Medications / Vaccines Flashcards
NSAID MoA
-Inhib prostaglandin synthesis via COX inhibition
MAYBE:
-Possibly inhib NFkB, neutrophil aggregation/ adhesion, thus: less superoxide, degradative enzymes, cytokines
COX1 vs COX2 selective drug examples
Nonselective: low dose ASA
-1 selective: ibuprofen, naproxen, indomethacin
-2 selective: diclofenac, meloxicam
-2 highly selective: celecoxib
** How do NSAIDs cause asthma**
– COX inhibition result in less PGE2 production (bronchodilator)
– COX inhibition → AA precursor shunting down leukotriene pathway (proinflammatory)
** Alternatives in RA if NSAID allergy**
-Tylenol
-Allergy Desensitization
-Leukotriene ANT
-COX2 selective inhibitor (Celecoxib)
-Salsalate (NSAID that does not inhib COX; decreases NFkb)
GC antiinflamm MoA
Genomic: Binds cytoplasmic GC R’s to enter nucleus increase transcription of antinflammatory proteins (IL10, IkB), and inhib proinflammatory cytokines genes (chemokines, COX2, adhesion molecules)
Nongenomic:
Antiinflamm via
- Binding lymphoctyes/monocyte membrane GC receptors
- Reducing Ca & Na cycling across cell membranes
GC fx on Innate Immune system
– Inhib NFkB → suppress Cox2 synthesis
– Inhib PG production (via lipocortin1 production)
– Causes more bradykinin degradation → vasoconstriction (less swelling/pain)
– Interfere w/ phagocytosis and cytokine production by macrophages/neutrophils
GC fx on Adaptive system
Inhib T helper, Th1> Th2 & Th17 production (anergy to TB and skin testing)
-Cause dendritic cell apoptosis
-Redistributes T cells and monocytes to tissues (monocytopenia)
-Inhib mast cell degranulation
Steroid conversion
Cortisol (hydrocortisone) 20mg =
-Prednisone = prednisolone = 5mg =
-Methylprednisolone = Triamcinolone = 4mg =
-Dexamethasone = 0.75mg
Factors affecting GC dose efficacy
– Increase clearance: Age (<12yo), hyperthyroid, nephrotic syndrome, HD,
– Increased metabolism: anticonvusants, rifampin
– Reduce absorption: aluminum/Mg antacid
– Decreased conversion: Liver dz
– Decreased metabolism: erythomycin, ketoconazole,
**GC adverse fx **
-Weight gain, increased TG and BG
-HTN
-Growth suppression (less if <0.5mg/kg)
-AVN, Osteoporosis
-Muscle weakness
-Cataract, Glaucoma
-Skin bruising, striae, hirsuttism, delayed wound repair
-PUD
-Infection: PJP, TB, fungal, herpes, CMV,
-Decreased response to vaccines
-Allergy testing affected
When to start PJP PPx
Steroid >15-20mg/d for >3-4wks
Age >60
-Disease affects lungs (GPA, DM)
-Additional immunosuppression (CYC, Ritux, TNFi)
-Low CD4
-Lymphopenia
**7 potential side-effects from intra-articular steroid injections
Pain
-Bleeding
-Nerve injury
-Post injection flare
-Infection
-Hypopigmentation
-Tendon rupture
-Tissue atrophy
-Vasovagal reaction
-Osteonecrosis
When to suspect adrenal insuff
Cushingoid
->20mg pred >3wks
->5mg >1y
-Fasting plasma cortisol <5-10ug/dL
HCQ dosing +
when to decrease dose
<5mg/kg daily
-Decrease if liver, renal dz, or tamoxifen use
** HCQ screening interval**
-Baseline
-Yearly after year 5
-Yearly after baseline if: higher than recommended dose, coexistent eye dz, >60yo, tamoxifen use, renal/liver dz
**HCQ screening regimen- what optho tests **
-Fundus examination
-Visual fields
-Spectral domain optical coherence tomography (SD OCT)
**How to reduce ocular tox in HCQ **
Prescribe correct dose
-Regular screening
-Assess for risk factors: higher than recommended dose, coexistent eye dz, >60yo, tamoxifen use, renal/liver dz
** 3 types of ocular tox from HCQ **
-Keratopathy (corneal deposits)
-Retinopathy/Bulls eye Maculopathy (binds melanin in retinal pigment epithelium damaging photoreceptors)
-Cycloplegia (Ciliary body dysfunction)
-Decreased visual acuity → blurred vision, photophobia
** HCQ nonocular side fx **
GI: N/V, diarrhea, cramps
-Derm: rash, HYPERPIGMENTATION, exacerbate psoriasis
-Cardio: Cardiomyopathy (test trop/BNP after 5-10y), QT prolongation
-CNS: H/A, dizzy, tinnitus
-MSK: Myopathy/neuropathy esp if renal insuff
-Heme: Aplastic anemia, hemolysis (rare unless G6PD def)
