Download Rheumatoid Arthritis

Rheumatology Overview, 2008
Focusing on RA and SLE
Jonathan Graf, M.D.
Assistant Adjunct Professor of Medicine, UCSF
Division of Rheumatology, San Francisco General
Hospital
Arthritis - Misconceptions
• “You’re an Arthritis Doctor. What’s it like
taking care of so many old patients”
• “Are all of your patients in wheelchairs?”
• “Arthritis is not a big deal because it’s not
life-threatening”
All Arthritis Patients are Old
• Many forms of Arthritis
• Rheumatoid Arthritis commonly affects
young women of childbearing age
• Osteoarthritis affects younger people who
run, have traumatized their joints, are
overweight, etc….
• Gout can affect people of all ages
Wheelchairs and Canes
• Thanks to recent advances and medical research,
not as many face life in a wheelchair
• Treatments for many inflammatory arthritic
conditions such as Spondylitis and Rheumatoid
Arthritis have improved dramatically
• Joint replacement surgery has improved outcomes
in Osteoarthritis
Arthritis is not Life-Threatening
• Systemic inflammatory diseases that cause
arthritis can affect other organs and lead to lifethreatening complications
• Chronic inflammation has now been linked to
heart disease
• Advanced Osteoarthritis limits mobility and can
lead to secondary health problems (obesity, heart
problems, etc…)
• An in cases that aren’t life-threatening, since when
is living in pain not life-altering/life-imparing.
Judgement call!!
Arthritis
All forms of arthritis are not created equal
• Inflammatory
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RA
SLE
Crystalline (Gout)
Vasculitis
• Non-Inflammatory
– Osteoarthritis
• “Arthritis”-like diseases
– Fibromyalgia
Inflammatory Arthritis
Joint swelling
Joint warmth
Joint redness
Joint pain and stiffness
Morning>Afternoon symptoms
Worse with rest, better with use (gelling)
Can Have Systemic Components
Inflammatory Arthritis- A Component of
Rheumatic Diseases
• Arthritis is a common, unifying feature to a whole host of
systemic auto-immune and inflammatory diseases!!!
• Characteristic pattern may vary by disease
• Crystals and inflammatory reaction
– Gout, pseudogout
• Rheumatoid Arthritis
• Seronegative Spondyloarthropathy
– Ankylosing spondylitis
– Psoriatic Arthritis
– Reactive Arthritis
– Inflammatory Bowel Disease Associated Arthritis
Inflammatory Arthritis, Diseases
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Lupus
Scleroderma
Myositis
Hashimoto’s Thyroiditis
Sjogren’s Syndrome
Many More!!!!!
Arthritis is a common, unifying feature to a whole
host of systemic auto-immune diseases!!!
Rheumatoid Arthritis
• One cause of inflammatory arthritis
• Systemic inflammatory disease, primarily
involving the synovial membrane of
diarthrodial joints
• Prevalence in North America between 1-2%
• Most prevalent in women of child-bearing
age (4th-6th decade)
• Can occur in any person at any age
ACR Criteria for Diagnosis of
RA (4 of 7)
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Morning Stiffness>1 hr. duration
Arthritis of 3 or more joints
Arthritis of the hand joints
Symmetric arthritis
Rheumatoid nodules
Serum rheumatoid factor
Radiographic changes
RA, Etiology
• Probable background genetic susceptibility
(multiple genes/risk factors involved)
– Concordance rates 15-30% identical twins
– 2.5-3.0 times more prevalent in Women>Men
• Likely environmental triggers in people with
genetic susceptibility
– Disease of the New World, ? 16th C. Ohio river valley
– Not seen until late 18th century in Europe
Genetic Risk Factors
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Family history
Female Sex
Specific genes: HLA-DR4
Specific region in HLA DRB1 gene confers
increased risk of RA and severity
Non Genetic Risk Factors
• ? Bacterial or Viral Agent
– Parvovirus, Hepatitis, Lyme, and Rubella
• ?Environmental Triggers
– Tobacco, Caffeine
RA, Clinical Features
How to Differentiate from other Osteoarthritis
• Symmetric polyarthritis
• Usually small-medium
joints are involved
• Generally chronic disease
(20% acute onset)
• Often leads to erosive,
deforming, and disabling
disease
• 20% have extra- articular
manifestations
Ethical Question: Does a disease have to be “life-threatening” for it to be
considered important?..... The ravages of a chronic destructive arthritis.
