RA
Etiology/pathophysiology
Treatment
Goals of therapy
Signs/symptoms
Diagnosis
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score of 6/10 on ACR/EULAR Rheumatoid Arthritis Classification Criteria
Prolonged morning stiffness (Normally >30 mins)
Changes in synovial tissue
Immune cascade dysregulation (overstimulation of innate immune system)
Primary Goal of Treatment: targeting disease remission, low disease activity ultimately aiming at enhancing quality of life.
Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody
Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR)
joint involvement (at least one joint required, more joints = more points!)
The ACR as well as the EULAR guidelines suggest a treat-to-target approach when treating patients with RA rather than a nontargeted treatment approach. This approach to treatment suggests that if remission cannot be achieved, low disease activity is an acceptable alternative target. (Textbook for 630, Ch 107)
Diseases with similar clinical features have been excluded
Initial Treatment: Methotrexate (DMARD of Choice)
The duration of symptoms is more than six weeks.
Alternate: Switch to another DMARD or biologic DMARDs or combination of DMARD
EARLY GOAL: Apply aggressive treatment as early as possible as no pharmacologic or non-pharmacologic treatments can currently reverse joint damage.
Joint Swelling
Presence of warmth with or without pain
Hands, Feet, Wrists, Ankles are most commonly affected
Non-pharmacologic
Monitoring
Risk Factors
Subluxations and deformities possible with advanced disease
Etiology unknown, thought to be genetic and environmental
Decreased functionality
RA is believed to be an independent risk factor for coronary artery disease; associated with an increased risk of cardiovascular mortality
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Patient education
●Psychosocial interventions
●Rest, exercise, and physical and occupational therapy
●Nutritional and dietary counseling
●Interventions to reduce risks of cardiovascular disease, including smoking cessation and lipid control
●Screening for and treatment of osteoporosis
●Immunizations to decrease risk of infectious complications of immunosuppressive therapies
Nongenetic or environmental factors possibly associated with RA include cigarette use, coffee consumption, and obesity
Monotherapy DMARD is preferred over combination DMARD therapy
MOA
Prior to treatment initiation: 1. Baseline complete blood count, serum creatinine, aminotransferases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in all patients 2. Hep B and Hep C screening
ADRs
Regimen
PK/PD/PGX
autoimmune origin: results in cell proliferation, inflammation, and destruction of tissues and fluids throughout one’s own body.
Monitoring
Duration
Warnings/precautions/contraindications
Interactions
Special populations
Education/counseling
Determinants of health
T cell mediated
Assess disease activity, disease manifestations, disease progression, joint injury, disability, and complications of the disease and to monitoring for adverse effects of medications
Drug Class non-TNF biologic
Unknown in RA, but may have effect on immune function
Genetic Factors
Extra-articular manifestations: systemic signs such as fever, anorexia, malaise, weight loss, and symptoms of CV disease
Drug Class: TNFi biologics
subjective improvement of RA symptoms with respect to joint pain, swelling and tenderness, morning stiffness, and fatigue, as well as on a patient’s ability to perform activities of daily living.
GI upset
monitoring of acute phase reactants such as CRP and ESR can be useful in assessing inflammation
Thrombocytopenia
Stevens-Johnson sydrome
Hepatic fibrosis
Initial: 7.5 mg subQ once weekly
CI: in pregnancy and breastfeeding, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency, and preexisting hematologic disorders, such as leukopenia and thrombocytopenia
Methotrexate excretion is reduced in renal impairment and may require dose reduction or discontinuation in some cases. Excretion is also reduced in ascites or pleural effusions
adalimumab
infliximab
Prior to initiation: complete blood count (CBC) with differential, alanine transaminase (ALT), aspartate transaminase (AST), and renal function
golimumab
etanercept
Adjust dose gradually
certolizumab
Monitored every 2 to 4 weeks for 3 months after initiation or following a dose increase, then every 8 to 12 weeks during 3 to 6 months of therapy, and every 12 weeks after 6 months of therapy
abatacept
rituximab
tocilizumab
Doses > 20 mg/wk increase incidence of toxic reaction
Oral bioavailability: 23-95% (dose dependent), subQ bioavailability: 100%
tofacitinib
Lifelong
Avoid other immunosuppressants
Renal Impairment:
CrCl 10 to 50 mL/minute: Administer 50% of dose.
CrCl <10 mL/minute: Avoid use.
May take up to 6 months to feel full effect
Food reduces Cmax by 50% and delays absorption
Hepatic Impairment: Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose; Bilirubin >5 mg/dL: Avoid use
Hydroxychloroquine
Methotrexate peak serum levels may be decreased if taken with food. Management: Administer without regard to food.
50% protein binding
Vd: 0.4-0.8 L/kg
May be more prone to getting infections - wash hands more
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May bleed more easily, use a soft toothbrush and electric razor
Hepatic metabolism
Avoid alcohol
PK/PK/PGX
MOA
Adverse drug reactions/allergies
Regimen
Monitoring (TVS: target concentrations, vitals/labs, and signs/symptoms) Watch the TVS!