** HCQ MoA**
-Weak bases accumulate in acidic lysosomes in APCs (DC, macrophage)→ disrupt Ag processing, MHC2 bonding, and presentation to T cell
-Inhib binding of RNA/DNA to TLR → less IL1, IL6, IFN, and PGs
-May also inhib NFKb and COX (block PG action)
-Inhib PLT aggregation/adhesion → prevent clots
-Increase lipoprot R → lower lipid lvl
-Decrease insulin degradation → prevent DM
** SSZ side fx**
N/V, Rash
-H/A, dizziness
-Hepatotox
-AZOOSPERMIA (reversible w/i 3 mo of DC)
- Leukopenia (neutropenia, agranulocytosis)
-HYPERSENSITIVITY rxn (transaminase, fever, adenopathy, rash)
-Eosinophilic pneumonitis
-HEMOLYSIS (if G6PD def)
**SSZ MoA **
SSZ → sulfapyridine via colonic bacteria → 5ASA (stays in bowel) = local antiinflamm via:
-1. Inhib COX: less PG and leukotriene
-2. Inhib NFkB: less TNFa, IL1, osteoclast formation
-3. Upregulates adenosine → antiinflamm
-4. Inhib B cell fcn
MTX mech of administration diff
-PO = SC at doses <15mg
-SC > PO at doses >15mg
-PO split dosing better than single dosing >15mg
MTX Side fx
SERIOUS:
-Pneumonitis (must not retry MTX)
-Myelosuppression
-Teratogenicity
-Oral ulcers
-Photosensitivity
-Hepatic tox
-Flu like sx
-Nodulosis
-LCV
-Lymphoma (eg in EBV lymphoma pt on MTX, tx lymphoma by DC MTX)
** List 3 MTX side effects that won’t be fixed by folic acid **
Related to folate antagonism:
-Anemia,
-Neutropenia,
-Stomatitis, oral ulcers
-Unrelated to folate antagonism (thought to be secondary to adenosine pathway):
-Nodulosis,
-Hepatic fibrosis,
-Pneumonitis,
-Fatigue
-Nephrotoxicity
**Ways to reduce side fx of MTX **
Split dosing
-Reduce dose
-Folinic acid (day after MTX)
-Folic acid
-SC over PO for GI
-OCP for teratogenicity
Dose adjusting MTX for renal fcn
Reduce by 25% for CrCl<80ml/min
-Reduce by 50% for CrCl<50ml/min
-DO NOT use if Cr Cl <30mL/min
Alcohol limit in MTX
<3-5/week
** MTX MoA**
Structural analogue of folic acid and enters cells to inhib purine/pyrimidine synthesis → less T cell proliferation via:
-1. Inhib AICAR transformylase (ATIC) → increases levels of adenosine (regulates neutrophils, suppresses IL6, TNF, IL8, enhances IL1/1RA)
-2. Inhib thymidylate synthetase (TYMS) → decreases pyrimidine synthesis
-3. Inhib dihydrofolate reductase (DHFR) → inhib transmethylation → disrupts cellular function, and decreases purine synthesis for DNA/RNA/prot synthesis
-Inhibit COX & LOX → ↓PG & LT
-Inhibit MMPs → ↓cartilage damage
** 3 reasons for pre-treatment MTX liver biopsy at baseline**
Prior excessive EtOH consumption
-Persistently abnormal baseline AST values
-Chronic Hep B/C infection
Whatis the rxn between MTX and Septra,
–How does it happen
– How to treat
BOTH are anti-folate
-Septra competes for tubular secretion and displacement of albumin binding sites increasing MTX lvls (decreased excretion)
-Tx: hold MTX, stop septra, give folinic rescue
-MTX is dialyzable
** How does injectable gold work**
~to HCQ: taken up into macrophages to inhib Ag processing and presentation
-Inhib NFkB → less TNF, IL1, IL6
-Blocks PG production
-Anti-angiogenic and anti-inflamm properties
LFN Side fx
Nonspec: N/V/D, rash
-ILD/Pneumonitis
-Peripheral Neuropathy
-HTN, DLPD
-Myelosuppression (Cytopenia)
-Hepatotox
-Teratogenecity
LFN MoA
Inhib dihydroorotate dehydrogenase (DHODH) →
Decreased synthesis of uridine →
Decreased pyrimidine synthesis → stopping lymphocyte cell division (less immune cells)
LFN dose
20mg PO daily
How to reverse LFN
Cholestyramine 8g TID x11d (does not hv to be consecutive)
Managing increased LFTs in LFN
> 1x but <2x = follow
->2x ULN or persistent minor elevation = reduce dose
->3x ULN = stop LFN and consider cholestyramine
** -List vaccine that are given in 40yF pre biologic start **
> 18yo and taking immunosuppressive
-Shingrix (herpes Zoster)
-Flu (high dose)
-Pneumovax (and under 65)
-+ COVID +/- hep B/C
->26yo and <45yo taking immunosuppressive and not previous vaccinated
-HPV
->65 with rheumatic disease
-Flu (high dose
** List nonlive and live vaccines **
Inactivated:
