Rheumatoid Arthritis Lecture.ppt

RHEUMATOID ARTHRITIS
Melanie Laine, PharmD
PGY1 Pharmacy Resident
University of Kentucky HealthCare
April 22, 2015

LEARNING OBJECTIVES
• Recognize the symptoms and characteristics of
rheumatoid arthritis (RA)
• Compare and contrast available pharmacologic
therapies for RA
• Design individualized therapeutic regimens and
monitoring plans for patients with RA

• Chronic, systemic
inflammatory disease
• Autoimmune
• Characterized by
symmetrical
inflammation of joints
Wahl K and Schuna AA. Chap 72. Rheumatoid
Arthritis. In: Pharmacotherapy: A
Pathophysiologic Approach. 9th ed. (2014).

EPIDEMIOLOGY
• Most common systemic inflammatory disease
• Prevalence: 1-2%
• Occurrence:
 Any age
 3:1 in females
• Unknown etiology
 Interplay between genetic predisposition and
environmental triggers
Wahl K and Schuna AA. Chap 72. Rheumatoid Arthritis. In:
Pharmacotherapy: A Pathophysiologic Approach. 9th ed. (2014).
McInnes IB and Schett G. New Engl J Med. 2011; 365 (23): 2205-19.

PATHOPHYSIOLOGY
• Autoimmune disease
 Lack of differentiation between
self and non-self tissues
 Destruction of synovial and
connective tissues
• Pannus
 Inflamed, proliferating
synovium
 Invades cartilage and bone
surface  joint destruction
 Characteristic of RA
Wahl K and Schuna AA. Chap 72. Rheumatoid
Arthritis. In: Pharmacotherapy: A Pathophysiologic
Approach. 9th ed. (2014).

Vollenhoven RF. Nat Rev Rheumatol. 2009; 5 (10): 531-41.
Drug Targets:
• TNF α
• IL-1
• IL-6
• B cells
• JAK

PATHOPHYSIOLOGY
LYMPHOCYTES
PRO-INFLAMMATORY
CYTOKINES
B Lymphocytes T Lymphocytes TNF α, IL-1, IL-6, IL-17
• Origin: bone marrow
• Produce rheumatoid
factor and anticyclic
citrullinated peptide
• Attract neutrophils to
sites of injury
• Act an APCs to
stimulate T cells and
activate the immune
process
• Origin: thymus
• Produce cytokines and
cytotoxins
• Further promote
inflammation and
tissue destruction
• Stimulate
macrophages to
release prostaglandins
and cytotoxins
• Initiate and continue
inflammatory process
• Stimulate osteoclast
formation
• Suppress osteoblasts
and bone formation
APCs = antigen-presenting cells

CLINICAL PRESENTATION
• Develop over several weeks to months
 Constitutional symptoms: fever, fatigue, weakness, loss of
appetite
 Tenderness, warmth, and swelling over affected joints
 Muscle aches and stiffness
 Joint deformity (late disease)
• Symmetrical joint involvement
• Joint pain and stiffness > 6 weeks

CLINICAL PRESENTATION
• Morning stiffness > 30 minutes
• Decreased range of motion and grip strength
• Stenosing flexor tenosynovitis (trigger fingers)
• Extraarticular involvement
• Laboratory abnormalities

EXTRAARTICULAR INVOLVEMENT
• Rheumatoid nodules
• Vasculitis
• Pulmonary complications
• Ocular involvement
 Keratoconjunctivitis sicca
• Sjogren’s syndrome
• Cardiac involvement
• Felty’s syndrome
 Splenomegaly
 Neutropenia
 Thrombocytopenia
• Lymphadenopathy
• Rare complications
 Kidney injury
 Amyloidosis

LABORATORY FINDINGS
• ↑ erythrocyte sedimentation rate (ESR)
• ↑ C-reactive protein (CRP)
• (+) Rheumatoid factor (RF)
• (+) Anticyclic citrullinated peptide (anti-CCP)
• Synovial fluid: turbid with many leukocytes
• Radiographic imaging

