25 - Rheumatoid Arthritis Flashcards
- *Pathophysiology**
- *RA**
Effects of Pro-inflammatory cytokines:
- *TNF** / IL-1 / IL-6
- *OUTWEIGH** those of anti-inflammatory cytokines
Chronic Inflammation & Proliferation of
SYNOVIAL TISSUE
which invades the cartilage –> bone surface –> erosions
Clinical Presentation
RA
- *Synovitis**
- *SYMMETRICAL joint swelling**
- *PIP / MCP**
Morning Stiffness > 1 hour
Symptoms in Small Joints
Hands / feet
Joint Pain & Tenderness, Muscle Aches
Low grade Fever
Weight Loss / Fatigue / Weakness / Loss of Appetite
ACR Diagnostic Criteria
AT LEAST 4 of 7
Morning Stiffness
Arthritis of > 3 joint areas
Arthritis of hand joints
Symmetric arthritis
Rheumatoid Nodules
RF = Serum rheumatoid Factor
Radiographic Changes
ACR/EULAR Criteria for Diagnosis
- *Effort to DIAGNOSE EARLIER DISEASE**
- not necessarily for clinical diagnosis*
> 6 points = DEFINITE RA
4 Domains, graded on points
Joint Involvement
Quantity of joints, swollen or tender on exam
Serology
RF // CCP antibody
Acute Phase Reactants
Duration of Symptoms
Non-Pharmacologic Therapy
RA
STOP SMOKING
Rest
8 hours of sleep // naps
- *Physical Therapy**
- *Passive range of motion / Exercise**
Occupational Therapy
Achieve
IBW
- *Corticosteroids**
- *RA Therapy**
Oral: Prednisone
Injectable: Triamcinolone Acetonide
MP Sodium Succinate
NON-DISEASE MODIFYING
controls symptoms quckly, within days
SOME anti-erosive effects –> NOT completely non-disease modifying
Added to other therapy in ACUTE flares
or used Chronically @ low doses <7.5 mg/day
Typically used SYSTEMICALLY
but may be use intraarticularly –> into JOINTS
limited by many LONG-TERM ADR’s > 3 months
Considerations b4 starting DMARDS
RA Therapy
- *Start DMARD - ASAP** in most patients
- continue Coticosteroids or NSAID until effect is seen*
Pt Specific factors or History effecting DRUG SELECTION
MTX + Alcohol
Abatacept + COPD
CHF + anti-TNF agents
AVOID LIVE VACCINES
while on biologics (herpes zoster)
Killed Vaccines are fine
Non-Biologic DMARDS
RA Therapy
- *Methothrexate = MTX**
- avoid alcohol*
Sulfasalazine = SSZ
Hydroxycholoroquine = HCQ
Leflunomide = LFN
Azathioprine / Ninocycline / Gold Sals / Cyclosporine
Methotrexate - Indication / MOA
RA Therapy
CORNERSTONE OF RA THERAPY
typically the INITIAL DMARD in many cases
Non-Biologic DMARD
1-2 Month onset
DIHYDROFOLATE REDUCTASE INHIBITOR
–> inhibits PURINE synthesis –> reduced cell turnover
inhibits production ofIL-1
Methotrexate - DOSE
RA Therapy
- *10-25 mg po WEEKLY**
- *2.5 mg tablets** –> 1 BIG DOSE on ONE DAY
- renally dosed*
Taken with:
Folic Acid 1-3mg/day
to decrease:
stomatitis / N+D / Alopecia
Methotrexate - ADR / CI’s
RA Therapy
ADR:
- *HEPATOTOXICITY**
- *lung disease / myelosupression / PREGNANCY CAT X**
CI’s
- *AVOID / MINIMIZE ALCOHOL**
- relatively contraindicated in* RENAL / LIVER impairment (renally dosed)
- *significant lung disease**
Leflunomide - Indication / MoA
RA Therapy
Non-Biologic DMARD
Alternative to MTX
or can be used in COMBINATION (lower dose 10mg QD)
LONG HALF LIFE
due to enterohepatic recirculation
- *INHIBITS DIHYDROOROTATE DEHYDROGENASE**
- inhibit PYRIMIDINE synthesis –> lymphocyte production*
Leflunomide - DOSE / ADR
Non-Biologic DMARD
RA Therapy
100 mg f3d –> then 20mg qd
EQUAL EFFICACY + SAME TOXICITY
As MTX
NOT FOR PREGNANCY OR BREAST FEEDING
requires a :
WASH OUT –> before fertility
since LONG HALF LIFE –> 2 YEARS
Hydroxychloroquine - Indication / MoA
Non-Biologic DMARD
RA Therapy
Interferes with ANTIGEN PROCESSING
in macrophages + other APCs –> down regulation of immune response
Mild Effects + *SLOW* Onset (2-6mo)
so used in COMBO w/:
SSZ or MTX
HCQ - Dose / ADR
Non-Biologic DMARD
RA Therapy
- *200 mg po BID**
- or 400mg QD*
Well Tolerated - occasional rash or GI
Potential for:
OCULAR TOXICITY
Cornea -> reversible
Retinopathy –> IRREVERSIBLE
loss of centreal/peripheral/night vision
Which Medication causes RETINOPATHY?