How does this person walk????
RA is a Systemic Disease –
Rheumatoid Arthritis can cause
Blindness
• Rheumatoid Nodules
• Interstitial Lung
Disease
• Vasculitits
• Felty’s Syndome
• Ocular Disease
• Secondary Amyloid
Rheumatoid Nodules
RA – Vasculitis. Rheumatoid
Arthritis can be life-threatening
RA – Synovitis: This is what an inflammatory
arthritis looks like. 81 YO female with Rheumatoid Arthritis
RA – R>L Knee Synovitis: 81 YO
Female Patient
RA – Rheumatoid Nodules
Normal Joint Histology
• Synovial lining 1-2
layers of synoviocytes
• Sub-lining layer of
loose connective tissue
and blood vessels
RA Joint Pathology
• Inflammation,
capillary leak, fibrin
deposition
• Synovial Hyperplasia
• Cellular infiltrate
– Macrophages
– Lymphocytes
– Can resemble
lymphoid tissue in 1/3
RA Pathology
• Synovium becomes laden
with macrophages,
fibroblasts, and multinucleated giant cells
(resemble osteoclasts)
• Synovial membrane
(pannus) expands, actively
invades and erodes
surrounding bone and
cartilage
Rheumatoid Arthritis
• Disability costs are high, both in terms of direct
and indirect medical costs
– 35% of patients with 10 years disease duration are
work-disabled
– Decline from 50% rate reported in 1987
Arthritis Rheum. 2008 Mar 27;59(4):474-480
RA: Chronic Joint Destruction and
Disability – What We Try to Prevent
Ra: Traditional Treatment Paradigm
• Pyramid of therapy
– Start conservatively
– Gradually ascend the
pyramid in order of
potency and toxicity of
therapy
– Only the most severely
affected patients receive
immuno-supressive,
DMARDs
– DMARD therapy begun
only after period of
significant delay
Re-Thinking the RA Treatment
Pyramid
• Emphasizes earlier diagnosis and initiation of therapy
with disease modifying anti-rheumatic drugs
Early RA: The Window of
Opportunity to Intervene
The Window of Opportunity
Eventually Closes for Many….
• Chronic disease progression
leads to permanent joint
deformity, destruction, and
disability
• Empirically, RA is a
different disease the longer
disease activity progresses
without effective control
– More difficult to suppress
activity and treat
– More extra-articular disease?
