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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 – – – – 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 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 • • • • • • • • 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 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 – – – – 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 (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 • • • • • • • • 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 • • • • • • • • • • • 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