– High dose adjuvanted Influenza yearly
– Pneumococcal @ start of DMARD therapy, 5y later, and at age 65
– HPV
– Hep B
– Age appropriate: tetanus, meningococcal, H Flu, Shingrix
-Other inactivated vaccines as appropriate: polio, rabies, Hep A/B, typhoid
-Live: MMR, zostavax, nasal flu vaccine, VZV, yellow fever, oral typhoid, rotavirus, smallpox
**MTX management for NON-LIVE vaccine **
– Influenza
– Other non-live attenuated
- Influenza: HOLD MTX for 2 weeks AFTER vaccine (if dz activity allows)
– Other non-live attenuated: CONTINUE
**RTX management for NON-LIVE vaccine **
– Influenza
– Other non-live attenuated
- Influenza: CONTINUE
– Other non-live attenuated: time vaccine for when next ritux due, then HOLD for 2 weeks AFTER (if dz activity allows)
**Prednisone management for NON-LIVE vaccine **
– Influenza
– Other non-live attenuated
- Influenza: GIVE vaccine at any dose
– Other non-live attenuated:
-GIVE vaccine unless 20mg or more (should wait until <20mg)
** Management of nonMTX/RTX immunosuppression for NON-LIVE vaccines:
– Influenza
– Other non-live attenuated**
- Influenza: CONTINUE
– Other non-live attenuated: CONTINUE
** Management of immunosuppression for LIVE vaccines: (GUIDELINES)**
-GC, MTX, AZA, LFN, MMF, CNI, PO CYC
-JAKi
-TNF, IL17, IL12/23, BAFF/BLySi, IL6, IL1i, Abatacept, Anifrolimab, IV CYC
-Ritux
-IVIG
- GC (continue if high risk flare or adrenal insuff), MTX, AZA, LFN, MMF, CNI, PO CYC: hold 4 weeks BEFORE AND AFTER live vaccine
– JAKi: hold 1 week before and 4 weeks after
– Inhibitors for TNFa, IL1, 6, 17, 12/23, 23, BAFF/BLyS, IV CYC: HOLD 1 dosing interval before and 4 weeks AFTER
– Ritux: hold 6 months before and 4 weeks after
– IVIG: hold 8,10,11months before and 4 weeks after for 300-400mg/kg, 1g/kg, and 2g/kg
When to give rotavirus vaccine to infants exposed to immunosuppression in T2/T3
– TNFi
– Ritux
TNFi: GIVE WITHIN 1st 6 months of life
-Ritux: DO NOT give until AFTER 6months of life
Recommendations for medication management for live vaccines
Pred<20 and DMARDS can get live vaccines
-If higher doses, lower to <20mg at least 1mo before live vaccine
-Biologic: off for 3 half lives before getting live vaccine, and restart 1 mo after vaccine
ACR20
20% improvement in TJC, SJC, and 3/5 of:
- Pt pain score,
- HAQ
- Pt global score
- Physician global score
- ESR or CRP
AZA side fx
-Myelosuppression (worse if TPMT deficiency)
-Hepatotox , Nephrotox
-Pancreatitis
-Hypersensitivity syndrome (fever, hepatitis, ARF, rash w/i 1st 2wks)
-N/V, rash
-Malignancy
-Infxn (HZV, CMV)
Why TPMT test
TPMT metabolizes thiopurines, if inactivated → excess AZA → fatal myelosuppression (cytopenias, macrocytosis)
How to adjust AZA with CBC or other drugs
If cytopenias → reduce by 50% or DC
-If use w/ allopurinol/febuxostat → reduce dose by 75% or do not use combo
AZA DDI
AZA inactivated by xanthine oxidase (inhibited by allopurinol and febuxostat) and TPMT (inhib by SFZ)
-Septra , SZS increase leukopenia risk
-AZA decrease warfarin fx
AZA MoA
Converted to 6MP then 6TGN which decreases purine synthesis → inhib DNA, RNA, protein synthesis → cytotox and decreased cell proliferation
MMF side fx
-Myelosuppression
-GI
-Hepatotox
-NOT nephrotoxic
-Infxn (PJP, HZV, CMV)
-Lymphoproliferative malignancy (EBV)
MMF dose
500-1500BID
-1000 BID if Cr Cl <30 and in Asians
MMF vs Myfortic
500mg MMF = 360mg Myfortic
-Switch to Myfortic if GI side fx w/ MMF
MMF MOA
MMF → hydrolyzed to active MPA → (inhibits inosine 5 monophosphate dehydrogenase) → decreased synthesis of purine, guanosine → inhib lymphocyte prolif
-MPA inhib carbohydrate transfer to glycoproteins → less adhesion molecules → decrease lymphocyte migration
CYC dosing
PO: 50-200mg (0.7-2mg/kg/d)
-IV: 0.5-1g/m2 BSA or 15mg/kg monthly
-OR 500mg IV q2wks x6
Adjusting CYC dosing
CBC 10-14d after each dose for nadir
-If WBC <3.5 or neuts <1.5 → reduce dose by 25%
-If nadir >4, dose increased if dz not controlled
CYC MOA
Alkylates DNA → crosslinks and breaks → apoptosis and decreased DNA synthesis.
