Transcript MarkFrancistotalho - SIU School of Medicine

Wrap-up Session for Ms. Long:
Part I
Mark Francis
Rheumatology
SIU School of Medicine
Impact of Musculoskeletal Problems
• $215,000,000,000 a year
• 2.5% of the GDP
• 1,500,000,000 lost days from work
• 34% of disability
– Heart disease 10%
– Lung disease 7%
• 315,000,000 visits per year
• 15-25% of patient visits
Sources of Information
• Best place to start:
– Kippel. The Primer on the Rheumatic Diseases.
– Chris at 545-0184. $11.
• Major Texts:
– Kippel
– Kelley
– Koopman
Acute Polyarticular Arthritis
• Viral infection (hepatitis, rubella, parvovirus, etc.).
• Bacterial endocarditis.
• Acute rheumatic fever.
• GC arthritis.
• Serum sickness reaction.
• Unknown.
• Start of a chronic polyarticular arthritis.
Chronic Polyarticular Arthritis
• Extremely broad differential diagnosis.
• The keys to the diagnosis of polyarticular arthritis:
– Extra-articular symptoms
– Extra-articular signs
The Specificity for Diagnosis a
Polyarticular Arthritis
• Review of Symptoms
• General Physical Exam
Rheumatoid Arthritis: Criteria
• AM Stiffness > 1 hour.
• Synovitis in 3 or more joint groups.
• Symmetric synovitis.
• Synovitis involving hands and wrists.
• Rheumatoid Nodules.
• RF.
• X-ray changes:
– Periarticular osteopenia
– Erosions
Rheumatoid Arthritis
• Arthritis needs to be present for 6 weeks.
• Should be on second line agent after ~8 to 12 weeks.
• Do not make diagnosis based on RF.
Some Common Features of Autoimmune
Disorders
• Interactions between:
– MHC genes.
– Non-MHC genes.
– Environmental factors.
• By itself, none of these features cause an
autoimmune disease.
• Women are more susceptible.
• Onset typically in patients aged 20-50.
Pathology: Pannus
• Edema
• Hypertrophy and Hyperplasia of synovial lining cells
• Proliferation of blood vessels, but relative ischemia
• Deposition of fibrin
• Perivascular inflitrates
– CD4+ > CD8+ lymphoytes
• Enhanced levels of MHC class II
• Enhanced levels of adhesion molecules
– B cells
– Macrophages
Pathology: Pannus
• Synoviocytes
– Type A, Macrophage-like
– Type B, Fibroblast-like
• Pannocytes (Fibroblast-like cells)
– Produce MMPs, esp at synovial-pannus-cartilage
junction
– Some increase in TIMPs
Synovial Fluid:
Elevated Levels of
• PMNs
– Many inflammatory mediators
– MMPs
• Platelet-derived growth factor
– Fibroblast proliferation
• GM-CSF
– Dendritic cell proliferation
Synovial Fluid:
Elevated Levels of
• IL-8
– Neutrophil accumulation
– Angiogenesis
• IL-6
– B cell differentiation
– Acute phase response
– Osteoclast differentiation
Synovial Fluid:
Elevated Levels of
• IL-1
– Lymphocyte activation
– PGE2 synthesis
– Fibroblast proliferation
– MMPs
– Inhibition of chondrocytes
– IL-1 receptor agonist (IL-1ra; IRAP)
– Increased osteoclasts
Synovial Fluid:
Elevated Levels of
• TNF-a
– Lymphocyte and monocyte activation
– Recruitment of leukocytes
– Cachexia
– MMPs
– PGE2 synthesis
– Expression of MHC class II molecules
IL-1 and TNF-a
• These cytokines stimulate each other’s secretion
• Overlapping activity; act synergistically
• Oversimplified dogma:
– TNF-a:
inflammation
– IL-1:
erosion
Synovial Fluid:
Elevated Levels of
• TGF-b
– Chondrocyte proliferation
– Collagen synthesis
– Neovascularization
– Decreased MMPs
– Increased TIMPs
Stimulation of
Cartilage Degradation
• IL-1 and TNF-a: degradation
• TGF-b: protection
• Fibronectin fragments: increased IL-1
• Hyaluronan fragments: increased IL-1 and TNF-a
• Cyclic compression: matrix synthesis
• Static compression: degradation
Wrap-up Session for Ms Long:
Part II
Mark Francis
Division of Rheumatology
SIU School of Medicine
Therapy Over Time
• Senandipitous Observations
– Hydroxychloroquine
– Methotrexate
• Treating an Infection
– IM Gold
– Sulfasalazine
• Antiproliferative Therapy
– Cyclophosphamide
– Azathioprine
– Leflunomide (Arava)
• Bench to Bedside: More Targeted Therapy
Effectiveness of Older Therapy
• Clinical response measured by ACR20
• Affect on erosive disease?