2010 ACR CLASSIFICATION CRITERIA
Aletaha D et al. Arthritis Rheum. 2010; 62 (9): 2569-81.
> 6/10 for classification of definite RA SCORE
Joint involvement 1 large joint 0
2-10 large joints 1
1-3 small joints 2
4-10 small joints 3
> 10 joints (at least one small) 5
Serology (> 1) Negative RF and negative anti-CCP Abs 0
Low-positive RF or low-positive anti-CCP Abs 2
High-positive RF or high-positive anti-CCP Abs 3
Acute phase reactants Normal ESR and normal CRP 0
Abnormal ESR or abnormal CRP 1
Symptom duration < 6 weeks 0
> 6 weeks 1
Large joints = shoulders, elbows, hips, knees, ankles
Small joints = metacarpophalangeal joints, proximal interphalangeal joints, metatarsophalangeal joints, thumb, wrists

RA VERSUS OSTEOARTHRITIS
• Morning stiffness > one
hour, worse with activity
• ↑ incidence females (3:1)
• ~ Age
• ↑ ESR
• Systemic symptoms
• ~ Obesity
• Wrists, hands, feet
• Symmetrical
OSTEOARTHRITIS
• Morning stiffness < 30
minutes, resolves with activity
• Equal gender prevalence
• ↑ Age
• Normal ESR
• Local symptoms
• ↑ Obesity
• Hands, knees, hips, spine
• Asymmetrical

PREDICTORS OF WORSE OUTCOME
• Older age
• Female gender
• Genotype (HLA-DRB1)
• Worse physical functioning
• Cigarette smoking
Saag KG et al. Arthritis Rheum. 2008; 59 (6): 762-84.

PROGNOSTIC FACTORS
• Functional limitation
• Extraarticular disease
• RF and/or anti-CCP antibody positivity
• Bony erosions on radiographic imaging
• Management of comorbidities
Disease duration and activity are also important when assessing prognosis

COMORBIDITIES
• Must be addressed in order to decrease morbidity
and mortality
• Comorbidities with greatest impact:
 Infection
 Osteoporosis
 Cardiovascular disease
O’Dell JR. New Engl J Med. 2004; 350 (25): 2591-602.

PATIENT CASE #1
• MJ is a 36 year old female who presents to her PCP c/o joint
pain in her hands and wrists (~6 joints) that has persisted for
the past 2 months. She receives little relief from OTC NSAIDs,
and on examination, the joints on both hands appear red and
swollen. Laboratory testing shows positive RF and anti-CCP
antibodies (high-positive) and ↑ ESR.
What signs and symptoms are indicative of RA?
What is MJ’s score using the 2010 ACR classification criteria for
definite RA?

GOALS OF TREATMENT
• Control disease activity and joint pain
• Maintain function in daily activities
• Slow destructive joint damage
• Achieve and maintain disease remission
Improve or maintain functional status and quality of life

TREATMENT OVERVIEW
• Non-pharmacologic therapy
• Pharmacologic therapy
 Non-disease modifying drugs
 NSAIDs
 Corticosteroids
 Disease-modifying antirheumatic drugs (DMARDs)
 Non-biologic
 Biologic

NON-PHARMACOLOGIC
• Rest
• Physical and occupational therapy
• Assistive devices
• Weight reduction
• Surgery

Non-disease modifying drugs
PHARMACOLOGIC THERAPY

NSAIDs
• Analgesic and anti-inflammatory properties
 Rapid symptomatic relief for pain and stiffness
• Adverse effects: ulcers and GI bleeding, renal
impairment, hypertension, fluid retention
• Helpful during the first few weeks until definitive
diagnosis is made
Adjunct to DMARD therapy

CORTICOSTEROIDS
• Suppress inflammatory response
 Bridge to effective DMARD therapy
 Rapid symptomatic relief
• Dose: Prednisone < 10mg PO daily
• Adverse effects: hypertension, hyperlipidemia,
hyperglycemia, fat redistribution, cataracts,
osteoporosis, etc.
Adjunct to DMARD therapy
LexiComp Online. online.lexi.com. Accessed April 12, 2015.