ACR RA Practice Guidelines 2002
• Most patients with
Rheumatoid Arthritis
should be evaluated
expeditiously
• Treatment with DMARD
instituted within 3 months
of diagnosis
• Goals are to prevent or
control joint damage,
prevent loss of function,
and decrease pain
RA Pharmacologic Therapy:
DMARDs
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Methotrexate
Leflunomide (Arava)
Sulfasalazine
Azathioprine
Mycophenolate Mofetil
“Corticosteroids”
“Hydroxychloroquine”
“Minocycline”
Methotrexate
• Cornerstone DMARD, now 1st line therapy, alone
or in combination for mod.-severe RA
• Blocks Dihydrofolate reductase
• Inhibits production of tetrahydrofolate, a single
carbon donor
• Leads to diminished production of purines and
inhibits DNA synthesis (although there are other
mechanisms likely involved)
• Reduces proliferative potential of replicating
immune and inflammatory cells
Methotrexate
• Long-term benefits in symptom improvement &
retardation of joint damage
• Long term – well tolerated with acceptable safety
profile (no ETOH)
• Available as IM/liquid/tablet preparations
• Starting dose 7.5 mg/WEEK – up to 25 mg/wk
• Renally cleared – be careful and adjust dose
Methotrexate Adverse Events
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GI - Mucositis, diarrhea, abdominal pain
Hematologic - Cytopenias, macrocytosis
Hepatic- Transaminitis, fibrosis, and cirrhosis
Pulmonary - Hypersensitivity pneumonitis,
pulmonary fibrosis
Infections
Neoplasia - reversible lymphoproliferative
disorder, lymphoma, and leukemia
Accelerated nodulosis and vascultitis
Reproductive – abortifacient and teratogen
– Must use birth control and d/c drug 2-6 months before
planned pregnancy
Combination DMARD Therapies:
Some Step Up, Others Step Down
• Methotrexate +SSZ +Plaquenil +/- Prednisone
• Arava + SSZ + Plaquenil +/- Prednisone
• Methotrexate X Arava ----- Generally not done
• More and more, combination therapies of
DMARDs and Biologic medications being used
earlier in the course of treatment
Why Move Towards Combination
Regimens with Biologics??
The Current Pyramid Paradigm
• Early initiation and titration of DMARD
• If incomplete response to DMARD alone, after reasonable
titration, addition of biologic recommended
Biologic Therapies
• What is meant by the term Biologic
Therapy?
• Double meaning:
– Organic compounds made by living cells
• As opposed to products from a chemistry lab
– Modify biologic responses
• Antibody-antigen interactions
• Cytokine-receptor interactions (both ends)
• Cell signaling proteins, inhibitors, or ligands
Families of Biologic Therapies
• Anti-Tnf medications
– Etanercept (cytokine receptor fusion protein)
– Infliximab (anti-cytokine antibody)
– Adalimumab (anti-cytokine antibody)
• B-cell depleting agents (monoclonal antibody)
– Rituximab
• T-cell costimulation inhibitors (receptor-ligand )
– Abatacept
• Il-1 Inhibitors (Il-1 cytokine receptor decoy)
– Anakinra
Anti-TNF Family of Biologics
Anti-Tnf medications
Etanercept (cytokine receptor fusion protein)
Infliximab (anti-cytokine antibody)
Adalimumab (anti-cytokine antibody)
TNF Effects: The Good and the Bad
• Good: TNFa and TNFb regulate biological functions necessary
for normal inflammatory and immune responses.
– TMF-a absolutely essential for granulomatous host defenses against
intracellular bacteria
– MTb, fungal infections, listeria
• Bad: TNF-a binds membrane-bound TNF receptors and
mediates pro-inflammatory processes implicated in
inflammatory arthritis.
Man-Made Advances in TNF
Biology
• The family of anti-TNF therapies
– Etanercept (Enbrel)
– Infliximab (Remicade)
– Adalimumab (Humira)
Etanerceot Infliximab Adalimumab
Etanercept
• Etanercept recombinant,
dimeric fusion protein
• Consists of the soluble
human p75 tumor necrosis
factor (TNF) receptor
coupled to the Fc fragment
of human IgG1 lacking the
CH1 domain.
• Binds soluble TNF-a and
TNF-b and prevents
activation of TNF-Rs
Infliximab
• Infliximab is a
“humanized” monoclonal
antibody
• TNF binding region
derived from mouse antiTNF monoclonal antibody
• Attached to constant
region of human IgG1
kappa antibody.
• Chimeric molecule not
100% human
Adalumimab
• Adalimumab is a recombinant,
fully human monoclonal IgG1
kappa antibody.
• All monoclonal anti-TNFs bind
membrane bound and soluble
TNF (May have added benefit
leading to clearance or
apoptosis of cells expressing
surface TNF)
• All monoclonals bind only
TNF-alpha (not TNF-b)
– May explain differential effects
of anti-TNF medications in
IBD
The Anti-TNF Clan
• Differences between agents:
Enbrel
Ab
Form.
