Update in Pharmacotherapy for Rheumatoid Arthritis Spencer A. Morris, Pharm.D., BCPS Southeastern Continuing Medical Education Consultants, LLC Georgetown, South Carolina

Commercial Support Disclosure Policy: Southeastern Continuing Medical Education Consultants, LLC, DOES NOT have any financial relationships with any manufacturers of any commercial pharmaceutical products and does not accept any pharmaceutical industry funding for planning or organization of its programs, as honoraria for its speakers, or in any other applicable manner, nor does it plan to in the future.

Speaker Disclaimer I represent Congressional District 7 on the South Carolina Board of Pharmacy. I am speaking today in my individual capacity as a health sciences educator and not as a member of the Board of Pharmacy. The views and opinions offered in this presentation are my own and do not reflect the collective views or positions of the current Board Members.

Educational Objectives & Content Outline: 1) Describe the etiology, pathophysiology, and clinical presentation of rheumatoid arthritis (RA).

•Review the natural history of RA.

• Identify risk factors for RA • Describe gender differences in RA.

• Review clinical manifestations and laboratory findings specific to RA

Educational Objectives & Content Outline: 2) Identify treatment options for patients with RA with respect to patient history, risk factors, current health status, and comorbid conditions.

•Discuss the role of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), diseasemodifying anti-rheumatic drugs (DMARDs), and adjunctive therapies in the treatment of RA.

Educational Objectives & Content Outline: 3) Review RA clinical •Discuss historical and recent clinical studies with regard to trial findings and their impact on treatment recommendations for RA. guideline recommendations •Summarize guideline treatment for pharmacological recommendations for RA from various professional treatment. organizations including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), etc.

Educational Objectives & Content Outline: 4) Discuss the importance of lifestyle changes, treatment compliance, and preventative healthcare for patients with RA.

Review the importance of:

• Exercise • Proper diet • Medication adherence • Preventative screenings • Patient follow-up

Patient Case Study PRESENTATION  37 year old healthy male with no significant medical Hx. Presents to his primary care provider with moderate to severe neck pain and bilateral hand swelling affecting several metacarpophalangeal joints on each hand. MEDICAL HISTORY • Left inguinal hernia repair as a toddler • Right elbow orthopedic surgery as teenager. • Social Hx: Non-smoker, drinks 3-4 alcoholic beverages/week     

Isolated severe right shoulder pain x 2 days, resolved spontaneously (August 2013) Bilateral hand swelling x 2 days, resolved spontaneously (August 2013) Moderate to severe URI, late October 2013 Received I.M. influenza vaccine, approx. November 30th 2013 Intermittent/persistent neck, shoulder pain and hand swelling thereafter

Patient Case Study PHYSICAL EXAM  Hands exquisitely tender and warm to the touch;  range of motion in wrists. Ganglion-like cyst swelling over both wrists. LABORATORY FINDINGS  Radiologic findings: bony mineralization and alignment are normal. Slight elevation of pronator fat pad indicative of soft tissue swelling.  CRP 2.5 H (Ref range: 0.2-0.9)  Citrulline AB > 250 H (Ref range: 0-19)  ESR 22 H (Ref range: 0-15)  Rheumatoid Factor 38.5 H (Ref range: 0.0-19.0)  Uric Acid 5.6 (Ref range: 2.0-8.3)

The State of Arthritis

50 million Americans > 36 million are Caucasian > 4.6 million are African-American > 2.9 million are Hispanic

The State of Arthritis

NOT a disease of old age! ⅔ of patients < 65 years of age > 300,000 are children

The State of Arthritis

27 million Americans have OA 1.5 million Americans have RA (Women affected 3 x more often than men)

Differentiating Osteoarthritis from Rheumatoid Arthritis Type

OA

Patient History • Palpable bony joint enlargment • Morning stiffness typically lasting < 30 minutes

RA

• Pain duration >6 wks • Morning stiffness lasting > 30 minutes • Systemic symptoms (e.g. fatigue, anxiety depression)

Physical Exam

Tests

•  range of motion • Joint malalignment

Radiologic findings

• Synovitis • Symmetrical joint involvement

Radiology

• Presence of osteophytes • Joints are tender but • Joint space narrowing NOT warm Laboratory findings • Crepitus • Clear synovial fluid

• Joints are tender AND warm • Joint destruction • Extra-articular manifestations

• Erosions on X-ray or MRI • Synovitis detected by ultrasound or MRI

Laboratory findings •  ESR or CRP • Anti-CCP antibodies •  /  Rheumatoid factor

Differentiating Osteoarthritis from Rheumatoid Arthritis Characteristics

Rheumatoid Arthritis

Osteoarthritis

Age of onset

Anytime

Typically, later in life

Speed of onset

Rapid-over weeks to months

Slowly over years

Joint symptoms

Painful and swollen

Painful and tender-little to no swelling

Patterns of joint involvement

Symmetrical, small and large joints

Begin on one side and may spread to the other. Large, weight-bearing

Duration of stiffness

More than 1 hour in the A.M.