DMARDs
• Retard or halt the progression of RA
 Sustained suppression of inflammation
• Initiate < 3 months of symptom onset
 Improve outcomes
 Reduce mortality
• All patients except those with limited disease
• Slow onset with regard to symptom management

NON-BIOLOGIC DMARDs
• Methotrexate
• Leflunomide
• Hydroxychloroquine
• Sulfasalazine
• Minocycline

METHOTREXATE
• Folate antimetabolite  inhibits purine synthesis
 May inhibit cytokine production and stimulate
adenosine release
• Initial therapy of choice: most likely to induce
long-term response
• Dose: 7.5-15mg PO once weekly
• Onset: 2-3 weeks

METHOTREXATE
• Adverse effects: diarrhea, N/V, stomatitis, thrombocytopenia
> leukopenia, ↑ LFTs*
• Folic acid 1-3mg PO daily
 Decreases toxic effects without compromising efficacy
• Contraindications:
 Pregnancy
 Liver or kidney disease
 Alcohol use
 Blood dyscrasias
 Effusions
*Discontinue therapy if sustained increase > 2x ULN

LEFLUNOMIDE
• Inhibits pyrimidine synthesis  decreased
lymphocyte proliferation
• Similar long-term efficacy to MTX
• Dose: 100mg PO daily x 3 days, then 20mg daily
• Onset: 4 weeks

LEFLUNOMIDE
• Adverse effects: ↑ LFTs, pancytopenia
• Enterohepatic recycling prolongs elimination half
life
 Cholestyramine can rapidly decrease plasma levels
 Pregnancy
 Pre-existing liver disease

HYDROXYCHLOROQUINE
• Inhibits PMN migration and eosinophil
chemotaxis; impairs Ag-Ab reactions
• Least potent, but best tolerated
 Recommended for patients without poor prognostic
factors, low disease activity, duration < 24 months
• Dose: 200-300mg PO BID x 1-2 months, then can
decrease to 200mg daily or BID
• Onset: 6 weeks

HYDROXYCHLOROQUINE
• Adverse effects: diarrhea, N/V, ocular toxicity,
rash, alopecia
• Limited monitoring
 Vision changes from therapy

SULFASALAZINE
• Prodrug  5-aminosalicylic and sulfapyridine
 MOA unknown
• First DMARD: similar efficacy to MTX
• Dose: 500mg-1000mg PO daily initially, then
1000mg PO BID (max 3000mg daily)
• Onset: 8 weeks
• Use limited by adverse effects

SULFASALAZINE
• Adverse effects: diarrhea, N/V, anorexia, rash
urticaria, serum sickness*, alopecia, stomatitis, ↑
LFTs, myelosuppression
• Contraindications: sulfa allergy
• Drug interactions
 Antibiotics
 Iron supplements
 Warfarin
*Treat with antihistamines ± corticosteroids

MINOCYCLINE
• Tetracycline antibiotic; may inhibit
metalloproteinases
• Mild disease without poor prognostic factors
 Limited data
• Dose: 100-200mg PO daily
• Adverse reactions: minimal

PATIENT CASE #1
• MJ is diagnosed with RA. After diagnosis, she is referred
to a rheumatologist who wishes to start her on a DMARD
as soon as possible. She does not have any pertinent
PMH and has a sulfa allergy. She also mentions that she
and her husband are trying to get pregnant.
Out of the non-biologic DMARDs, what is the best option for
initial therapy for MJ?