Human
T½
N
Injection
Y
S
Remicade
Y
Infusion
N
L
Humira
Y
Injection
Y
L
Contraindications
• History of latent tuberculosis unless/until they have completed an adequate
courses of prophylactic therapy (Duration up for debate)
• Active acute or chronic infections (HCV may become exception)
• Active or suspected malignancies.
• Hypersensitivity to an anti-TNF agent or mouse product (infliximab)
• Anti-TNF agents in the setting of hepatic disease or renal failure has not
been studied.
• Anti-TNFs are generally contraindicated in patients with moderate or
severe congestive heart failure (some have black box warning)
• History of demyelinating disease
Anti-TNFs: Like all success
stories, there are always
complications
• Increased risk of infections! (OR of 2.0 for serious
infection in large meta analysis published in JAMA
2006)
• Increased malignancy risk: Always thought of as a
theoretical risk, now controversial evidence that RA
patients may be at increased risk of lymphoma and/or
solid tumors
• May worsen symptoms of congestive heart failure.
Anti-TNF Therapy: Allergic and
Idiopathic Reactions
• Dermatologic reactions
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Localized: Mild-moderate injection site reactions
erythema, pruritis, pain, and/or swelling
reactions are commonly self-limiting early in the course of therapy.
FDA has recent case reports of Steven’s Johnson and TEN with all
three
• Infusion reactions, especially with infliximab
– within 1-2 hours after receiving the therapy
– fever, chills, urticaria, and cardio-pulmonary symptoms
– antibody mediated serum-sickness type of syndrome also reported
that’s separate than from typical infusion reaction
Systemic Lupus Erythematosis
• Systemic Disorder, involving multiple
organs in multiple ways
• Women:Men = 9:1
• African American/Caribbean in US/UK: Dz.
is 3 times more common
• Peak Age of Onset 20’s & 30’s
• Incidence has tripled since 1970’s to
5.56/100,000 population
SLE: ACR Criteria:
4 of 11 Criteria without better
explanation (Not diagnostic)
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Malar Rash
Discoid Rash
Photosensitivity
Oral Ulcers
Arthritis
Serositis
Renal Disorder
SLE Criteria Cont.
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Hematologic Disorder
Immunologic Disorder
ANA
Neurologic Disorder
Malar Rash
• Fixed malar
distribution of
erythema, flat or
raised
Discoid Rash
• Erythematous raised
patches with keratotic
scaling and follicular
plugging; some
atrophic scarring in
chronic lesions
Photosensitivity
• Skin rash as an
unusual reaction
sunlight, by patient
history or physical
examination
Oral Ulcers
• Oral or
nasopharyngeal ulcers,
usually painless,
observed by a
physician
Arthritis
• Non-erosive arthritis
involving two or more
peripheral joints,
characterized by
tenderness, swelling,
or effusion
Other SLE Criteria
• Serositis
– Pleuritis (convincing
history of pleuritic pain
or rub heard by a
physician or evidence
of pleural effusion
– Pericarditis
(documented by EKG,
rub, or evidence of
pericardial effusion)
• Renal Disorder (can
lead to renal failure)
– Persistent proteinuria
>0.5g/day (or>3+)
– Cellular casts of any
type (glomerulonephritis)
Hematologic Abnormalities
• Hemolytic anemia (usually coomb’s
positive)
• Leukopenia (WBC < 4,000 on at least 2
occasions)
• Lymphopenia (<1500 on 2 or more
occasions)
• Thrombocytopenia (PLT<100,000 on 2 or
more occasions)
Immunologic Disorder