Affects rapidly dividing cells (eg B and T cells)
CYC side fx
-Myelosuppression (WBC nadir)
-Infection (esp HSV, screen hep B/C, HIV, TB)
-Hemorrhagic cystitis & bladder Ca (less w/ IV, mesna)
-Malignancy
-Infertility (ovarian failure, azoospermia)
-Teratogenicity
-Pneumonitis, pulm fibrosis
-SIADH
-PRES
** Cyclosporine/Tacro/Sirolimus MoA**
Inhib calcineurin to prevent transcription and production of IL2 and subsequent T cell proliferation
Cyclosporine/Tacro Side fx
-Nephrotox (reversible), HTN, anemia,
-Hyperuricemia (switch to tacro - less hyperuricemia)
-Hepatotox rare
-Bone pain (lower dose or use CCB)
-Malignancy (lymphoma, skin Ca)
-Infxn,
-H/A, tremor, hyperpigmentation
Apremilast indication and dose
PsO, PsA, Behcet
-10mg daily → 30mg BID
Apremilast side fx and monitoring
Side fx: diarrhea, weight loss, H/A
-Monitoring: NONE
Apremilast MoA
Inhib PDE4 → more intracellular cAMP → decreased proinflammatory mediator (TNFa, IL12, IL23, IFNgamma, inducible NO synthase), increased antiinflamm cytokines (IL10)
Name the JAKs
Jak 1, 2, 3
-TYK2
** JAK -STAT normal pathway**
- Cytokine/Growth factors bind and causes dimerization and phosphorylation of receptors
- STAT transcription factors bind phosphorylated R’s
- JAK associated w/ R phosphorylates STAT that dimerize and translocate to nucleus to start transcription of inflammatory mediators
** JAKi MOA**
JAKi bind JAK on R’s to prevent phosphorylation and STAT binding → Less transcription of proinflamm cytokines
Cytokine receptors assoc’d w/ each JAK
-JAK 1: Same as JAK 3 (IL2, 4, 7, 9, 15, 21) + IL6, 10, 27, IFNa/b/g
-JAK 2: IL 6, 12, 27, IFNg, EPO, thrombopoeitin, Prl, growth hormone, GCSF
-JAK 3: IL2, 4, 7, 9, 15, 21
-TYK 2: IL6, 10, 12, 23, 27, IFNa/b
** List 4 cytokines that are NON-JAK associated cytokines (2016)**
-IL1
-IL17
-IL18
-TNF
-TGFb
** JAKi and which JAK they inhib**
Tofacitinib: Jak 1,3 > Jak 2
-Baracitinib and Ruxolitinib: Jak 1 = 2
-Upadacitinib: Jak 1 highly selective
-Deucravacitinb (TYK2)
-*all JAKi inhib all JAK to some degree
Tofa MoA
-Jak 1 inhib → less (IL2, 4, 7, 9, 15, 21) as well as less IL6, 10, 27, IFNa/b/g
-Jak 3 inhib → less IL 2, 4, 7, 9, 15, 21 and less T/B cell signaling
** JAKi dose **
Tofa 5mg BID or 11mg XR daily (5mg if severe liver/renal dz)
-Can be used alone or with MTX (avoid combo w/ AZA, bDMARDs, cyclosporine)
Upadacitinib 15mg daily
Baracitinib 2mg daily
Tofa monitoring
CBC, liver, Cr, LIPIDS
**Tofa Side fx **
~IL6i: HYPERLIPIDEMIA (LDL and HDL), GI PERFORATION , Zoster, myelosuppression
-Hepatotox, Cr increase
-Nasopharyngitis, diarrhea, headache
-MACE events, VTE
-Infxn: decreased vaccine response, CMV, TB, cryptococcus, BK virus, toxo, candidiasis
-Malignancy (lymphoma, solid tumor)
Tofa dose adjustment
5mg if severe renal/liver
Decrease by half if on antifungal (eg ketoconazole, fluconazole)
Bara and Upa side fx
Same as tofa
-CK elevation WITHOUT weakness or rhabdo
IVIG dosage
1-2g/kg over 1-5d
IVIG side fx
-ANAPHYLAXIS if IgA deficiency
-Aseptic meningitis
-Serum sickness: H/A, Flushing, fevers, chills , Nausea, Hypotension
-Chest tightness, back pain, myalgias
-Leukopenia
IVIG indications
-DM/PM
-AOSD, MAS
-Kawasaki
-CIDP
-ITP
-Offlabel: APLA, AIHA,
IVIG MoA
– Binds proinflammatory cytokines & decrease complement activation
– Enhance Treg function
– Inhib dendritic cells to decrease number of activated T cells
– Increases degradation of pathogenic IgG
– AB bind B cell surface Ig to prevent binding to autoantigen
PLEX MoA
Removes immune complexes and autoantibodies
PLEX used for
-TTP
-CAPS
-SLE w/ DAH, NPSLE
-NMO
-AAV w/ DAH or RPGN
-Hep B PAN
-Hep C Cryo
-PANDAS
**Nomenclature for biologics **
– Cept (eg ETN, abatacept, rilonacept)
– Ximab (eg infx, rtx)
– Zumab (eg certolizumab, tocilzumab, ixekizumab, eculizumab)
– Umab (eg adalimumab, golimumab, belimumab, usteikinumab)
– Ra (eg anakinRa)
-Cept: R drug mops up ligand, so it can’t bind to real R
-Ximab: CHIMERIC monoclonal AB
-Zumab: HUMANIZED monoclonal AB
-Umab: FULLY HUMAN monoclonal AB
-Ra: R-ANT
** Structure of Infliximab vs Etanercept **
Infliximab = Chimeric mouse-human monoclonal antibody: constant regions of human IgG1k + variable region of high affinity anti-human TNF antibody
Etanercept = Two soluble p75 TNF-R extracellular domains linked to Fc portion of human IgG binds TNF to prevent it from binding cell bound TNF-R
