Signs and Symptoms of RA

- common symptom

- how is it diff from OA

- Define Felty's Syndrome

a.    Fatigue, weakness, low grade fever, loss of appetite, and joint pain

b.    Stiffness and muscle aches

c.    Joint swelling à common

d.    Fevers, polyarthritis, depression, anxiety, anorexia, weight loss (~20)

e.    Stiffness

                                          i.    Tends to correlate to disease activity

                                         ii.    Usually > 30 mins (longer) à Morning stiffness longer than OA (30 mins)

                                        iii.    May persist all day—OA can go away when you move around

                                       iv.    Chronic RA without adequate exercise

1.    Loss of ROM

2.    Muscle atrophy

3.    Weakness

4.    Deformity à because no structure

f.     Extra-articular involvement

                                          i.    Rheumatoid nodules—usually not a problem; just a nuisance

                                         ii.    Vasculitis

                                        iii.    Pulmonary —problem if in the lungs; not a problem if it is in the periphery

                                       iv.    Ocular—dry eyes are common due to ducts drying up

                                        v.    Cardiac—33% have an increased risk of dying early due to cardiac problems

                                       vi.    Osteoporosis

                                      vii.    Felty’s Syndrome = combo of RA + Large Spleen + Leukopenia àincreased risk of infection.  In addition, there is a risk of thrombocytopenia, anemia, etc.

1.    Rheumatoid arthritis

2.    An enlarged spleen

3.    Low WBC

a.    Rheumatoid factor—antibody to ourselves.  If it is present, then it means there is an increased chance of RA.  It’s a sign of inflammation—can be seen in sickle cell, lupus, etc. If positive, it doesn’t mean you have RA and vice versa

                                          i.    Usually present in 60 to 70% of patients

b.    Erythrocyte sedimentation rate (ESR)

                                          i.    Increases with inflammatory diseases

c.    C-reactive protein (CRP)

                                          i.    Increases with inflammatory diseases

d.    Anemia

                                          i.    Hematocrit may fall as low as ~ 30%

e.    Thrombocytosis

                                          i.    Platelets counts rise and fall

f.     Thrombocytopenia

g.    Mimics Felty’s syndrome

a.    Prevent or control joint damage

b.    Prevent loss of function

c.    Decrease pain

d.    Complete remission, defined as absence of: must have ALL of these gone to be in remission

                                          i.    Symptoms of active inflammatory joint pain

                                         ii.    Morning stiffness

                                        iii.    Fatigue

                                       iv.    Synovitis on joint examination

                                        v.    Progression of radiographic damage on sequential radiographs

                                       vi.    ESR or CRP elevation

a.    Educating patient and family

                                          i.    Learning to live with RA

                                         ii.    Risk vs. benefit of drug therapy

                                        iii.    Loss of function

                                       iv.    Joint protection

b.    Resting

                                          i.    Moderate rest to conserve energy

                                         ii.    Too much rest/immobility can actually lead to decreased range of motion

c.    Weight reduction

d.    Use of supportive devices: canes, crutches, walkers

e.    Physical and occupational therapy

                                          i.    Aerobic/muscle strengthening activity

                                         ii.    Psychological well being with symptoms

f.     Surgical treatment

                                          i.    Tendon repair

                                         ii.    Joint replacement

NSAIDs

- indication

- place in therapy

- limitations

- agent preference

- concerns

a.    Indications: reduce joint pain and swelling to improve joint function

b.    MOA: inhibits prostaglandin synthesis

c.    First line, must be used in combination

d.    Limitations: Does not prevent damage

e.    Cyclooxygenase-2-specific NSAIDs

                                          i.    Better GI safety profile

f.     Recent Cardiac à a lot of issue with COX2s esp after Vioxx; Weigh Pros and Cons before use

DMARDs

- use

- when to start

- when to change

- what to monitor

a.    Use: patients with established diagnosis and disease progression despite NSAID treatment, persistent ESR or CPR levels, or radiographic damage, for untreated patients with synovitis and joint damage

b.    Start DMARDs within 3 months

                                          i.    Reassessed periodically for disease activity and toxicity of treatment

                                         ii.    Repetitive flares, unacceptable disease activity (defined as ongoing disease activity following 3 months of maximum therapy) or progressive joint damage require consideration of changes to the DMARD regimen