Less than 1 hour in the A.M. but returns after periods of activity or at the end of the day

Systemic disease and symptoms

Fatigue and general feeling of being ill.

Not present.

Comparing joints affected by Osteoarthritis vs. Rheumatoid Arthritis Normal Joint

Osteoarthritis

Rheumatoid

Normal Knee Joint vs. Degenerated Knee Joint (OA)

Potential Causes for Asymmetrical Swelling of the Hand Legend: DIP = distal interphalangeal OA = osteoarthritis PIP = proximal interphalangeal SLE = systemic lupus erythematosus RA = rheumatoid arthritis MCP = metacarpophalangeal CMC = carpometacarpal

Image Source: Fauci AS, Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison’s Principles

Of Internal Medicine, 17th Ed. www.accessmedicine.com

Pathogenesis of RA

Pathogenesis of RA

Dislocation & malalignment of joints

Hand radiograph of a patient with advanced rheumatoid arthritis with severe destruction of the joint architecture

Asterisks indicate bone erosion.

Arthritis Research & Therapy 2007 9(Suppl 1):S2 doi:10.1186/ar2166

Risk Factors for Osteoarthritis  Advanced

age  Overweight / obesity  Mechanical stress / Joint Trauma 

“Wear and tear” arthritis

 Occupation  Increased 

risk in females

(Not as great as with RA)

 Bone

deformities

OA risk factors specific to military personnel: 

Early in the wars in Iraq and Afghanistan, soldiers would often carry between 80 and 120 pounds of gear.  Soldiers now have access to tactical vests that weigh less than 20 pounds, but still protect vital organs  Commanders decide in what circumstances soldiers can wear the lighter armor.



Lifetime of lifting weights and performing other strenuous physical activities to pass fitness exams.

http://www.stripes.com/news/rigors-of-war-leave-troops-battling-arthritis-at-a-young-age-1.156110

OA risk factors specific to military personnel:  Battlefield

injuries

 Veterans

are more and more commonly being diagnosed with “traumatic arthritis” about two years after being exposed to a blast. Broken bones  Explosive shock waves kill cartilage cells, which the body can’t replace. 

http://www.stripes.com/news/rigors-of-war-leave-troops-battling-arthritis-at-a-young-age-1.156110

Diagnosing Osteoarthritis 

Careful patient history



Rule out other potential causes before determining OA: 

RA, Septic Arthritis, etc.



Joint aspiration?



X-rays / MRI

RHEUMATOID ARTHRITIS

8 Things Not to Say to Someone Living with Rheumatoid Arthritis 1) 2) 3) 4) 5) 6) 7) 8)

___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________

http://rheumatoidarthritis.net/living/things-not-to-say-to-someone-who-has-ra

Defining Rheumatoid Arthritis 

Autoimmune disorder that attacks the joints, and causes destruction of the cartilage, bone, and ligaments.



Symmetrical joint involvement.



WBCs attack healthy tissue. The end results are deformity of the joints.



Research suggest a faulty immune response but environmental factors may also play a part, i.e.. Smoking, infection, obesity, etc.

Defining Rheumatoid Arthritis      

Approximately 1.5 to 2 million people currently diagnosed with RA in the U.S. 75% are women. Worldwide, 3 cases per 10,000 with a prevalence rate of 1%. Usually after age 40 but before age 60. Peak ages are between 35-50 years old. Native Americans have a 5-6% prevalence rate. Possible genetic link. First-degree relatives of RA patients have a 2-3 fold increased risk for RA.

Risk Factors for RA 

Genetic predisposition



Female sex



Environmental (smoking, silica exposure)



Links to periodontal disease 



Porphyromonas gingivalis and citrullination

Adverse life events / extreme stress

Symptoms of RA         

Joint stiffness and soreness Limited mobility and tightness particularly in the morning and afternoon. Fatigue Lumps called rheumatoid nodules below the skin Weight loss, low-grade fever and sweats, difficulty sleeping, weakness and loss of mobility Sexual dysfunction and depression. Progressive articular deterioration. Extra-articular involvement. Difficulty performing ADLs.

