Transcript Treatment

Rheumatoid Arthritis
Sarah Cotner, PharmD
PGY1 Pharmacy Resident
[email protected]
Learning Objectives
• Recognize signs and symptoms of
rheumatoid arthritis (RA)
• Describe the pathophysiology of RA
• Discuss therapies available for treatment
of RA
DISEASE STATE OVERVIEW
Rheumatoid Arthritis
• Autoimmune,
inflammatory disease
characterized by
symmetrical joint
involvement
• Affects three times as
many women as men
• Increased prevalence
with advancing age
Wahl K, Schuna AA. Chapter 72. Rheumatoid Arthritis. In: Pharmacotherapy: a
pathophysiologic approach. 9th ed. (2015).
Etiology
Genetics
Environment
Etiology
Genetic Factors
• Female
• Anti-citrullinated protein
antibodies (ACPA)
• Rheumatoid factor (RF)
• Human leukocyte antigen
(HLA)-DRB1, HLA-DRB4
Environmental Factors
• Advanced age
• Smoking
• Silica exposure
• Comorbidities
– Diabetes mellitus type 1 and
2, inflammatory lung disease,
dyslipidemia
• Lower education level
Environmental Factors
Controversial Factors
• Reproductive levels and sex
hormone levels
– Menstrual cycle, parity,
pregnancy, age at menopause
– Oral contraceptive use
– Testosterone levels
• Obesity
• Periodontal disease
• Infection
Protective Factors
• Fish oil, olive oil
• Alcohol consumption
• Schizophrenia
Pathophysiology
Antiinflammatory
cytokines
Proinflammatory
cytokines
Synovitis
• Infiltration of
inflammatory cells into
the synovial tissue
• Local tissue
microenvironment
changes
• Inflamed, proliferating
tissue termed pannus
Wahl K, Schuna AA. Chapter 72. Rheumatoid Arthritis. In: Pharmacotherapy: a
pathophysiologic approach. 9th ed. (2015).
Immune System Activation
Rodgers JM. Yale J Biol Med. 2012;85(4):447-468.
Immune System Involvement
Wahl K, Schuna AA. Chapter 72. Rheumatoid Arthritis. In: Pharmacotherapy: a
pathophysiologic approach. 9th ed. (2015).
Promotion of Extra-articular Complications
McInnes IB. N Engl J Med. 2011;635:2005-19
Clinical Presentation
• Symmetrical synovitis in small joints
– metacarpophalangeal, proximal interphalangeal,
second through fifth metatarsophalangeal,
thumb interphalangeal, wrist
• Warm and tender joints with decreased
range of motion
• Morning stiffness > 30 minutes
Joint Involvement
DiPiro JT. Pharmacotherapy.
Radiographic Changes
DiPiro JT. Pharmacotherapy.
Laboratory Findings
•
•
•
•
•
•
•
Anemia
Thrombocytosis
↑ erythrocyte sedimentation rate (ESR)
↑ C-reactive protein (CRP)
Positive RF
Positive ACPA
Synovial fluid: turbid with many leukocytes
Disease Course
• Gradual onset
– Progressive joint structure changes
• Extra-articular manifestations
– Rheumatoid nodules
– Interstitial lung disease
– Cardiovascular: vasculitis, PVD, pericarditis
– Felty’s syndrome
– Ocular inflammation
DIAGNOSIS
RA Classification Criteria
• Collaboration of the American College of
Rheumatology (ACR) and the European
League Against Rheumatism (EULAR)
• 4 different domains in scoring algorithm
• Aimed at newly presenting patients who:
– Have ≥ 1 joint with clinical synovitis
– Synovitis is not better explained by another
disease
2010 ACR/EULAR Criteria
Characteristic
Score
A. Joint involvement
1 large joint
0
2-10 large joints
1
1-3 small joints (with or without large joint involvement)
2
4-10 small joints (with or without large joint involvement)
3
>10 joints (at least one small joint)
5
B. Serology
(-) RF and (-) ACPA
0
Low (+) RF or low (+) ACPA
2
High (+) RF or high (+) ACPA
3
2010 ACR/EULAR Criteria (cont)
Characteristic
Score
C. Acute-phase reactants
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
D. Duration of symptoms
<6 weeks
0
>/= 6 weeks
1
Score of characteristics A through D
of ≥6 of 10 gives diagnosis of RA
Disease Activity Measures
• ACR endorses use of any of 6 different
activity measurement tools
Treatment Goals
Maintain function for activities of daily living
Maximize quality of life
Prevent joint destruction
Control disease activity
Induce remission of disease
Nonpharmacologic Therapy
TREATMENT
Nonpharmacologic Treatment
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Smoking cessation
