mediated signaling

IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by RA

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Tocilizumab (Actemra)


Serious infections, immunosuppression, lowered blood counts, elevated LFTs, gastrointestinal perforation, reactivation of TB/fungal infections, hyperlipidemia


Rituximab (Rituxan)Chimeric monoclonal antibody against CD20

antigen present on surface protein of B cells which mediates B-cell lysis.

B cells believed to play a role in pathogenesis of RA and associated synovitis, thus Rituxan may interfere with production of autoantibodies, antigen presentation, T-cell activation, and/or cytokine production


Rituximab (Rituxan)


Serious infections, infusion reactions, reactivation of JC virus causing incurable progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation, cardiovascular events

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Janus kinase (JAK) inhibitor

Tofacitinib (Xeljanz)Modulates the signaling pathway of JAKs

(intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on cell membranes influencing immune cell function) by preventing phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs), which modulate intracellular activity including gene expression.

Janus kinase (JAK) inhibitor

Tofacitinib (Xeljanz)


Serious infections, reactivation of TB/fungal infections, malignancy, lowered blood counts, elevated LFTs, hyperlipidemia, gastrointestinal perforation

2015 American College of Rheumatology Guidelines for treatment of early RA

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2015 ACR recommendations for treatment of established RA

2015 ACR recommendations for treatment of established RA

Clinical Case #1 revisited

47 y.o. female with recently diagnosed RA is currently maintained on oral methotrexate at 20mg once weekly in addition to prednisone 5mg daily. Recent labs included an ESR of 12mm/hrand elevated CRP at 10mg/L. She has 2 tender joints and 2 swollen joints on exam, global health evaluation of 10/100, and DAS 28 score of 3.06 indicating moderate disease activity. Recent hand XR reveal marginal erosions on bilateral 2nd MCPs.

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67 y.o. female with history of long-standing RA and HTN presents for a routine follow up and inquires about immunizations. Her RA has been well controlled on Enbrel, parenteral methotrexate 25mg once weekly, and prednisone 5mg daily.

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A.) Pneumococcal

B.) Hepatitis B

C.) Herpes Zoster

D.) Influenza (IM)



A.) Pneumococcal

B.) Hepatitis B

C.) Herpes Zoster

D.) Influenza (IM)


64 y.o. female presents with an inflamed left PIP joint as well as tenderness of all PIPs, DIPs, and bilateral knees. She relates long-standing joint discomfort and laboratory evaluation reveals a negative RF and anti-CCP Ab. Both ESR and CRP are normal.

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A.) Yes

B.) No



A.) Yes

B.) No

(She appears to meet criteria for RA, but this is a case of erosive OA)


53 y.o. male with history of RA and NYHA Class III CHF presents for routine follow up visit. He has been maintained on oral methotrexate 20mg once weekly for his RA and relates recurrent flare activity. He has multiple tender and swollen joints on exam and DAS28 score is 4.7, consistent with moderate disease activity.

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Clinical Case #5

42 y.o. male who presents with a 4 week history of polyarticular joint pain. On exam, he has tenderness and synovitis involving bilateral 2nd-4th

MCPs. Laboratory evaluation reveals negative RF and anti-CCP Ab. ESR is normal, but CRP is elevated.

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A.) Yes

B.) No



A.) Yes

B.) No

(This patient may have early seronegative RA and be classified prospectively)

Summary

RA is more common in women, affects ~1% of the worldwide population, and risk increases with age

RA leads to disability in >1/3 of patients, decreases life expectancy, and increases cardiovascular risks

Studies in very early RA indicate radiographic progression with evidence of erosive disease common within 2 years of diagnosis

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Summary

A paradigm shift in treatment of RA

2010 ACR/EULAR changes in classification criteria for RA

2014 update on treat-to-target (T2T) recommendations

2015 ACR recommendations for treatment of both early and established RA

The primary target of treatment is clinical remission by employing early intensive therapies

Summary

The development of novel treatments including biologics often used in conjunction with DMARDs has transformed RA therapy and positively impacted the outcome of patients

Balancing new developments with patient safety will remain important along with continued communication between the patient and rheumatologist regarding treatment strategy

References 1. Helmick C.G., Felson D.T., Lawrence R.C., National Arthritis Data Workgroup Estimates of the prevalence of arthritis and other rheumatic conditions in

the United States: Part I. Arthritis Rheum. 2008;58(1):15–25. [PubMed]

2. Crowson C.S., Matteson E.L., Myasoedova E. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633–639. [PMC free article] [PubMed]

3. Allaire S., Wolfe F., Niu J., Lavalley M.P. Contemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US. Arthritis Rheum. 2008;59(4):474–480. [PMC free article] [PubMed]

4. Sokka T., Kautiainen H., Pincus T., QUEST-RA Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther. 2010;12(2):R42. [PMC free article] [PubMed]

5. Turesson C., O'Fallon W.M., Crowson C.S., Gabriel S.E., Matteson E.L. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29(1):62–67. [PubMed]

6. Gabriel S.E., Crowson C.S., Kremers H.M. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48(1):54–58. [PubMed]

7. Lindhardsen J., Ahlehoff O., Gislason G.H. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011;70(6):929–934. [PubMed]

8. Semb A.G., Kvien T.K., Aastveit A.H. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study [published online ahead of print June 15, 2010] Ann Rheum Dis. 2010;69(11):1996–2001. [PubMed]

9. Maradit-Kremers H., Crowson C.S., Nicola P.J. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52(2):402–411. [PubMed]

10. Nicola P.J., Crowson C.S., Maradit-Kremers H. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum. 2006;54(1):60–67. [PubMed]

11. Nicola P.J., Maradit-Kremers H., Roger V.L. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52(2):412–420. [PubMed] K.P. Machold, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of the disease. Rheumatology. 2007; 46:342-349.

12. J.A. Singh, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research. 2015

13. Smolen, J. S. et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 69, 631–637 (2010).

14. Smolen, J. S. et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann. Rheum. Dis.

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Questions/Comments?

rheumatoid arthritis update...1/4/2016 4 clinical case #4 53 y.o. male with history of ra and nyha...

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