SUMMARY: NON-BIOLOGICS
DRUG DOSE MONITORING
Methotrexate PO/IM: 7.5-15mg weekly
• Baseline LFTs, CBC, SCr/BUN,
hepatitis panel
• CBC, AST/ALT, albumin q1-2 months
Leflunomide
PO: 100mg daily x 3 days, then 10-20
daily OR 10-20 mg daily w/o LD
• Baseline LFTs, CBC
• CBC, AST/ALT monthly, then q6-8
weeks
Hydroxychloroquine
PO: 200-300mg BID x 1-2 months,
then can ↓ to 200mg daily or BID
• Baseline eye exam
• Ophthalmoscopy q9-12 months
Sulfasalazine
PO: 500mg BID, then ↑ to 1000mg
BID
• Baseline CBC
• CBC weekly x 1 month, then q1-2
months
Minocycline PO: 100-200mg daily
• LFTs, BUN/SCr with long-term
treatment

BIOLOGIC DMARDs
• Infliximab
• Etanercept
• Adalimumab
• Golimumab
• Certolizumab
• Anakinra
• Abatacept
• Ritubimab
• Toclizumab
• Tofacitinib

BIOLOGIC DMARDs
• Genetically engineered protein molecules that
target pro-inflammatory cytokines or lymphocytes
• Not considered first line therapy
 High disease activity with poor prognostic factors
• May be effective when non-biologic DMARDs
have failed
• Expensive
Singh JA et al. Arthrit Care Res. 2012; 64 (5): 625-39.

TNF α INHIBITORS
• Inactivate TNF α, preventing interaction with receptor
and inhibiting immune cell activation
• Increased infection risk
 Tuberculosis: must test prior to initiation
 Avoid live vaccines
• Multiple sclerosis-like illness
• Increased risk for lymphoma and other cancers
• Contraindication: NYHA class III-IV heart failure

TNF α INHIBITORS
DRUG DOSE ADVERSE REACTIONS COMMENTS
Infliximab IV: 3 mg/kg at 0, 2, & 6
weeks, then q8 weeks
Infusion reactions: flu-like
symptoms
Given with MTX to prevent
Ab formation (superior to
monotherapy)
Etanercept SQ: 50mg once weekly OR
25mg two times a week
Local injection-site
reactions
• Avoid in MS
• Preferred with HCV
• May slow erosive
disease > MTX
Adalimumab SQ: 40mg every 2 weeks Local injection-site
reactions
Less antigenic than
infliximab
Golimumab SQ: 50mg once a month
IV: 2 mg/kg at 0 & 4 weeks,
then q8 weeks
Local injection site
reactions
Given in combination with
MTX
Certolizumab SQ: 200mg at 0, 2, & 4
weeks, then every 2 weeks
• Local injection site
reactions
• Nausea
Given as monotherapy or in
combination with MTX

B CELL DEPLETING AGENT
• Rituximab
• Depletes peripheral B cells by binding CD20
 Recovery takes several months – intermittent therapy
• For patients who have failed MTX therapy or TNF
α inhibitors (second line)
 Also preferred in recently treated solid malignancy and
PMH of treated lymphoma or skin melanoma
• Better outcomes when given with MTX

B CELL DEPLETING AGENT
• Dose: 1000mg IV at 0 and 2 weeks
• Adverse reactions:
 Infusion reactions – pre-medicate*
 HBV reactivation – screen prior to initiation
• Black box warning for fatal infusion reactions
*Acetaminophen, diphenhydramine, and methylprednisolone 30 minutes prior to infusion

CD80/CD86 CO-STIMULATOR
MODULATOR
• Abatacept
• Binds to antigen-presenting cells, preventing
interaction with T cells and subsequent T cell
activation
α inhibitors
 Response rate of 50% in clinical trials

CD80/CD86 CO-STIMULATOR
MODULATOR
• Weight-based dosing: IV infusion at 0, 2, & 4 weeks,
then q4 weeks
 < 60kg: 500mg
 60-100kg: 750mg
 > 100kg: 1000mg
 Alternative: 125mg SQ weekly
• Adverse reactions: headache, nausea,
nasopharyngitis, infection, infusion reactions

INTERLEUKIN-6 INHIBITOR
• Tocilizumab
• IL-6 receptor antagonist, reducing production of
cytokines and acute phase reactants
α inhibitors
• Can be as monotherapy or in combination with
MTX