                                        iii.    Helps prevent disease progression

                                       iv.    Try for 3 months before any change

c.    3 things all of them need to be tested for

                                          i.    LFTs, CBC and SCr (Kidneys)

Methotrexate

- place in tx

- indications

- adult dose

- tx response

a.    Methotrexate (Rheumatrex®)

                                          i.    DMARD of choice

                                         ii.    MOA: inhibits cytokine production and purine biosynthesis

1.    May stimulate release of adenosine

                                        iii.    Indications:

1.    Mod-severe

2.    Polyarticular course juvenile RA

                                       iv.    Adult Dose: 7.5-15mg/week (PO, SQ, IM) à KNOW

                                        v.    JRA: 10mg/m2 QW (Max 20mg/m2/W)

                                       vi.    Therapeutic response: 2 to 3 weeks

Methotrexate

- ADR

- req to receive

- when to D/C

- safety precautions

- contraindications

                                          i.    Safety

1.    ADRs

a.    Gastrointestinal—common

b.    Myelosuppression

c.    Hepatic fibrosis/cirrhosis

d.    Pulmonary infiltrates or fibrosis

2.    Perform Hep B and C testing prior à if positive, must be treated

3.    D/C if AST/ALT > 2X ULN

4.    Folic acid supplementation to prevent deficiency and reduce toxicity

5.    Contraindication(s0:

a.    Pregnancy

b.    Nursing

c.    Chronic liver disease

d.    Immunodeficiency

e.    Pleural or peritoneal effusions

f.     Leucopenia

g.    Thrombocytopenia

h.    Blood disorders

i.      CrCl < 40mL/min

Methotrexate Counseling:

- avoid

- safety measures

- contact MD if

- may cause

1.    Avoid

a.    Alcohol—affects the liver

b.    Salicylates

c.    Prolonged exposure to sunlight/sunlamps—increases risk of sensitivity

2.    Use contraception post d/c for at least

a.    Males: 3 months

b.    Females: 1 ovulatory cycle

3.    Notify MD if occur (sign of toxicity)

a.    Diarrhea/abdominal pain

b.    Black stools

c.    Fever and chills— means immunosuppression is greater than what you want

d.    Sore throat/sores in or around the mouth

e.    Cough

f.     Yellow discoloration of the skin or eyes

4.    May cause (if persist notify MD)

a.    Nausea/vomiting/loss of appetite—common in beginning

b.    Hair loss

c.    Skin rash

d.    Fever

e.    Dizziness

5.    50-60% of people are on it for about 5 years

6.    Use MTX within the first 3 months

Lefluonamide

- brand name

- MOA

- indications

- therapeutic response

- req to receive

a.    Leflunomide (Arava®)

                                          i.    MOA: inhibits pyrimidine synthesis leading to a decrease in lymphocyte proliferation and modulation of inflammation

                                         ii.    Indications: Some trials show it to be as effective as MXT.  If MXT fails, wait 3 mo and start this.

1.    RA + NSAIDs or low dose corticosteroids

2.    Off-label: Juvenile Idiopathic Arthritis

                                        iii.    Dose LD 100mg x 3days, then 10-20mg QD

                                       iv.    Therapeutic response: 1^st month

1.    Perform Hep B/C test prior, high risk

Arava(R) SAFETY

- ADE

- BBW/CI

- DDI

a.    Leflunomide (Arava®)

                                          i.    Safety

1.    Adverse Effects: diarrhea, rash, headache, reversible alopecia à affects hair and intestine because killing cells

2.    BBW/CI: pregnancy, pre-existing liver disease

3.    Women of child bearing age/sexually active males

a.    Enterohepatic circulation—months to drop below safe plasma concentrations (long t1/2)

4.    Cholestyramine to rapidly clear product

Hydroxychloroquine

- brand

- indication

- tx response

- advantage

a.    Hydroxchloroquine (Plaquenil®)

                                          i.    MOA: prevention of heme polymerization?