One of the Following
• Anti-dsDNA
• Anti-Smith
• Positive findings of anti-phospholipid Abs
– Abnormal level of either IgG or IgM CLIP Abs
– Positive test for Lupus Anticoagulant (RVVT)
– False positive RPR/VDRL > 6months neg. FTA
Positive ANA
• An abnormal titer of ANA in the absence of
drugs known to be associated with “druginduced lupus syndrome”
Neurologic Disorder
• Classically defined only as:
– Seizures (in the absence of other causes)
– Psychosis (in the absence of other causes)
• Other CNS manifestations
– Headaches
– Cognitive dysfunction
Organ System Involvement in
Flares of SLE, Hopkins Cohort:1991
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Constitutional
Musculo-skeletal
Dermatologic
Renal
Neurologic
Hematologic
Serositis
Pulmonary
66%
58%
47%
22%
21%
17%
12%
7%
Permanent Organ Damage in
SLE, Hopkins Cohort: 1991
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Musculo-skeletal
Neuro-psychiatric
Ocular
Renal
Pulmonary
Cardiovascular
GI
Skin
Peripheral Vascular
5.5%
Malignancy
Premature Gonadal Failure
25.2%
15%
12.6%
11.7%
10.4%
10.1%
7.4%
7.4%
2.5%
1.2%
Cyclophosphamide
• Pulse IV therapy mainstay for Diffuse
Proliferative GN secondary to SLE
• Less-studied, but significant therapy for
severe systemic manifestations
– CNS vasculitis
– Transverse Myelitis
– Pulmonary capillaritis/ diffuse alveolar
hemorrhage/severe interstitial pneumonitis
Cyclophosphamide Therapy:
Glomerulonephritis
• 0.5 – 1.0 g/m2 dosed
monthly for 6 months
• 1 mg/kg/day concomitant
prednisone Rx.
• Dosed every 3 months for
next 18 months
• 5-year renal survival rates:
60-90%
• Frequent monitoring
– Cell counts nadir 10-14
days post therapy
– Urinalysis: Hemorrhagic
cystitis
Annals of Internal Medicine, 2001
Cyclophosphamide: Side Effects
• Short-Term
– Nausea, alopecia
– Immunosupression, opportunistic infections
– Cytopenias
• Medium-Term
– Hemorrhagic Cystitis
• Long Term
– Transitional Cell Carcinoma
– Hematologic malignancies
– Infertility
• Non-responders (to follow)
• Relapses: Re-treat or try alternative therapies
Minimizing Toxicity: Other
options?
• Lower, more frequent dosing of Cytoxan
• Shorter courses of induction therapy
followed by maintenance therapy
– Azathioprine
– Mycophenolate Mofetil
• Induction therapy with MMF
Mycophenolate Mofetil
• Hydrolyzed to active form: Mycophenolic acid
• Inhibits Inosine Monophosphate Dehydrogenase: Blocks
purine synthesis
• Affects activated/dividing lymphocytes
• Originally developed to prevent allograft rejection
• Dosed: 500 Mg PO BID – 1.5g PO BID
Potential Novel Therapies
• Anti B-cell therapies
• Anti-T-cell therapies
– Co-stimulatory signal blockade
• Vaccination Strategies
• Marrow Ablation - Transplant
B-cell Depleting Therapies:
Rituximab
• Attractive for diseases characterized by
aberrant, pathologic auto-antibody
formation (SLE, APLA, ITP)
• CD20 expressed almost exclusively on Bcells
• CD20 not expressed on Plasma cells
• Anti-CD20 Antibody binds B-cells and
depletes B-cells through unclear
mechanism(s)
– Apoptosis, reticulo-endothelial system
clearence, etc…
Rituximab
• (Rituximab) approved to deplete B-cell
lymphomas
• Phase I/II open label, dose-escalation study
of 18 patients with non-threatening SLE
• B-cell depletion correlated with
improvement in rash, arthralgias, fatigue
• Case reports of use in severe, refractory
disease with some possible utility
The Sun is Rising for Patients with Rheumatic
Diseases: The Future is Bright