Duration
Warnings/precautions/contraindications
Interactions (drug-drug, -food/drink, and –disease)
Special populations (age, body composition, pregnancy/lactation, and organ dysfunction)
Education/counseling
Determinants of health
leflunomide
May affect fertility
Renal excretion
Pediatric: Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Methotrexate doses >500 mg/m2 require leucovorin calcium rescue.
Sulfasalazine
Half-life: 3-10 hours, longer with doses > 30 mg
Tablets (Methotrexate (Anti-Rheumatic) Oral)
2.5 mg (per each): $4.05
Antimalarial: Interferes with digestive vacuole function within sensitive malarial parasites by increasing the pH and interfering with lysosomal degradation of hemoglobin; inhibits locomotion of neutrophils and chemotaxis of eosinophils; impairs complement-dependent antigen-antibody reactions.
PK/PD/PGX
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MOA
ADR/allergies
Regimen (LOT and FAR):
Onset of action: Rheumatic disease: May require several weeks to respond
Absorption: Incomplete and variable (~70% [range: 25 to 100%]) (Tett 1993)
Protein binding: ~40%, primarily albumin (Tett 1993)
Metabolism: Hepatic; metabolites include bidesethylchloroquine, desethylhydroxychloroquine, and desethylchloroquine
Half-life elimination: ~40 days
Excretion: Urine (15% to 25%
Monitoring
Duration
Warnings/Precautions/Contraindications
Interactions
Use caution with dose selection in elderly, renally impaired, hepatically impaired
CBC with differential, liver function, renal function, blood gluose
common: nausea
Geriatric: Oral: Initial: 5 to 7.5 mg per week.
liver function tests
Education/Counseling
CBC with differential
Special Population
Determinants of Health
G6PD deficiency may result in Anemia
periodic urinalysis
Pregnancy/breast feeding: fetal and infant risk cannot be ruled out
serious: retinal disorder, EPS, QTc prolongation, hypoglycemia
signs of anaphylaxis and infection
Contraindicated with hypersensitivity reactions. Warnings/precaution include cardiovascular effects, skin reactions, blood disorders, monitor for hypoglycemia, myopathy and neuromyopathy, and renal toxicity
Counsel on side effects: vertigo, tinnitus, visual field defects, N & V, fatigue, decreased appetite, headaches, dizziness, irritability
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Use in rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy.
Methotrexate can cause embryo-fetal toxicity, including fetal death.
Methotrexate has the potential to cause serious adverse reactions in the breastfed infant.
This drug may change the color of urine or skin to a yellow or orange color. This is not harmful.
may cause GI upset
watch for signs and symptoms of allergic reaction (esp if have sulfa allergy)
Report symptoms of toxicity (rash, visual changes)
Mechanism Unknown; maybe chemical mediator response from leukotrienes
Take with a meal or glass of milk
stomach pain, upset stomach, vomiting, low appetite
skin rash
headache
Cost: relatively inexpensive, ~$20 for 30 tablets
Serious infections, like sepsis and pneumonia
leukopenia/thrombocytopenia
diziness
oligospermia
CNS Effects: Deaths occurred from CNS and neuromuscular changes
Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Kumar 2013). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (manufacturer’s label).
May not be in stock due to increased demand as a result of COVID
Dermatologic Reactions: SJS, exfoliative dermatitis, TEN
Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates.
Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates
BCRP/ABCG2 substrate
Hepatic necrosis
Lifetime
Contraindication: If have hypersensitivity to med or its metabolites
No dose adjustment with hepatic or renal impairment
use with caution in hepatic and renal patients
Do not take antacids or kaolin within 4 hours of this drug
Onset of action: >4 weeks
Absorption: oral <15% as parent drug
Max dose: 3g/day for adults
Initial dose: 0.5g PO daily or 1g/day in 2 divided doses; increase dose to 3g/day with careful monitoring (if inadequate response in 12 weeks)
not preferred in pregnancy (crosses the placenta)
Protein binding: >99% to albumin
Maintenance dose: 2g/day in 2 divided doses
Distribution: Vd: 7.5 ± 1.6 L
Indefinite
Low cost: $13 for 30 tablets
Metabolism: Via colonic intestinal flora to sulfapyridine and 5-aminosalicylic acid (5-ASA). Following absorption, sulfapyridine undergoes acetylation to form AcSP and ring hydroxylation while 5-ASA undergoes N-acetylation (non-acetylation phenotype dependent process); rate of metabolism via acetylation dependent on acetylation phenotype
Bioavailability: <15%
Half-life elimination: 7.6 ± 3.4 hours (prolonged in elderly patients)
Time to peak: 3 to 12 hours (mean: 6 hours)
Excretion: Primarily urine (as unchanged drug, conjugates, and acetylated metabolites); feces (small amounts)