                                         ii.    Indication: unsatisfactory response to drugs with  less potential for serious side effects

1.    Usually added to MXT or sulfasalazine

                                        iii.    Dose: 200-300mg BID

                                       iv.    Delayed therapeutic response: up to 6 weeks

1.    Failure after 6 mo without response

                                          i.    Advantage (lack of toxicities):  less severe than others

1.    Myelosuppressive

2.    Hepatic

3.    Renal

Hydroxychloroquine

- adrs

1.    Adverse Effects

a.    Nausea

b.    Diarrhea

c.    Neurologic (mild)

                                                                                          i.    HA

                                                                                         ii.    Vertigo

                                                                                        iii.    Insomnia

d.    Dematologic toxicity

                                                                                          i.    Rash

                                                                                         ii.    Alopecia

                                                                                        iii.    Increase skin pigmentation

e.    Visual changes à counsel pt and tell them to stop Rx and contact MD

                                                                                  i.    Accommodation defects

                                                                                 ii.    Benign corneal deposits

                                                                                iii.    Blurred vision

                                                                               iv.    Scotomas

                                                                                v.    Night blindness

                                                                               vi.    Must report any visual changes

                                                                              vii.    High Risk: Annual exams; Do eye exam before you start

1.    Liver problems (elevated LFTs)

2.    > 50 yo

3.    Vision problems

Sulfsalazine

-MOA

-Indications

-Therapeutic Response

                                          i.    MOA: inhibits DNA synthesis, immunosuppressive

                                         ii.    Broken down in intestine into 2 products by bacteria à so antibiotics can affect MOA

                                        iii.    Indication(s):

1.    Inadequate response to salicylates/NSAIDs*

2.    Polyarticular-course juvenile rheumatoid arthritis (> 6 years)

·         Can use combo: Leflutamide + Sulfasalazine, MTX + sulfasalazine + hydroxycholorquineàmonitor toxicities and liver function

·         Can use monotherapy with MTX, Lef, and Slef but not with hydroxy

·         “3^rd option” before Hydroxychloroquine (MTX à Lef à Sul)

                                       iv.    Adult Dose: 1000mg BID-TID

                                        v.    JRA: 30-50mg/kg/day (BID; MDD = 2g) (Juvenile Arthritis = > 6 yo)

                                       vi.    Delayed release tabs only

1.    Begin with ¼ - 1/3 dose increase weekly

                                      vii.    Therapeutic response within 2 months

Sulfsalazine

-ADRS

-Counseling points

-DDIs

                                          i.    Safety

1.    Adverse Effects

a.    Myelosuppression—leukopenia

b.    Stomatitis

c.    Alopecia

d.    Gastrointestinal (often limit use)

                                                                                          i.    n/v

                                                                                         ii.    diarrhea

                                                                                        iii.    anorexia

e.    Rash/urticaria (manage with anti-hist)

f.     Elevated LFTs

g.    Urine/skin à turns yellow/orange

h.    Make sure they don’t have jaundice

                                         ii.    Counseling

1.    Avoid GI intolerance

a.    Start low and titrate

b.    Divide doses more evenly

c.    Enteric coated

d.    Take with food

2.    Absorption decreased

a.    Antibiotics—don’t let it to convert

b.    Iron supplements—bind to it

c.    Avoid concomitant use with these drugs

3.    Take each dose with full glass of water

a.    Encourage drinking up to 2L per day

4.    Warfarin patients: monitor INR

5.    Avoid sulfonamide/salicylate hypersensitivity

6.    Urine/skin DISCOLOR not clinical concern

Biologic Agents

- Uses

- Advantages

- Disadvantages

- Common BBW

- Caution/Avoid Use

- Baseline evaluations

a.    Expensive

b.    Efficacy not better than DMARDS

c.    Genetically engineered proteins affecting pro-inflammatory cytokines or immune response

                                          i.    TNF alpha, Il-1 and Il-6 (key cytokines)

                                         ii.    T-cells/ B-cells

d.    Uses

                                          i.    Moderate to severe acute RA

                                         ii.    Some JIA (juvenile idiopathic arthritis)

e.    Advantages

                                          i.    Novel targeted therapy

                                         ii.    Some juvenile idiopathic arthritis (JIA)

f.     Disadvantages

                                          i.    Infections

                                         ii.    Malignancy

                                        iii.    Cost

                                       iv.    Storage à ALL need to be refrigerated!