10 things to tell your patients about Etanercept
- Biological protein made in a lab to block a specific inflammatory protein TNFa
-2. Injxn self administered under the skin once weekly
-3. Takes 6-8 weeks to see effect
-4. Increases risk for infections
-5. Increases risk of reactivating prior infxn (hep B, TB)
-6. Can cause allergy/site reaction
-7. Malignancy risk controversial for melanoma
-8. Should not be used for CHF (Class 3-4)
-9. Avoid in personal/fam hx of MS or hx of optic neuritis
-10. Need to have vaccinations up to date, and avoid live vaccines during
-11. Need to be held before surgeries
-12. Small risk of paradoxical psoriasis (on palms and soles)
-13. RIsk of drug induced lupus
List actions Infliximab has that etanercept does not on TNF producing cells
-What can ETN bind that IFX cannot
– IFX binds BOTH soluble and cell bound TNFa→ ability to induce apoptosis of cells w/ TNFa bound to surface (including T cells)
– IFX can FIX complement and lyse cells w/ TNFa on surface (ETN cannot)
– IFX forms stable complex w/ soluble TNFa (etanercept forms unstable complexes)
-ETN can bind TNF-B (lymphotoxin)
Biologic comorbidity screening
-Infxn: HIV, Hep B/C, TB, Fungal exposure
-Demyelinating dz
-Cancer
-Cardiac history, DLPD, VTE history
-Liver dz
-Preg
-Meds
** Why inhibit TNFa in rheum**
TNFa-R on monocyte and macrophage
-TNFa binding →
– PG
– Proinflamm cytokines/chemokines
– Adhesion molecules (recruit neutrophils/ monocytes into synovium),
– Induce chondrocyte to produce MMP and RANKL
Why is IL1 inhibited
Proinflamm cytokine existing as IL1a (cytosol & membrane bound) & IL1b (secreted into extracellular space after cleavage from proIL1b by caspase1
ILb is predominant form binding IL1-R →
- Same as TNF: Proinflamm response, PG adhesion molecules, Induce chondrocyte/synoviocyte production of MMP and RANKL
-B cell activation, RF production,
- Activate Th17
Why is IL5 inhibited
-Produced by Th2 cells and mast cells
Binds IL5-R to:
-Stim B cell growth,
-Produce immunoglobulins
-Activate eosoniphils
Why is IL6 inhibited
Soluble IL6-R binding IL6 proinflammatory
-Stim Th17 development → IL17 production
-Activate B cell, macrophages, and OC
-Recruits neutrophils
-With IL1 and TNF –> acute phase response (CRP, fibrinogen, fever, anorexia)
-Acts w/ other cytokines to form pannus
Why is IL17 inhibited
Important in inflammation
-IL17A produced by TH17cells from CD4 Tcells stimulated by IL1, 6, 23, TGFb
-IL17 binds R → increasing IL1, 6 for inflammation; MMPs for cartilage damage, and RANKL for bone erosion
Why is IL23 inhibited
IL23 produced by macrophages and dendritic cells
-Enhances survival of Th17 cells,
-Activates memory T cells
-Stimulation of antigen presentation by DCs
** Biologic dosing **
– Etanercept
– Infliximab
– Adalimumab
– Golimumab
– Certolizumab
- Etanercept: 50mg SC once a week
– Infliximab: 3mg/kg (RA) or 5mg/kg (SpA) IV at week 0,2,6, then q8wks; can increase to 10mg/kg q4weeks
– Adalimumab 40mg SC q2weeks (in uveitis, give 80mg initially then as above); can increase to weekly
– Golimumab: 200mg week 0, 100mg week 2, then 50mg SC monthly
– Certolizumab: 400mg SC at weeks 0,2,4, then monthly
Etanercept contraindication
Uveitis (not effective) or IBD
** TNFi side fx**
- Injxn site rxn , Infusion rxn
- Infxn: bacterial, TB, opportunistic, PJP
- Malignancy (bc TNF induced apoptosis of tumor cells; lymphoma, melanoma)
- Demyelinating syndrome (eg MS, optic neuritis, GBS, myelitis, polyradiculopathy)
- Autoimmune phenomenon (eg drug induced lupus, LCV, Paradoxical psoriasis, Palmoplantar psoriasis)
- CHF (avoid in class 3/4)
- Cytopenia (neut, thrombo, pan)
** Ways to circumvent limitations of biologics eg infusion or injection rxn, costs **
Costs → use biosimilar
-Infusion rxn: treat w/ steroid or antihistamine
-Injection rxn: rotate site, use citrate free formulation, use lyophylized ETN or certolizumab pegol
** TB in TNFi**
– Which TNF worse
– Which test to screen
– When to start TNF if positive
IFN > SC formulation
-Monoclonal > ETN to reactivate
-Repeat TB test if ongoing exposure
-Tspot.TB more sensitive than Quantiferon if on immunosuppresive
-If latent: Start TNFi after 4 wks of therapy
If active: complete anti-TB therapy before starting TNFi
Hep B/C w/ TNF
– When to start TNF
Resolved Hep B→ can receive TNF and check hepatic enzymes and viral loads periodically
