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RA (Signs/symptoms, Etiology/pathophysiology, Treatment, Goals of therapy,…
RA
Signs/symptoms
Prolonged morning stiffness (Normally >30 mins)
Joint Swelling
Presence of warmth with or without pain
Hands, Feet, Wrists, Ankles are most commonly affected
Subluxations and deformities possible with advanced disease
Decreased functionality
Etiology/pathophysiology
Changes in synovial tissue
Immune cascade dysregulation (overstimulation of innate immune system)
Etiology unknown, thought to be genetic and environmental
autoimmune origin: results in cell proliferation, inflammation, and destruction of tissues and fluids throughout one’s own body.
T cell mediated
Treatment
Initial Treatment: Methotrexate
(DMARD of Choice)
MOA
Unknown in RA, but may have effect on immune function
ADRs
GI upset
Thrombocytopenia
Stevens-Johnson sydrome
Hepatic fibrosis
Regimen
Initial: 7.5 mg subQ once weekly
Adjust dose gradually
Doses > 20 mg/wk increase incidence of toxic reaction
PK/PD/PGX
Oral bioavailability: 23-95% (dose dependent), subQ bioavailability: 100%
Food reduces Cmax by 50% and delays absorption
50% protein binding
Vd: 0.4-0.8 L/kg
Hepatic metabolism
Renal excretion
Half-life: 3-10 hours, longer with doses > 30 mg
Monitoring
Prior to initiation: complete blood count (CBC) with differential, alanine transaminase (ALT), aspartate transaminase (AST), and renal function
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
Duration
Lifelong
Warnings/precautions/contraindications
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
Interactions
Avoid other immunosuppressants
Methotrexate peak serum levels may be decreased if taken with food. Management: Administer without regard to food.
Special populations
Renal Impairment:
CrCl 10 to 50 mL/minute: Administer 50% of dose.
CrCl <10 mL/minute: Avoid use.
Hepatic Impairment: Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose; Bilirubin >5 mg/dL: Avoid use
Pediatric: Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Methotrexate doses >500 mg/m2 require leucovorin calcium rescue.
Geriatric: Oral: Initial: 5 to 7.5 mg per week.
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.
Education/counseling
May take up to 6 months to feel full effect
May be more prone to getting infections - wash hands more
May bleed more easily, use a soft toothbrush and electric razor
Avoid alcohol
May affect fertility
Determinants of health
Tablets (Methotrexate (Anti-Rheumatic) Oral)
2.5 mg (per each): $4.05
Alternate: Switch to another DMARD or biologic DMARDs or combination of DMARD
Monotherapy DMARD is preferred over combination DMARD therapy
Drug Class non-TNF biologic
abatacept
rituximab
tocilizumab
Drug Class: TNFi biologics
adalimumab
infliximab
golimumab
etanercept
certolizumab
tofacitinib
leflunomide
Non-pharmacologic
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
Hydroxychloroquine
PK/PK/PGX
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%
MOA
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.
Adverse drug reactions/allergies
common: nausea
serious: retinal disorder, EPS, QTc prolongation, hypoglycemia
Regimen
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).
Monitoring (TVS: target concentrations, vitals/labs, and signs/symptoms) Watch the TVS!
CBC with differential, liver function, renal function, blood gluose
Duration
Lifetime
Warnings/precautions/contraindications
Contraindicated with hypersensitivity reactions. Warnings/precaution include cardiovascular effects, skin reactions, blood disorders, monitor for hypoglycemia, myopathy and neuromyopathy, and renal toxicity
Interactions (drug-drug, -food/drink, and –disease)
Special populations (age, body composition, pregnancy/lactation, and organ dysfunction)
Use caution with dose selection in elderly, renally impaired, hepatically impaired
Pregnancy/breast feeding: fetal and infant risk cannot be ruled out
Education/counseling
Counsel on side effects: vertigo, tinnitus, visual field defects, N & V, fatigue, decreased appetite, headaches, dizziness, irritability
Report symptoms of toxicity (rash, visual changes)
Take with a meal or glass of milk
Do not take antacids or kaolin within 4 hours of this drug
Determinants of health
Cost: relatively inexpensive, ~$20 for 30 tablets
May not be in stock due to increased demand as a result of COVID
Sulfasalazine
PK/PD/PGX
Onset of action: >4 weeks
Absorption: oral <15% as parent drug
Protein binding: >99% to albumin
Distribution: Vd: 7.5 ± 1.6 L
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)
MOA
Mechanism Unknown; maybe chemical mediator response from leukotrienes
ADR/allergies
stomach pain, upset stomach, vomiting, low appetite
skin rash
headache
leukopenia/thrombocytopenia
diziness
oligospermia
Regimen (LOT and FAR):
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)
Maintenance dose: 2g/day in 2 divided doses
Monitoring
liver function tests
CBC with differential
periodic urinalysis
signs of anaphylaxis and infection
Duration
Indefinite
Warnings/Precautions/Contraindications
G6PD deficiency may result in Anemia
Serious infections, like sepsis and pneumonia
CNS Effects: Deaths occurred from CNS and neuromuscular changes
Dermatologic Reactions: SJS, exfoliative dermatitis, TEN
Hepatic necrosis
Contraindication: If have hypersensitivity to med or its metabolites
Interactions
Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates.
Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates
BCRP/ABCG2 substrate
Education/Counseling
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)
Special Population
No dose adjustment with hepatic or renal impairment
use with caution in hepatic and renal patients
not preferred in pregnancy (crosses the placenta)
Determinants of Health
Low cost: $13 for 30 tablets
Goals of therapy
Primary Goal of Treatment:
targeting disease remission, low disease activity ultimately aiming at enhancing quality of life
.
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)
EARLY GOAL:
Apply aggressive treatment as early as possible
as no pharmacologic or non-pharmacologic treatments can currently reverse joint damage.
Risk Factors
RA is believed to be an independent risk factor for coronary artery disease; associated with an increased risk of cardiovascular mortality
Nongenetic or environmental factors possibly associated with RA include cigarette use, coffee consumption, and obesity
Genetic Factors
Diagnosis
score of 6/10 on ACR/EULAR Rheumatoid Arthritis Classification Criteria
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!)
Diseases with similar clinical features have been excluded
The duration of symptoms is more than six weeks.
Monitoring
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
Assess disease activity, disease manifestations, disease progression, joint injury, disability, and complications of the disease and to monitoring for adverse effects of medications
Extra-articular manifestations: systemic signs such as fever, anorexia, malaise, weight loss, and symptoms of CV disease
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.
monitoring of acute phase reactants such as CRP and ESR can be useful in assessing inflammation