& what are the risk factors?
HYDROXYCHLOROQUINE = HCQ
Retinopathy is IRREVERSIBLE
continued deteriotion in vision AFTER DC OF DRUG
Risk Factors:
Daily Dose > 5mg/kg (ABW)
Duration of use >5 years w/o other RF
Renal impairment / Tamoxifen use / Previous eye disease
What tests must be done if taking HCQ?
Baseline Eye Exam within 1 year of initiation
due to RETINOPATHY
Annual Screening after 5 years if no other RF
sooner than 5 years if Risk Factors
Sulfasalazine (SSZ) - Indication / MoA
Non-Biologic DMARD
RA Therapy
Often used in combination w/:
HCQ +/- MTX
1-3 Month Onset
MoA is Unknown in RA
SSZ - Dose / ADR / CI
Non-Biologic DMARD
RA Therapy
500-1500mg po BID WF
WARFARIN DRUG INTERACTION
ADR:
GI ADVERSE EFFECTS
common, tend to wane after first few months, take WF
lessened by starting low –> slow w/ dose
RASH
uticaria / leukopenia / alopecia / elevated hepatic enzymes
yellow-orange skin or urine
SSZ
pregnancy / Fertility concerns?
Pregnancy
OK if <2g/day
Breast Milk
Yes, but considered safe
- *REDUCES SPERM COUNT**
- but reverisble after 2-3 months*
LFN WASH OUT
- to prevent TERATOGENICITY*
- Long half life of ~2 years*
CHOLESTYRAMINE
8g TID for 11 days
CHARCOAL SUSPENSION
50g BID for 11 days
Goal:
Teriflunomide concentration < 0.02mg/L
verify with 2nd test after 14 days
When to ADVANCE DMARD therapy?
DMARD therapy should be MODIFIED in:
Repetitive FLARES
Unacceptable DISEASE ACTIVITY
Progressive JOINT DAMAGE
Biologic DMARDS
RA Therapy
Anakinra = Kineret
LESS EFFECTIVE, NOT USED OFTEN
Recombinant IL-1 receptor antagonist
Abatacept = Orencia
works on t-cell receptor resulting in down regulation of T-cells
Rituximab = Rituxan
works on CD20 on B-cells –> B-cell depletion
- *Tocilizumab / Sarilumab**
- *IL-6 receptor inhibitors**
Basics of BIOLOGIC DMARDS
RA Therapy
Parenteral Administration
WORK QUICKLY
days - weeks , vs months for non-biologic DMARDS
significant improvement within 12-16 weeks
Serious side effects / High Costs
Biologic DMARDS - USE / INDICATIONS
RA Therapy
Moderate to severe RA
Often used in those who have FAILED MTX
due to intolerance / unsatisfactory response
Steroid Sparing Agent
Used alone or in combo with NON-BIOLOGIC DMARD
combination therapy is BETTER
Biologic DMARDs: ADRs
RA Therapy
Many ADR are overlapping (bacterial infxns)
do NOT combine with >1 biologic DMARD
INFECTION
update vaccinations, but AVOID live vaccines
consider DC in acute infxn // hold b4 procedures
Malignancy / Neutropenia / Injection Site Reactions
Anti-TNF Agents: USE
RA Therapy
Generally, FIRST LINE Biologic DMARD
due to:
Efficacy / fast onset / clinical experience / SC DOSING
no evidence that any 1 anti-tnf > others
- *Reasonable to try SECOND anti-TNF**
- *after FAILURE of 1st**
- AB -formation*
Anti-TNF Agents: ADRs / Contraindications
RA Therapy
INFECTION
- *TB SKIN/BLOOD TEST** prior to use
- -> if positive check CHEST X-RAY
- *LTB (latent TB) ID’d then start treatment of Isoniazid**
- *Check HEP B surface Ag_ & _core Ab**
- before start of anti-TNF*
MALIGNANCY
- *above baseline eleveted risk in RA patients**
- already high w/o drugs*
- *Leukemia / Lymphoma**
- *HSTCL / Skin Cancer**
NEUTROPENIA / HEPATOXICITY
need to monitor CBC / Liver
What needs to be monitored / tested b4 taking:
ANTI-TNF AGENTS?