-Chronic/Inactive Hep B = NO TNFi or must receive concurrent antiviral ppx (lamivudine etc)
-Hep C → can get TNFi w/o antiviral (monitor hepatic enzyme and viral RNA load)
TNF Cancer recommendations
Do not use in pt w/ melanoma or lymphoma
-Do not start agent until pt cancer free for 5y
May be able to use in pt w/ previously tx solid organ malignancy
** list classes of meds that are contraindicated in:
– Paradoxical psoriasis
– Recurrent anterior uveitis
– 70M w/ HTN
– Optic neuritis**
- Paradoxical psoriasis: antiTNFa
– Recurrent anterior uveitis: etanercept (and other TNF), bisphosphonates, moxi, PD1i, immune checkpoint inhibitors
– 70M w/ HTN: LFN (increases BP)
– Optic neuritis: antiTNFa (demyelinating)
IL1 Biologics
-list them and their
- MoA and Dose
Anakinra: Recombinant IL1R-ANT competitively binds IL1R, so IL1a or IL1b cannot bind
-100mg SC daily (FU CBC like DMARDs)
Canakinumab: IgG1k monoclonal AB that targets IL1B so it can’t bind IL1R for MWS, CAPS, sJIA
-150mg SC q8wks (FU CBC and LFTs)
Rilonacept: soluble decoy receptor for IL1a and ILb for MWS and CAPS
-Loading dose 320mg then 160mg SC weekly (FU CBC and lipids)
Mepolizumab MoA and Dose
Human IgG1k monoclonal AB that targets IL5 which affects activation/survival of eosinophils
-300mg SC q4weeks for eGPA
** Toci MoA and dose**
-What to monitor
IgG1k monoclonal AB binds soluble and membrane bound forms of IL6R inhibiting IL6 activity → less Th17 cells (less neutrophil recruitment, OC and B cell activation, and pannus formation)
-162mg SC weekly
-FU CBC, LFT, lipids
Managing Toci dose w/ increased LFT
> 1-3x ULN: reduce dose and/or switch
->3-5x ULN: DC until < 3x then restart lower dose or switch
->5x = DC toci
Managing Toci dose w/ cytopenias
ANC >1 = continue
-ANC .5-1 = stop until ANC >1, then restart at lower dose
-ANC<.5 =DC toci
-Thrombocytopenia <50 = DC
** Toci side fx **
~to JAKi: Cytopenias, Lipid elevation, GI PERFORATION, infection (eg zoster, fungal)
-MAS
-Lowers fx of PPI, statin, OCP
Sarilumab MoA and Dose
Anti IL6Ra monoclonal B that binds soluble/membrane bound human IL6Ra
-200mg SC q2weeks
** Ustekinumab (Stelara) MoA and Dose**
Human IgG1k monoclonal AB that binds p40 subunit of BOTH IL12 and IL23 preventing binding to shared cell surface receptor
-Inhib of IL12 → less Th1 response and less TNFa, IFNg, IL2 production
-Inhib 23 → less Th17 response and less IL6, 17, 22, TNFa production
-TH17 and IL23 production by DCs and keratinocytes important in psoriasis
-45mg SC week 0 and 4 then q12wks
Ustekinumab adverse rxn
Nasopharyngitis
-Nonmelanoma skin cancers
-Serious infxn (IL12/23 important for resistance against mycobacteria/salmonella; IL17 important for resistance against fungal infxn)
-Hypersensitivity rxn
No Nephrotoxicity, hepatotoxicity, cytopenias
** Sekukinumab (Cosentyx) dose**
150mg SC weekly x4 (loading dose), then 150mg SC q4weeks
** Ixekizumab (Taltz) dose & side fx**
160mg SC loading dose, then 80mg q4wks
-Side fx: injxn rxn,
-nasopharyngitis,
-IBD flare/development
-Fungal infxn
** Guselkumab (Tremfya) MOA and dosing**
IgG1 monoclonal AB binds IL23 to prevent binding to R → less inflammatory cytokines and chemokines
-100mg week 0,4, then q8weeks
** Ritux MoA **
- IgG1k monoclonal AB against CD20 antigen on B cells
– B cells eliminated by complement mediated lysis, antibody-dependent cell-mediated cytotox, or apoptosis
– Less CD4+ T cell activation, plasma cell production
-Igs preserved bc plasma cells dont hv CD20
** Ritux dose **
RA: 1g IV repeated 2 weeks later
-GPA/MPA:
– 375mg/m2 IV weekly x4 or
– 1g on day 1 and 15; maintenance 500mg IV q6m
** Ritux indications**
SLE, APLA, IIM
Sjogrens, IgG4, Cryo
ITP, AIHA,
Castleman, NMO
-**DOES NOT WORK IN SPA
** Ritux side fx**
Infusion rxn, serum sickness
-Increased infxn compared to other biologics
-Viral infxn : Hep B reactivation, hep C, JC virus
-HYPOGAMMAGLOBULINEMIA
-Late onset neutropenia
-Immunizations (give 2-4wks before or 6mo post RTX)
-PML
-**NO CHF, demyelinating, Ca, mycobacterial infxn; ie use Ritux if cant use TNF bc of these
Complement targeted therapies MoA
Avocopan: Blocks C5a from binding C5a R (prevents neutrophil priming)
-Eculizumab - anti C5 used in HUS
Belimumab MoA
IgG1k monoclonal AB against B lymphocyte stimulator protein (BLyS)/Bcell activating factor (BAFF) so it cannot promote survival, growth, maturation of autoreactive B cells and allows apoptosis to occur