• Dose:
 IV: 4-8 mg/kg q4 weeks (max dose 800mg)
 SQ: 162mg every other week (< 100kg) or 162mg
weekly (> 100kg)
• Adverse reactions: infusion reactions,
hyperlipidemia, ↑ LFTs*, infection
• Monitoring: baseline and periodic CBC and LFTs

• Anakinra
• IL-1 receptor antagonist, preventing migration of
inflammatory leukocytes to tissues
• Literature suggests less efficacy
 No longer included in guideline recommendations
 Patients who fail MTX and TNF α inhibitors
• Should not be used with TNF α inhibitors

• Dose: 100mcg SQ daily
• Adverse reactions: local injection-site reactions,
headache, arthralgias, neutropenia (rare),
infection
• Monitoring:
 Baseline: TB test, PMN count
 PMN count monthly x 3 months, then q3 months for
one year

JANUS KINASE (JAK) INHIBITOR
• Xeljanz (tofacitinib)
• FDA approved in 2012
 Moderate to severe RA refractory to MTX
• Versus placebo and MTX: significantly less
symptoms and improved physical function
• Dose: 5mg PO BID
Pfizer Laboratories, Inc. Xeljanz (tofacitinib) Package Insert.
Fleischmann R et al. New Engl J Med. 2012; 367 (6): 495-507.
Lee EB et al. New Engl J Med. 2014; 370 (25): 2377-86.

JANUS KINASE (JAK) INHIBITOR
• Adverse effects: diarrhea, headache, infections,
malignancy
• Must test for tuberculosis and hepatitis B/C prior
to therapy initiation
• Monitoring:
 Baseline: hepatitis panel, TB test, LFTs, CBC, Hgb/Hct
 Lipids in 4-8 weeks then periodically
 CBC, Hgb/Hct q3 months
Pfizer Laboratories, Inc. Xeljanz (tofacitinib) Package Insert.

OTHER AGENTS
• Gold salts, azathioprine, D-penicillamine,
cyclosporine, and cyclophosphamide
• Infrequently used or not recommended
 Toxicity
 Lack of long-term benefit
 Both

COMBINATION THERAPY
• Typically effective when monotherapy fails
• May be appropriate initially in moderate to high
disease activity
• Biologics in combination with MTX may be more
effective than biologic monotherapy
• Combination therapy with > one biologic is not
recommended

PATIENT CASE #2
• JF is a 63 year old female who was recently diagnosed
with RA. PMH significant for osteoporosis. She reports
difficulty performing her daily activities and painful,
swollen joints that keep her up at night. She has high
disease activity with the presence of bony erosions on
imaging.
What RA treatments would you consider for JF?
What other recommendations might you make?

EVALUATION OF THERAPY
• Clinical signs and symptoms of RA
 Swelling, warmth, and tenderness
 Pain, stiffness, and functional limitations
 Radiographic imaging
• Adverse effects and other drug monitoring
• American College of Rheumatology Improvement Criteria
 ACR20: 20% improvement in disease activity
 ACR50: 50% improvement in disease activity

REFERENCES
1) Aletaha D et al. Arthritis Rheum. 2010; 62 (9): 2569-81.
2) Fleischmann R et al. New Engl J Med. 2012; 367 (6): 495-507.
3) Lee EB et al. New Engl J Med. 2014; 370 (25): 2377-86.
4) LexiComp Online. online.lexi.com.
5) McInnes IB and Schett G. New Engl J Med. 2011; 365 (23): 2205-19.
6) O’Dell JR. New Engl J Med. 2004; 350 (25): 2591-602.
7) Pfizer Laboratories, Inc. Xeljanz (tofacitinib) Package Insert.
8) Saag KG et al. Arthritis Rheum. 2008; 59 (6): 762-84.
9) Singh JA et al. Arthrit Care Res. 2012; 64 (5): 625-39.
10) Vollenhoven RF. Nat Rev Rheumatol. 2009; 5 (10): 531-41.
11) Wahl K and Schuna AA. Chap 72. Rheumatoid Arthritis. In: Pharmacotherapy:
A Pathophysiologic Approach. 9th ed. (2014).

melanie.laine@uky.edu

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