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Rheumatology Overview, 2008Focusing 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 life-threatening 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!!
ArthritisAll forms of arthritis are not created equal
• Inflammatory– 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
• 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)
• 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
• 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 FeaturesHow 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 multi-nucleated 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 1987Arthritis 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
• 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• 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 anti-TNF 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 Remicade Humira
Ab N Y Y
Form. Injection Infusion Injection
Human Y N Y
T ½ S L 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– 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)
• Malar Rash
• Discoid Rash
• Photosensitivity
• Oral Ulcers
• Arthritis
• Serositis
• Renal Disorder
SLE Criteria Cont.
• 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 (glomerulo-nephritis)
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 DisorderOne 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 “drug-induced 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• Constitutional 66%• Musculo-skeletal 58%• Dermatologic 47%• Renal 22%• Neurologic 21%• Hematologic 17%• Serositis 12%• Pulmonary 7%
Permanent Organ Damage in SLE, Hopkins Cohort: 1991
• Musculo-skeletal 25.2%• Neuro-psychiatric 15%• Ocular 12.6%• Renal 11.7%• Pulmonary 10.4%• Cardiovascular 10.1%• GI 7.4%• Skin 7.4%• Peripheral Vascular 5.5%• Malignancy 2.5%• Premature Gonadal Failure 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 B-cells
• 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