Rest
Physical therapy, occupational therapy
Weight loss
Surgery
– Tenosynovectomy, tendon repair, joint
replacement
Non-disease modifying therapy
TREATMENT
NSAIDs
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•
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Anti-inflammatory, analgesic effects
Inhibition of COX-1 and COX-2
No disease modification
Common products
– Celeboxib, ibuprofen, naproxen
Corticosteroids
• Controls RA symptoms quickly
• Potent inhibitory effects of proinflammatory cytokines  some disease
modifying activity (anti-erosive)
• Useful for early disease before DMARD
activity present, acute flares, combination
maintenance therapy
• Long-term adverse events limit use
Corticosteroids (cont)
• Systemic
– Prednisone
– Prednisolone
– Methylprednisolone
sodium succinate
– Methylprednisolone
acetate
• Intra-articular
– Triamcinolone acetonide
Proposed
Dosing
Nomenclature
Dose per day in
prednisone
equivalents
Low dose
≤7.5 mg
Medium dose
>7.5 mg, ≤30 mg
High dose
>30 mg, ≤100 mg
Very high dose
>100 mg
Pulse therapy
≥250 x 1-3 days
Nonbiologic disease modifying antirheumatic drugs
(nonbiologic DMARDs)
TREATMENT
Methotrexate (MTX)
Mechanism of Action
• dihydrofolate reductase
inhibitor
– Inhibition purine synthesis
– Inhibition of cytokine
production
– Increase of adenosine
Dosing and Administration
• Initiation: 7.5 mg po qweek
or 2.5 mg bid three days per
week, titrate up by 2.5 mg
q2weeks
• Consider parenteral admin
with doses ≥ 15 mg
• Combine with folic acid
supplementation
Nonbiologic DMARD of choice
Methotrexate (MTX)
PK Considerations
• Variable oral absorption,
less reliable in high doses
• 35-50% protein bound
• Onset of action 2-3 weeks
• 80% excreted renally as
unchanged drug
Adverse Events
• Folic acid deficiency
• Gastrointestinal toxicity
– Stomatitis, N/V/D
• Myelosuppression
• Hepatotoxicity
• Pulmonary fibrosis,
pneumotosis
• Pregnancy category X
Leflunomide
Mechanism
of Action
Dose
Adverse
Events
• Dihydroorotate dehydrogenase inhibitor
• Inhibition of pyrimidine synthesis,
lymphocyte production
• Loading dose: 100 mg daily x 3 days
• 20 mg po once daily
• Gastrointestinal toxicity
• Hepatotoxicity
• Alopecia
• Pregnancy Category X
Hydroxychloroquine
Mechanism
of Action
• Proposed that as a weak base drug
increases pH  attenuates antigen
processing
Dose
• Initial dose: 200-300 mg po bid
• Maintenance: 200 mg daily or bid
Adverse
Events
• Gastrointestinal
• Ocular toxicity
• Dermatologic
Sulfasalazine
Mechanism of Action
• Poorly understood
• Prodrug
• Broken down in gut into 5aminosalicylic acid (5-ASA)
and sulfapyridine
• 5-ASA has antiinflammatory activity
Dosing and Administration
• Start at 0.5 – 1 g po daily
• Increase weekly to 1 g bid
• Max: 3 g per day
Clinically significant
interaction with warfarin
Sulfasalazine Adverse Events
• Gastrointestinal
– N/V/D, anorexia
• Dermatologic
– Rash, urticaria
• Myelosuppression
• Yellow/orange skin, urine
• Decreased fertility in men
Biologic disease modifying antirheumatic drugs
(Biologic DMARDs)
TREATMENT
Overview of Biologic DMARDs
• Mechanisms: neutralization of cytokines,
depletion of B cells, prevention of T cell
activation
• Quick onset of action (days to weeks)
• Expensive, requires prior authorization
Considerations for Use
Tuberculosis Screening
Hepatitis Screening
Vaccinations
TNF-α Inhibitors
• Block proinflammatory activity of TNF-α
• Class adverse effects
– Infection (TB, opportunistic infections, hepatitis)
– Malignancy
– Psoriasis
– Lupus-like syndrome
– CNS myelination disorders
– Heart failure
– Hepatotoxicity
Anti-TNFα Products
Etanercept
• Fusion protein of two soluble TNF receptors
• 50 mg subcutaneous qweek or 25 mg 2x/week
Infliximab
• Chimeric antibody
• 3 mg/kg IV at weeks 0, 2, and 6, then q8weeks
Adalimumab
Golimumab
Certolizumab
• Human antibody
• 40 mg subcutaneous q14 days
• Human antibody
• 50 mg subcutaneous once monthly
• Human antibody
• 400 mg subq at week 0, 2, and 4, then 200 mg q2weeks
Abatacept
• Fusion protein
• Mechanism: costimulation modulator