g.    Common black box warnings

1.    Risk of serious infections (I)

2.    Risk of malignancies (M)

3.    Risk of new or re-infection of tuberculosis (TB)

                                 ii.    Avoid use with live vaccines

                                iii.    Caution in CHF à may be exacerbated

                               iv.    Controversy on agent selection/switching

                                v.    Baseline evaluations (all DMARDs)

1.    CBC

2.    LFTs

3.    SCr

                               vi.    Multiple biologics should not be used together—predispose patient to infection

                              vii.    Every patient must undergo PPD test and be up to date with vaccinations (don’t give LIVE vaccines)

Etanercept

- MOA

- Indication

- Tx Response

- BBW

- CI

- ADRs

a.    Etanercept (Enbrel®)

                                          i.    MOA: anti-TNFα

                                         ii.    Indication:  RA or JIA + MTX

1.    Response seen in 60-70%

                                        iii.    Dose: 25 mg SQ BIW or 50mg SQ QW

                                       iv.    Therapeutic response: days to 12 weeks

                                        v.    BBW:I + M + TB

                                       vi.    Contraindicated in sepsis

                                      vii.    ADRs

1.    Injection site reaction

2.    Infection

                                     viii.    Antibody response—you are injecting proteins, which our body will see as foreign and mount an immune response

Infliximab

- MOA

- Indication

- Tx response

- BBW

- ADRs 

a.    Infliximab (Remicade®)

                                          i.    MOA: Ant-TNFα

                                         ii.    Indication: mod-severe + MTX

1.    Must use with MTX

                                        iii.    Dose: 3mg/kg IV at 0,2,6 wks then Q8 wks

                                       iv.    Therapeutic response: few days to a month

                                        v.    Combination is superior to MTX alone

                                       vi.    BBW:  I + M + TB

                                      vii.    Adverse effects

1.    Injection site reactions

2.    URTI

3.    UTI

4.    Antibody response—greater antibody response which is why you need to use MTX IV; Don’t use higher doses and cannot give out patient!

5.    Increased liver function tests (LFTs)—monitor more frequently   

Adalimumab

- MOA

- Indications

- Tx Response

- BBW

- ADRs

a.    Adalimumab (Humira®) à Humira = Human Antibody

                                          i.    MOA: anti-TNFα

                                         ii.    Indications: mod-severe + MTX; JIA

                                        iii.    Dose: human  so there is no need to give MTX

1.    (+) MTX: 40mg SQ QOW (Adult)

2.    (-) MTX: 40mg SQ QW (Adult)

3.    JIA 15-30kg: 20mg QOW

4.    JIA >30kg: 40mg QOW

                                       iv.    Therapeutic Response: 1-4 weeks

                                        v.    BBW: I + M + TB

                                       vi.    ADRs: Injection site reactions/rash, URTI, UTI

Golimumab

- MOA

- Indications

- Tx response

- BBW

- ADRs

                              i.    Golimumab (Simponi®)

1.    MOA: Anti-TNFα

2.    Indications: mod-severe + MTX

3.    Dose: 50mg SQ QM + MTX

a.    Less frequent

b.    No need to build up and can do once monthly injections but WITH MTX

4.    Therapeutic response: 6-13 months

5.    BBW: I + M + TB

6.    ADRs

a.    URTI

b.    Nasopharyngitis

c.       Prevalence of antibody response is less

Certolizumab

- MOA

- Indications

- BBW

- ADRs

                              i.    Certolizumab Pegol (Cimzia®)—humanized

1.    MOA: Anti-TNFα

2.    Indications: mod-severe

3.    Dose: (advised to give with MTX)

a.    Initially, W2, W4: 400mg SQ (given as two 200mg)

b.    Maintenance: 400mg SQ Q4W

c.       Attached to polyethylene glycol, allowing for less frequent dose and increased duration

d.    But must build up to dose

4.    BBW: I + M + TB

5.    ADRs

a.    URTI

b.    UTI

c.        Rash

Anakinra

• MOA
• Indication
• Tx Response
• ADRs

                              i.    Anakinra (Kineret®) à “Kineret = affects kidney (CrCl)”