American College of Rheumatology
ACR 20
• >20% improvement in joint tenderness
• >20% improvement in joint swelling
• >20% improvement in 3 of the following:
– Sedimentation rate
– Physician global assessment
– Patient global assessment
– Pain
– Disability
Effectiveness of Older Therapy
• Clinical response measured by ACR20
• Affect on erosive disease?
Second Line Agents
5 years later
Lack of Efficacy
• Hydroxychloroquine
• Sulfasalazine
• Oral Gold
• Minocycline
Toxicity Problems
• IM Gold
• Cyclophosphamide
• Azathioprine
• D-Penicillamine
• Cyclosporin A
Immunosuppresive Agents: Complications
Common to Most
• Major:
– Bone marrow suppression
– Liver toxicity
– Infections
– Increased risk of cancer
– Teratogenesis
• Minor:
– GI Intolerance
– Rash
Methotrexate
• Weekly dosing.
• May have an earlier effect (6-8 weeks).
• Tolerated for longer periods of time.
• Folic acid for minor side effects.
• Hepatic fibrosis.
• Increased nodulosis.
• Pneumonitis.
• Adenopathy.
Methotrexate: Problem Patients
• Liver Problems:
– Hepatitis
– Alcohol
• Psoriasis.
• Sexually active, either sex.
Biologic Agents
• Not at all clear this approach would work
– RA is a cytokine soup
– Redundancy of cytokines
• Biologic Modifiers: Negative Studies
– Anti-CD4
– Anti-CD5
– Anti-CD52
Blocking TNF-a:
Etanercept (Enbrel)
• p75 TNF-R Fc Fussion Protein
• 25mg subcutaneously twice weekly
SS
S
S
S
S
• Recent shortage resolved last month
SS
C H3
S
S
S
S
SS
C H2
Fc region of
human IgG1
Extracellular domain of
human p75 TNF receptor
ACR 20 Responses: Early RA
80
Year 1
Year 2
72%
*p<0.05
72%*
65%
59%
% patients
60
40
20
0
MTX Etanercept
MTX Etanercept
20 mg
20 mg
25 mg
25 mg
Genovese. Arthritis Rheum. 2000.
Blocking TNF-a:
Infliximab (Remicade)
• IV infusion (3mg/kg)
– At 0, 2, and 6 weeks, then
– Every 8 weeks
• Blocking antibodies and combined therapy v D2E7
Mouse
(Binding site for TNF)
Human (IgG1)


ATTRACT
Study Design
Five Treatment Groups
(428 Patients)
MTX Control
(week 0, 2, 6)
Every 4 weeks
(week 6-102)
3 mg/kg
REMICADE® (infliximab)
(week 0, 2, 6)
Every 4 weeks
(week 6-102)
Every 8 weeks*
(week 6-102)
10 mg/kg
REMICADE® (infliximab)
(week 0, 2, 6)
Every 4 weeks
(week 6-102)
All Treatment groups received MTX
*Matched with placebo infusions given at interim 4-week visits
Every 8 weeks*
(week 6-102)
ATTRACT: Primary Efficacy Analysis
ACR20 at 30 Weeks
All
Infliximab
178/340
(52%)
ATTRACT: Secondary Efficacy Analyses
ACR50 at 30 Weeks
All
Infliximab
94/333
(28%)
ACR70 at 30 Weeks
All
Infliximab
40/333
(12%)
ATTRACT
REMICADE® (infliximab)
Sustained Clinical Improvement
Improvement in Swollen Joints
Non-Pharmaceutical Therapy
• Education
• Function: Importance of PT and OT
• Exercise and Rest
• Podiatry
• Surgery
• Nursing Support
• Social Work
NSAIDS
• How often
• How much
• When to change
• What to expect
• What about Cox-2 inhibitors?