RA statistics  Approximately

40% of RA patients become disabled after 10 years.

 Having

RA almost doubles your risk of MI in the first 10 years of being diagnosed.

 Having

RA and increased inflammation can raise a patients risk for interstitial lung disease and pleurisy.

Extra-articular disease  Anemia

Half of patients with RA are affected.  Bone marrow inflammation and/or nephritis leading to a decreased number of RBCs 

 Pleuropericarditis  Neuropathy  Myopathy  Splenomegaly

Extra-articular disease 

Sjogrens Syndrome



Scleritis



Vasculitis



Renal disease



Carpal Tunnel



Stroke



Osteoporotic Fractures

Diagnosing RA 

Rheumatoid arthritis should be considered in any patient with joint pain or swelling lasting more than a few weeks.



The diagnosis of rheumatoid arthritis requires a consistent history and the presence of joint swelling unexplained by another diagnosis.



Neither radiologic nor laboratory abnormalities are required to make a firm diagnosis.



Many patients who have RA will have normal values for rheumatoid factor, anticitrullinated protein antibodies (anticyclic citrullinated peptide antibodies), erythrocyte sedimentation rate, and C-reactive protein level

Diagnosing RA (typical physical exam findings)

RA physical exam findings

Classical (historical) RA findings

The 2010 ACR-EULAR classification criteria for rheumatoid arthritis A. Joint involvement

SCORE

large joint¶

0

2-10 large joints

1

1-3 small joints (with or without involvement of large joints)#

2

4-10 small joints (with or without involvement of large joints)

3

>10 joints (at least 1 small joint)**

5

B. Serology (at least 1 test result is needed for classification)††Negative RF and negative ACPA

0

Low-positive RF or low-positive ACPA

2

High-positive RF or high-positive ACPA

3

C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡ Normal CRP and normal ESR

0

Abnormal CRP or abnormal ESR

1

D. Duration of symptoms 250 H (Ref range: 0-19)  ESR 22 H (Ref range: 0-15)  Rheumatoid Factor 38.5 H (Ref range: 0.0-19.0)  Uric Acid 5.6 (Ref range: 2.0-8.3)

RA approach to treatment  Early

aggressive treatment

 Proactive  Target

vs. reactive

tight control of inflammation toward low disease activity and remission.

The Art and Science of Selecting Pharmacotherapy for RA: 

James T. Rosenbaum, M.D. – Division Head, Arthritis & Rheumatic Diseases, Oregon Health & Science University



“Who am I," he said to me when I was a medical student, "to tell someone he would be better off with nausea but improved vision or improved mobility but increased risk of infection. I cannot pretend to know how it feels to be someone else."



Likens his role as a physician to a waiter describing the evening specials to his patient. 

As recounted by Dr. Rosenbaum’s daughter in the Huffington Post Blog, “Treating Patients with Antibiotics,” by Lisa Rosenbaum, M.D.

Patient Considerations 

Patients need information on a level they can understand.



Patients need to know the diagnosis, prognosis, and treatment options in detail.



Respect and empathy is vital for patient “buy-in” 



The Affect Heuristic

Shared-decision making between the provider and the patient makes for the best outcomes.

2012 ACR recommendations update for the treatment of early RA, defined as a disease duration < 6 months.

Therapies for RA - DMARDs Common Agents:  Methotrexate  Hydroxchloroquine  Sulfasalazine  Leflunomide  Azathioprine

Less common and/or rarely used:  Cyclosporine  Gold sodium thiomalate  Minocycline  Pencilliamine  Cyclophosphamide

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Self-reported medication use in the RA in America Study 2013

42% 40%

30%

39%

39%

33%

20% 10%

http://rheumatoidarthritis.net/ra-in-america-2013/

DMARDS Medication

Dosage

Side Effects

Additional Instructions

Azathioprine Azasan® Imuran®

50-150mg in 1-3 doses

Chills, Take with fatigue, fever, food. loss of appetite, liver problems, anemia, nausea, vomiting, weakness

Periodic Liver and CBC screenings. Avoid Allopurinol

Cyclophosphamide Cytoxan®

50-150mg daily Can be given IV

Hematuria, acanthosis of skin, alopecia, anemia, amenorrhea, nausea, vomiting

Use two forms of birth control. Increase risk for cancers and infection. Frequent CBC and UA testing.

Take with breakfast and increase fluids. VERY toxic.