– Blocks CD80/86 from its counterpart CD28 to
inhibit T cell activation
• Weight based IV infusion or subcutaneous
injection
• Adverse effects
– URI/nasopharyngitis, infection, nausea,
malignancy, infusion related reactions
Rituximab
• Chimeric antibody
• Mechanism: binds to CD20 on mature B cells
– Peripheral B cell depletion
• Dose: 1 g IV q2weeks x 2
– Repeat every 6-8 weeks as needed
– Premedication necessary
• Serious adverse effects
– Cardiac arrhythmias, SJS, PML
Tocilizumab
• Human antibody
• Mechanism: IL-6
receptor antagonist
– Blocks cytokine from
binding to receptor
• Dose: 4 mg/kg IV
q4weeks
– May escalate to 8 mg/kg
if needed
• CYP3A4 inducer
• Adverse effects
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–
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GI perforation
Elevated LFTs
Dyslipidemia
Infusion reactions
Tofacitinib
• Mechanism: tyrosine kinase (JAK) inhibitor
– JAK mediates cytokine signal transduction
• Dose: 5 mg po bid
– 5 mg daily in renal dysfunction, concomitant
3A4 inducers, moderate hepatic impairment
• Adverse effects
– Serious infection, malignancy, elevated LFTs,
dyslipidemia, GI perforation, headache, diarrhea
Other Agents
• Infrequently used
– Minocycline
– Anakinra
• Not recommended
– Gold salts
– Azathioprine
– D-penicillamine
– Cyclosporine
– Cyclophosphamide
American College of Rheumatology
GUIDELINE TREATMENT
RECOMMENDATIONS
2015 Early RA Guidelines
DMARD naïve
DMARD
monotherapy
Moderate or high
disease activity
TNF inhibitor ± MTX
Combination of
traditional DMARDs
Moderate or high
disease activity
Non-TNF biologic ±
MTX
2015 Established RA Therapy
Combination of traditional DMARDs
TNF inhibitor ± MTX
Non-TNF biologic ± MTX
Tofacitinib ± MTX
Patient Case
• 33 YOF presenting to rheumatology clinic for
follow up with generalized arthralgias,
fatigue, and morning stiffness.
– Diagnosed with RA 3 months ago
– Initiated oral methotrexate, naproxen
• DAS28
– 6.82 (down from 7.59)
Treatment Plan Adjustment?
• Patient expresses desire to start a family
within the next year. What is your
recommendation for her RA therapy?
a)
b)
c)
d)
Continue regimen as is
Discontinue MTX, initiate leflunomide
Discontinue MTX, initiate etanercept
Discontinue all treatment while patient starts
family
Treatment Pearls
• “Treat-to-target”
– Treatment target is low disease activity or
remission
• Utilize low dose glucocorticoids as needed
• Continue treatment in low disease activity
• Consider tapering treatment in remission
– Do not discontinue
References
1.
2.
3.
4.
5.
Wahl K, Schuna AA. Chapter 72. Rheumatoid Arthritis. In:
Pharmacotherapy: a pathophysiologic approach. 9th ed. (2015).
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham
CO, et al. 2010 Rheumatoid arthritis classification criteria.
Arthritis & Rheumatism. 2010;62(9):2569-2581.
Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi R, Michaud
K, et al. Arthritis & Rheumatism. 2012;64(5):640-647.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis.
N Engl J Med. 2011;365:2205-19.
Ferreira JF, Mohamed AA, Emery P. Glucocorticoids and
rheumatoid arthritis. Rheum Dis Clin N Am . 2016;46:33–46
SUPPLEMENTAL SLIDES
Tuberculosis (TB) Screening
• Need initial tuberculin skin test (TST) or
interferon-release gamma assay (IGRA)
• CXR if TST or IGRA positive
– Negative  presumed latent TB, treat x 1 month
– Positive  sputum for AFBs to rule out active TB
• Must complete treatment for active TB prior
to initiation of biologics or tofacitinib
Hepatitis Screening
• Necessary prior to treatment
• If hepatitis B or C positive, refer for active
anti-viral therapy
• Treat these patients no differently than
hepatitis negative patients
• Must monitor viral load regularly
– If less immunosuppression is needed, consider
sulfasalazine or hydroxychloroquine
Vaccinations in Biologic DMARDs
Prior to initiation
• Killed/inactivated vaccines permitted
• Live/attenuated vaccines permitted
• Must wait 2 weeks after injection to initiate
After initiation
• Killed/inactivated vaccines permitted
• Live/attenuated vaccines not recommended