Key Points in Managing
Immunosuppresive Agents
• Understand Unique Complications:
– Alopecia (CTX)
– Hypertrichosis (CSA)
– Stomatitis (MTX, AZA)
– Gum hyperplasia (CSA)
– Liver toxicity (MTX, CSA, AZA)
– Azospermia (CTX)
– Amenorrhea (CTX)
Key Points in Managing
Immunosuppresive Agents
• Understand Unique Complications (2):
– Cystitis (CTX)
– Pneumonitis (MTX)
– Renal toxicity (CSA)
– Hypertension (CSA)
– Neurotoxicity (CSA)
Key Points in Monitoring
Immunosuppresive Agents
• When in doubt, monitor more frequently.
• Be particularly careful at initiation or with dose
changes.
• Adjust frequency for concurrent diseases or
medications.
• Watch for trends.
• Be cautious with refills.
• I got it! I got it! Know who is doing what.
Steroids
• Broadest effect on the immune system.
• Quickest onset of action.
• The cure for arthritis, but . . .
• Treating one disease with another:
– Is the patient’s problem worse than Cushing’s
syndrome?
Steroids: Side Effects 1
• Increased appetite and weight gain.
• Fluid retention.
• Acne.
• Cushingoid habitus.
• Hypertension.
• Osteoporosis.
• Athrosclerosis.
Steroids: Side Effects 2
• Diabetes.
• Glaucoma.
• Cataracts.
• Avascular necrosis
• Increased susceptibility to infection.
• Impaired wound healing.
• Myopathy.
• Mood alteration.
Methotrexate
• Weekly dosing.
• May have an earlier effect (6-8 weeks).
• Tolerated for longer periods of time.
• Folic acid for minor side effects.
• Hepatic fibrosis.
• Increased nodulosis.
• Pneumonitis.
• Adenopathy.
Methotrexate: Problem Patients
• Liver Problems:
– Hepatitis
– Alcohol
• Psoriasis.
• Sexually active, either sex.
Leflunomide (Arava)
• Monitoring is similar to methotrexate with similar concerns
about liver toxicity.
• Beware of unknown side effects with new medications.
• Loading dose (100 mg per day x 3 days).
• Do not use if at risk for pregnancy. Cholestryamine to eliminate
drug.
• Decreases erosions.
Hydroxychloroquine (Plaquenil)
• Excellent side effect profile.
• Monitor for retinal toxicity (rare).
• Does not require blood monitoring.
Hydroxychloroquine (Plaquenil):
Not Quite Dead Yet
• Elderly patients
• Milder disease
• Problem with monitoring
• SLE still in differential diagnosis
• Combination therapy
• Low risk tolerant patients
Azathioprine (Imuran)
• Myelosuppression.
• Increased risk of myelosuppression if:
– Renal insufficiency.
– Use of ACE inhibitors.
• Risk of lymphoproliferative disorders.
• Adjust dose if used with allopurinol.
IM Gold
• Weekly injections.
• Start with test dose (1mg).
• Nitrinoid reactions possible.
• Arthralgias and myalgias.
• Eosinophilia: beware of pending toxicity.
• Rashes and oral toxicity.
• Renal toxicity.
Oral Gold
• Much less toxic than IM gold.
• Primarily GI toxicity, esp diarrhea.
Sulfasalazine (Azulfidine)
• Contraindicated if hypersensitive to sulfonamides or
ASA.
• Relatively safe side effect profile.
• Hemolytic anemia if G6PD deficiency.
• Oligospermia.
D-Penicillamine
• Induction of autoimmune disorders: SLE,
Myesthenia Gravis, Goodpasture’s, etc.
• Skin rash with oral lesions: possible pemphigoid
reaction: stop the medicine.
• Dsyguesia: loss of taste.
• Penicillin allergy is not a contraindication.
D-Penicillamine
• For toxicity, the rate of change is more significant
than the absolute level. Go low; go slow.
• Myelosuppression.
• Patients with adverse reactions to IM gold are more
prone to adverse reactions, esp proteinuria.
Cyclosporin A
• Narrow therapeutic window.
• Dosing is less aggressive for RA compared to
transplantation.
• Need a compliant patient.
• Hypertension. Monitor BP.
• Renal Failure. Monitor Cr.
• Gout.