Caution

DMARDs Medication

Dosage

Cyclosporine Neoral® Gengraf®

2.5mg-4mg/kg Abd. Pain, gingivitis, HTN, in 2 doses

Hydroxychloroquine

200mg to 400mg per day in 1-2 doses

Placquenil®

Side Effect

CRD, loss of appetite, nausea, parasthesia

Abd. Cramps, blurred vision, diarrhea, nausea, vomiting, rash, pruritis, loss of appetite. Can suppress RBC production.

Additional Instructions

Caution

Take at the same time everyday. Avoid grapefruit juice.

Avoid in CKD, anyone with an active infection, or HTN. Rate of absorption of unpredictable. Increased risk of cancers and infection.

Take with food or milk. Avoid excessive sunlight exposure.

Blurred vision, tinnitus, blue or black skin discoloration, muscle weakness, mood or mental changes,

Medication

Dosage

Leflunomide Arava®

Methotrexate Rheumatrex®, Trexall®

DMARDs Side Effects

Additional Instructions

Caution

10 to 20 mg per Vertigo, GI, day H/A, Liver, Anemia, neuropathy, rash sneezing, sore throat

Use two forms of birth control.

Remains in the body 2 years, unless given a wash-out with cholestyramine.

7.5mg to 20 mg orally once a week. May be given IV.

Increase fluids, avoid ETOH, ASA, wear sunscreen.

TB skin testing prior to starting this medication. Check liver and CBC prior to start and 6 weeks later then every other month.

GI, chills, vertigo, fever, malaise, H/A, puritis, liver toxicity, anemia, rash, sores in the mouth, SOB, yeast infections, Can suppress RBC production.

DMARDs Medication

Dosage

Side Effects

Additional Instructions

Caution

Minocycline Minocin®

200mg per day in 2-4 doses

GI distress, Photosensitivity, dizziness

Take on an empty stomach, Increase fluids. Wear sun screen.

Wear sunscreen. Off-label indication; NOT approved by FDA for RA. Can cause permanent tooth discoloration in children.

Avoid antacids with aluminum or magnesium.

Use two forms of birth control. Periodic testing of CBC and liver.

Mycophenolate 500mg to N/V/D, GI mofetil 2,000mg daily ulcers, bleeding, CellCept® in 1-2 doses photosensitivity.

Medication

Dosage

Side Effects

N/V/D, rash

5mg bid daily, 5mg/day for people with kidney or liver Disease.

Caution

Take with water after a meal. Minimize sun exposure.

Avoid in patients allergic to ASA or Sulfa. Failure to adequately hydrate can lead to crystals in the urine. Lower sperm counts. Periodic CBC , Liver and UA testing.

Take with or without food. Can be given with MTX.

TB skin testing prior starting. Live vaccines should NOT be given while on this drug.

DMARD

GI distress, Sulfasalazine 500mg to 3 Azulfidine® grams daily in loss of appetite, H/A 2-4 doses

Tofacitinib Xeljanz®

Additional Instructions

Anemia, diarrhea, H/A, HTN, increased lipids, URI.

Methotrexate (MTX)  Considered

the “anchor” drug for RA  Low-dose anti-inflammatory vs. antimetabolite  Long-term treatment is safe: 

RA studies demonstrate MTX is more likely to be continued 5 years after initial therapy than any other DMARD.

What is the correct dosage of methotrexate for RA? A.

15mg by mouth once weekly

B.

25mg I.V. every week

C.

20mg subcutaneously once weekly

D.

2.5 mg by mouth once daily

E.

“A” and “C”

Methotrexate hepatotoxicity

• It is estimated 1 in 1,000 patients treated with MTX will develop hepatotoxicity:  Usually occurs in patients with pre-existing liver disease or alcohol abuse.

• Social use of EtOH while taking Methotrexate? http://livertox.nih.gov/Methotrexate.htm

Methotrexate Side Effects

Alopecia Areata

Aphthous stomatitis

Other Side Effects: Gastrointestinal distress, nausea and vomiting, tinnitus blurred vision, dizziness, etc.

Hydroxychloroquine (Plaquenil®) 

Rarely leads to symptom control as monotherapy.



Best as combination therapy



Target dose 400mg/day



Best efficacy in patients with  rheumatoid factor (RF) and  anti-citrullinated antibodies (anti-CCP).



Rare retinal toxicity, periodic ophthalmology exams to monitor.