TB SKIN TEST
HEP B
surface Ag & core Ab
Monitor:
CBC - Neutropenia
LFTs - Hepatotoxicity
ANTI-TNF Agents
Dosing / Administration
most is available as SUBQ
- EXCEPT:*
- *Infliximab = IV (3mg/kg over 2 hours)**
Golimumab = IV (2mg/kg over 30 min)
also available SQ monthly
Abatacept
Biologic DMARD for RA
avoid with patients with COPD
they have more ADRs
- *CTLA-4**
- inhibits T-cell activation*
- *IV & SC**
- longer time to effect vs Anti-TNF agents*
Rituximab
Considerations / Indications
Biologic DMARD for RA
safest drug for CANCER PATIENTS / TB
recommended biologic for pts w/:
- *Treated Cancer within 5 years**
- no evidence of an increase of malignancy in RA patients*
- *no need to screen for TB**
- no evidence for increased incidence of TB*
CD20 binding –> depletes B-cells
Does NOT require continuous therapy
to maintain response, lasts 4mo >1 year
Rituximab
Dosing / ADR
Biologic DMARD for RA
1000 mg IV INFUSION
over course of 2 infusons 2 weeks apart –> repeat 16-24 weeks later
little dosing
ADR: INFUSION REACTIONS (1st dose)
- *Screen for HEP B + C**
- reactivation*
Tocilizumab / Sarilumab
ADR / Contraindications
Biologic DMARD for RA
Tocilizumab = IV + SC
Sarilumab = SC
decrease IL-6 mediated signaling
do NOT start if any of the following:
ANC < 2000
ALT or AST > 1.5x ULN
PLT < 100k(Tocilizumab) //PLT < 150k (Sarilumab)
ADR:
GI PERFORATION** // **DYSLIPIDEMIA
eleveated LFTs / neuropenia / malignancy / infxns
JAK-Inhibitors
CONTRAINDICATIONS
RA Therapy
- do NOT start if:*
- *ANC < 1000**
- *Lymphocytes < 500**
- *Hb <9** (tofacitinib) // Hb <8 (baricitinib
do NOT combine with BIOLOGIC
- AVOID in patients taking:*
- *OTHER potent immunosuppresive drugs**:
- *AZA / TAC / CSA**
Tofacitinib = Xeljanz
Considerations
RA Therapy
JAK-Inhibitor
- *70% LIVER METABOLISM**
- *CYP 3A4 / 2C19 –> DRUG INTERACTIONS**
- lossess effectiveness with inducers*
- Reduce to 5mg PO qd in patients wtih:*
- *Renal Insufficiency** / moderate Hepatic Impairment
- *enzyme inhibitors (ketoconazole / fluconozole)**
NOT FOR BREASTFEEDING
Baricitinub = Alumiant
Considerations
RA Therapy
JAK-Inhibitor
Also CYP3A4 but no meaningful DI’s
- *75% Renal ELimination**
- NOT RECOMMENDED with* CrCl < 60
DI with:
Strong inhibitors of OAT3 = Probenecid
ADR:
THROMBOSIS = Arterial + Venous
with high doses
- *JAK-Inhibitor ADRS**
- *Tofacitinib / Baricitinib**
GI PERFORATION
LIPID CHANGES
INCREASE in TC / LDL / TG / HDL
For Baricitinib:
THROMBOSIS - Venous / arterial
Common ADR for both:
URI / HA / HTN / nasoparyngitis
Infections
malignancy / hepatotoxicty / lymphopenia / neutropenia
BREASTFEEDING
Concerns for BIOLOGICS / JAK-I
Most are LARGE MOLECULES
unlikely to penetrate into breast milk in large quantities
likely destroyed by GI tract if present
EXCEPT FOR
TOFACITINIB
small molecule –> can get into breast milk
PREGNANCY
Concerns for Biologics / JAK
_*AVOID for* 3-6 months b4 pregnancy_
anakinra / abatacept / rituximab
Tocilizumab / saralumab / tofacitinib
Safest is:
- *certolizumab / etanercept**
- *Anti-TNF’s**
What RA drug should be avoided for patients with
COPD?
ABATACEPT
orencia
Anti-TNF –> CTLA4
Biologic drug
Which RA drug has the ADR of
THROMBOSIS
arterial & venous
w/ higher doses
BARICITINIB
olumiant
JAK 1 / 2 Inhibitor
Also:
GI PERFORATION
LIPID CHANGES
↑TC / LDL / TG / HDL
Monitoring for:
- *IL-6 Inhibitors**
- *Tocilizumab / Sarilumab**
- *Jak Inhibitors**
- *Tofacitinib / Baricitinib**
CBC** & **LFTs
@baseline & q4-8 wks –> q3mo
LIPID PANEL
4-8 weeks after start –>q6mo
Infections
Which RA drug has drug interactions with
2C19?
Cyp2c19 Inhibitors –> reduce dose
Fluoxetine / PPIs
Indomethacin / Ketoconazole
Isoniazid / Probenecid
- *TOFACITINIB** = Xeljanz
- *Jak 1/3 inhibitor**
Need to reduce dose to 5mg f so
Also a CYP3A4 issue
Efficacy Monitoring for RA
What Labs?
- reduction in inflammatory markers:*
- *ESR_ or _CRP**
- no longer RH or Anti-CCP*
Patient Global Assessment
DAS** or **DAS28
Joint Pain / Morning Stiffness / Active inflammation / Xray / Fatigue
Toxicity Monitoring for:
MTX / SZA / Leflunomide
CBC
SCr
LFT
@ baseline and more
For MTX: also CXR for pulmonary changes