1.    MOA: IL-1 receptor antagonist

2.    Indication: mod  to severe failing 1 or more DMARDs (> 18 years)

a.    + non-biologic DMARDs

3.    Dose: 100mg SQ daily

a.    CrCl < 30mL/min—consider 100mg QOD

4.    Therapeutic Response: 4-12 weeks

5.    Adverse Effects: local injection site reactions, infections, neutropenia

Toclizumab

• MOA
• Indication
• BBW
• Warnings
• Not recommended in
• ADR

                              i.    Tocilizumab (Actemra®)

1.    MOA: IL-6 receptor inhibitor

2.    Indication: mod to severe after TNF antagonist failure

a.    + MTX or non-biologic DMARDs

3.    Dose: 4mg/kg IV followed by an increase to 8mg/kg based on clinical response

a.    Dose every 4 weeks

4.    BBW: I + TB (No malignancy)

5.    Warnings: GI performation, changes in neutrophils, platelets, lipids and liver function tests, hypersensitivity

6.    Not recommended

a.    ANC < 2,000/mm³

b.    Platelets < 100,000/mm³

c.    ALT/AST > 1.5x’s ULN

7.    ADR: URTI, nasopharyngitis, headache, HTN

Abatacept

• MOA
• Indication
• Warning(s)
• ADRs

                              i.    Abatacept (Orencia®)

1.    MOA: bind to CD80/86 on T cells to prevent the costimulation needed to fully activate T cells

2.    Indication: mod to severe disease

a.    + non-biologic DMARDs

3.    Dose: 500-100mg IV (initial dose) then 2 or more (at weeks 2 and 4); Q4 weeks thereafter

4.    Indication: JIA > 6 years + MTX

a.    Usual Dose (< 75kg): 10mg/kg

5.    Warning in COPD patients

6.    No live vaccines within 3 months of d/c

7.    ADRs:

a.    Headache

b.    URTI

c.    Nasopharyngitis

d.    Nausea

e.    Other: dizziness, cough, back pain, HTN, dyspepsia, UTI, rash, and extremity pain

Rituximab

• MOA
• Indication
• Warnings/Precautions
• BBW
• ADRs

                              i.    Rituximab (Rituxan®)

1.    Monoclonal antibody targeting CD20 on B cells

2.    MOA: depletes peripheral B cells

3.    Indication: mod to severe after TNF antagonist failure + MTX

4.    Dose: 2 IV infusions of 1000mg (two wks apart)

a.    May repeat after 24 wks; no sooner than 16 wks

5.    Pre-medication (minimize infusion reactions)

a.    Methylprednisolone 100mg IV given 30 min prior

6.    BBW

a.    Fatal infusion reactions à if it isn’t fatal, can restart at 50% of dose

b.    Tumor lysis syndrome (TLS)—concern in cancer patients

c.    Severe mucocutaneous reactions

d.    Progressive multifocal leukoencephalopathy (PML)

7.    Non-fatal infusion rxns

a.    Potentially restart at 50% of dose

8.    Give nonlive vaccines at least4 weeks prior

9.    ADR

a.    URTI, nasopharyngitis, UTI, bronchitis, serious infections, CV events

a.    Prednisone, methylprednisolone, triamcinolone

b.    MOAs

                                          i.    Interferes with presentation to T lymphocytes

                                         ii.    Inhibit prostaglandin/leukotriene synthesis

                                        iii.    Inhibit neutrophil/monocyte superoxide radical generation

c.    Uses

                                          i.    Bridging therapy while awaiting DMARDs response

                                         ii.    Adjunct Sx control: lowest dose possible QD

                                        iii.    Flare-ups

1.    High dose PO with taper     OR

2.    IA (intra-articular) for localized flares—involved knee joints

d.    Dosage forms: oral, IM, IV, intraarticular

e.    ADR: osteoporosis, HTN, weight, gain, fluid retention, hyperglycemia, etc.

f.     Prevention of bone loss

                                          i.    Calcium (1500mg) + vit D (400-800IU)/day

                                         ii.    Bisphosphonates—if PT had osteoporosis