Sulfasalazine (Azulfidine®)  Equal

efficacy to MTX early in treatment, but effect diminishes over time.  Target dose: 2 grams per day  High rate of GI side effects Administer with meals  Enteric-coated formulation better tolerated 

 Use

with caution in patients with G6PD deficiency; hemolytic anemia may occur.

Leflunomide, Cyclosporine & Azathioprine 

Leflunomide has similar efficacy to MTX, but not tolerated by as many patients.  



Cyclosporine  



Used more often abroad vs. U.S. Biologics are often used instead Useful in acute flares Chronic use limited by nephrotoxicity

Azathioprine 

Chronic use limited by bone marrow suppression

Biologics for RA Chemical Name Trade Name

Route of Admin.

Frequency

Abatacept

Orencia ®

I.V. or subcut

Adalimumab

Humira ®

Subcut injection

Anakinra

Kineret ®

Subcut injecton

Once daily

Certolizumab

Cimzia ®

Subcut injection

Once every 2-4 wks

Etanercept

Enbrel ®

Subcut injection

Once a week

Golimumab

Simponi ®

I.V. or subcut

I.V. : every 8 wks Subcut: every mo.

Infliximab

Remicade ®

I.V.

Every 4 to 8 weeks

Rituximab

Rituxan ®

I.V.

Tocilizumab

Actemra ®

I.V. or subcut

Two doses, 2 weeks apart every 6 mo. I.V. : once monthly Subcut: Weekly or every other week

Tofacitinib

Xeljanz ®

Oral

5mg twice daily

I.V. : once/month Subcut: once/week Weekly or every other week

FDA-Approved Biologic Agents by Indication and Year of Indication Approval

U.S. FDA, Drugs@FDA: FDA Approved Drug Products, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ (data current as of 01 January 2013).

Biologics for RA  Biologics,

in general, should be considered when response to MTX, alone or in combo. with other DMARDs, is inadequate after 3 to 6 months of therapy.  Very expensive therapies ($1,000 to $3,000/month) Specialty pharmacies  Insurance plans / patient assistance programs 

Mechanism of Action of Biologics 

Etanercept, golimumab, infliximab, adalimumab and certolizumab, reduce inflammation by blocking tumor necrosis factor (TNF).



Anakinra works by blocking a cytokine called interleukin-1 (IL-1)



Rituximab stops the activation of B cells.



Abatacept blocks the overproduction of T cells.



Tocilizumab works by blocking interleukin 6 (IL-6).

Biologics for RA  On

average, 2 in 3 patients will respond  Individual responses do vary: 

Patients may need to try 2 to 3 different agents before finding one that works.

 Powerful

immunosuppressive effects

TB screening mandatory  HIV screening 

 Hold

in the instance of active infection

Economic burden of RA 

RA is one of the highest-cost conditions for employers, with estimated direct medical expenditures in the U.S. totaling over $73 billion.



RA accounts for ¼ of all specialty drug spending in the U.S.



The cost of biologic DMARDs is approx. 9,000% higher than conventional or traditional DMARDs

Arthritis Care & Research. Direct Medical Expenditure Associated with Rheumatoid Arthritis in a Nationally Representative Sample From the Medical Expenditure Panel Survey. Vol. 64, No. 11, Nov. 2012.

Check it out Mates: A study from “Down Under” that’s definitely worth a ponder…

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Proudman SM, et al. Ann Rheum Dis 2013;0:1–7.

Reasons for study withdrawal: a - Only 1 patient could not tolerate fish oil. Other reasons: •Patient moved •Changed hospitals •Other health issues after week 5 •Withdrew from trial demands but •Non-attendance after weeks 2 & 4 b - No intolerance to fish oil. Other reasons: same as above c - Patient met entry criteria but developed sx of systemic sclerosis

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use.

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use.

American College of Rheumatology recommendations update regarding the use of vaccines in patients with RA starting or currently receiving DMARDs or biologic agents*

Accepting a “New Normal”…  RA

is a potentially disabling disease, but doesn’t have to be a “life-changing” disease.  Finding the right balance with REST and EXERCISE.  Occupational and Physical Therapy can be beneficial

Rheumatoid arthritis and pregnancy 

Possible remission vs. possible disease exacerbation.  In general, all DMARDs should be discontinued 3 to 6 months prior to conception.  Limited data  Arthritis, Pregnancy and the Path to Parenthood - www.suzieedwardmay.com

The future of RA therapy  Stem

cell research  Further laboratory research to identify RA ‘triggers”  Newer targeted medications  Enhanced joint replacement surgery  Potential vaccines

Questions?  [email protected]