** Belimumab indication and dose**
Seropositive SLE (low complements and high dsDNA)
Respond best: Fatigue, Rash, Arthritis
Can be used for LN (NOT SEVERE)
little data for CNS
Heme does not respond
-Dose:
-IV: Loading 10mg/kg at 0,2,4 weeks, then q4weeks for maintenance
-SC: 200mg weekly
Belimumab tox
Infxn
-Infusion rxn
-Malignancy
-Depression/suicide
** Abatacept (Orencia) MoA and dose**
- Human fusion protein made of extracellular portion of CTLA4 fused to Fc fragment of IgG1
- Binds CD80/CD86 on APCs preventing molecule binding to ligand, CD28, on T cells (ie less T cell activation and less proinflammatory cytokines)
-SC 125mg weekly
-IV weight based
Risk factors for biologic nonresponse
-Young, obese, females
-Smoking
-High dz activity
Eculizumab MoA, Indications, and side effect
IgG2/4K monoclonal AB binds C5 and inhib cleavage to C5a and C5b preventing generation of MAC (C5b-9)
-Indication: TMA, atypical HUS, PNH, MG
-Side fx: meningococcemia
Colchicine MoA
Irrev binds free tubulin dimers to disrupt microtubule formation → inhib neutrophil chemotaxis, phagocytosis, and cytokine secretion
-Inhib phopholipase A2 → less inflammatory PG and leukotrienes
-Modulates pyrin expression
Colchicine indications
-FMF
-Behcet, Aphthous stomatitis
-Neutrophilic dermatoses eg Sweets
-Cutaneous LCV
-Pericarditis
-Gout Tx and PPX
Colchicine Toxicity RF
Elderly
-Renal/hepatic impairment
-Chronic use
-CYP3A4 inhibitors
Colchicne tox
-GI (N/V/D)
-Neuromyopathy (CK, prox weakness, periph neuropathy), rhabdo
-Hepatotox, Nephrotox
-Myelosuppression
-Circulatory collapse
ULT dosage
Allopurinol 50 or 100mg and increase by similar q2-5wks until <6 or <5 if tophi
-If fail or contraindication: Febuxostat: 40mg and increase to 80mg after 2-5wks
-If contraindication & uricosuric: Pegloticase 8mg over 2hr
-If not uricosuric: Probenecid 250mg BID x1wk then 500mg BID and increase to 500mg q4w if not at goal
ULT DDI
Allopurinol and Febuxostat
-Do not use with AZA or 6MP
-Allopurinol: increases CYC, warfarin, cyclosporine lvls. Decreases excretion of thiazide.
Manifestations and Tx of allopurinol hypersensitivity syndrome
Skin rash (SJS, TEN), fever, eosinophilia, hepatic necrosis, leukocytosis, renal failure
-Tx AHS: high dose steroids and HD (removes oxipurinol)
Risk factors allopurinol hypersensitivity syndrome
Female
-Hx of rash on allopurinol
-Renal insuff
-Concomittant diuretic therapeutic,
-Elderly
-HLAB5801
-Korean, Han chinese, Thai
Probenecid MoA
Competitively inhib URAT1 and GLUT9 → decreased tubular reabsorption of urate → increased uricosuria
Probenecid side fx
-Acute gouty flare
-Urate nephropathy/stones, Nephrotic syndrome
-GI: N/V
-Dermatitis
-Cytopenia eg Hemolytic anemia from G6PD deficiency
-Hypersensitivity, eg SJS
Probenecid contraindications
-Elderly and Low CrCl<50
-24h urine collection >800mg uric acid
-Avoid w/ salicylates (increases uric acid excretion)
-Uric acid stones
-G6PD def
How to minimize Urate nephropathy/stones
-2L/d fluid intake
-Urine alkalinzation (usually not needed) w/ Na bicarb or K citrate → urine pH>6
Pegloticase MoA and precautions
Recominant mammalian uricase
-Precaution: G6pd def (hemolytic anemia and methemoglobinemia); can cause gout flare; infusion rxn and anaphylaxis
-Do not use with other ULT
Type of Calcium to use in osteoporosis
Ca Carbonate absorbed less if achloryhydria or PPI
-Ca Citrate less affected by PPI and if hx of stones
How much Ca and Vit D in what
Ca (target 1200mg): 300mg in 1 cup milk/yogurg/fruit juice w/ Ca, 1 oz of cheese
-Vit D (target 800 daily): 400IU in 1qt of fortified milk or 3.5oz fatty fish
Reasons for low vit D
-Low intake (malabsorption, bypass, celiac)
-Severe liver dz,
-Antiepileptic drugs,
Bone remodeling process
Osteocytes = mechanoR that sense skeletal stress and send signals eg sclerostin to organize bone remodelling
-OC resorbs bone via acid/enzymes over 3-4wks
-OB migrate into resoprtion pits and secrete osteoid → mineralizes w/ CaPO4 crystals (hydroxyapaptite) over 3 mo
Roles of RANK, RANKL, OPG
RANK = R-activator of NFkB = receptor on OC
-RANKL on OB (or secreted by other cells) binds RANK to stim OC bone resorption
-Osteoprotegerin (OPG) = soluble decoy R produced by OB and BM stromal cells that bind RANKL → prev binding to RANK
-Bone resorption driven by RANKL and inhib by OPG
OP meds dosing
Alendronate 10mg/d or 70mg/wk
-Risedronate 5mg/d or 35mg/wk or 150/mo
-ZA 5mg yearly
-Denosumab 60mg SQq6mo
-Raloxifiene 60mg/d
-Calcitonin 200U/d
-Teriperitide 20mcg SC/d
-Romosozumab 210mg SQ/mo
Bisphosphonate MoA
Pyrophosphate analogs that affect OC acting on bone by blocking farnesyl diphosphosphate synthase (FDPS) affecting protein trafficking needed for “ruffled border” →OC apoptosis
BP side fx
PO → GI sx
-IV → acute phase rxn, afib
-**Hypocalcemia, ONJ, AFF ** (as with all OP meds except teriperitide)
-Uveitis, keratitis, optic neuritis, orbital swelling
How to take BPs
1st thing in morning on empty stomach w/ water → upright and NPO x30-60min
BP contraindications
Esophageal problems (stricture, achalasia, dysmotility, amalabsorption) → IV>PO
-Hypocalcemia
-Cr Cl<35
-DC as early as possible before pregnancy
-Not sure if affects breastfeeding
Denosumab MoA
Monoclonal AB against RANK-L ie preventing OB from binding RANK to cause OC activity
Dental recommendations w/ denosumab
-Do invasive dental work (extraction, implants) before starting Denosumab to decrease ONJ risk
-Schedule procedure 6mo after injxn
-Give next injxn after dental procedure healed
How to bridge when DC prolia
Start PO BP 6mo after last injxn
-Start IV ZA 9mo after last injxn
ONJ Risk factors
-Old
-Invasive oral procedure
-Use of GC, prolonged BP use
-Comorbidities: DM, HTN, DLPD, CKD
-EtOH, Smoking
BP recommendations to prevent AFF
1-2 y D holiday after 5y of BP for osteopenic
-Switch to anabolic or nonBP agent if prev fragility # or v low BMD
-Stop ZA after 3y (no fragility #) or after 6y (hx of fragility #) for 3 years
Counsel HRT
Estrogen replacement prevents # but increases risk BCa and CV events
-Give only for up to 3 y for postmenopausal hot flash
SERM (Raloxifene) MoA
E2 Ag in some tissue (bone), E2 ANT (breast)
SERM side fx
Hot flash, cramps, VTE
TRT pros/cons
Increase bone mass
-No # reduction
Teriparatide MoA and dose
34 amino acid fragment of intact PTH activates PTH R on OB and OB precursor prolif, differentiation, and survival → osteoid formation and increased BMD.
-20mcg/d SC x18-24mo
Teriparatide contraindication
-Other bone diseases: Paget’s disease, HyperPTH, bone mets
-HyperCa, Increased ALP
-Children or young adults w/ open epiphyses
-Pregnancy
-Prior external beam or implant radiation therapy (bc drug can cause osteosarcoma)
Teriparatide side fx
HyperCa (dig, kidney stone)
-Hyperuricemia
-GI upset
-Arthralgia
When to end drug holiday / What is definition of drug failure
Fragility fracture occurs
-BMD decreases more than least significant change
-Bone turnover markers increase by >30% or rise to upper 50% of reference range
Markers for:
– Bone formation
– Bone resorption
Formation: ALP, osteocalcin, P1NP
-Resorption: Urine/serum N- telopeptides, serum C telopeptides
Romosozumab MoA & dose
Humanized monoclonal AB against sclerostin (protein made by osteocyte that inhibits Wnt; Wnt stimulates OB bone formation)
-Blocking sclerostin = less inhib of Wnt = more bone formation
-210mg SC /mo
Romosozumab side fx
Arthralgia
-Headache
-Injxn site rxn
-MACE events
-Hypocalcemia
-ONJ
-AFF
Indications for splinting
CTS
-DQ tenosynovitis
-1st CMC OA
-Inflammatory arthritis
Types of splints for RA or PsA hands
Finger splint for swan neck or bouttoneire
-Resting hand splint
-Wrist support
-CMC splint (more for OA)
-Knee sleeves
Etoposide MoA
Topoisomerase II inhibitor → DNA strand breaks and cell arrest
Which part of cannabis induces psychotic symptoms? **
-Max dose of cannabis per day as per the statement **
THC (ie preferred lower THC and higher CBD)
-3g
** 3 populations where you should not use cannabis **
<25 years
-Allergic
-Pregnant/breastfeeding
-Personal Hx of psychotic illness, substance use disorder, suicidal attempts/ideation
*Side effects of cannabis in the short term **
Psychomotor,
-Dizziness,
-Appetite,
-Mood changes,
-Disorientation and
-Psychosis,
-Anxiety.
** Young guy with RA on MTX, vaping marijuana, comes in with acute dyspnea, cough, fever - name 4 DDx **
RA induced lung injury (Organizing pneumonia/hypersensitivity pneumonitis)
-MTX-induced hypersensitivity pneumonitis
-Pneumonia
-Vaping associated lung injury
Prolia side effectss
AFF
HypoCa
ONJ
Infection
GI side effects
Cytopenias
