Rheumatoid Arthritis

Acknowledgements Dr. Andrew Thompson, rheumatologist at SJHC and developer of the UWO rheumatology medical school program

Objectives Gain a basic understanding of Rheumatoid Arthritis Understand the presentation of Rheumatoid Arthritis (Inflammatory Arthritis) Understand the current treatment paradigm and medications used

Case Presentation 43 yo woman, has been healthy apart from: C-Section for Mild depression Her current medications are Sertraline 100 mg per day (depression) Naproxen 500 mg twice a day (recent joint pain)

Case Presentation 4 months ago developed pain in the left knee with some mild swelling. The episode lasted a few days and then went away.

Case Presentation About a week later the right knee began to swell and become sore Then both wrists began to swell and become sore. She also noticed some soreness in her feet. About two weeks later her hands started to stiffen up and she couldn’t get her rings on.

Case Presentation She feels stiff when she wakes up in the morning and this stiffness lasts for at least 3 hours She has no energy and has missed the last week of work Her sleep is difficult because she is uncomfortable She isn’t running because it “hurts too much”

Differential Diagnosis INFLAMMATORY POLYARTHRITIS Infection Rheumatoid Arthritis Seronegative Arthritis (Psoriatic) Connective Tissue Disease (SLE etc) Associated with another Systemic Disease

Who gets RA? ANYONE CAN GET RA Common Age to Start: 20’s to 50’s From babies to the very old Common Age to Start: 20’s to 50’s Sex: Females more common than males 3:1

How does RA start? RA usually starts off slowly (insidious) over weeks to months and progresses (70%) It can come on overnight (acute) but this is rare (10%) It can come on over a few weeks (subacute – 20%) Palindromic Presentation RACECAR, RADAR, MOM, DAD

How does RA start? Initially, most patients notice stiffness of the joints which seems more pronounced in the morning Some fatigue Some pain

What Joints are affected? RA usually begins as an oligoarticular process (<5 joints) and progresses to polyarticular involvmement Has a predilection for the small joints of the hands and feet!

Small Joints of the Hand

What Joints are affected?

How are the Joints Affected Joints are usually Swollen Warm NOT RED (might be a bit purple)

NO REDNESS!

Morning Stiffness Prominent Feature Greater than 60 minutes of morning stiffness (Patients minimize) Some patients have difficulty answering the question because they are stiff all day “How long does it take until you are the best you are going to be?”

Morning Stiffness Inflammatory fluid increases in and around the joint As patients get moving the fluid gets resorbed Stiffness can occur after rest “gelling”

Constitutional Features Fever – Unusual Weight Loss – Can be seen with severe polyarticular disease (again not common) Anorexia – Unusual Fatigue – VERY COMMON Sleep Disturbance – VERY COMMON Musculoskeletal Reasons Neurologic Reasons – Carpal Tunnel Psychological Reasons – Worry about illness, finances, job, family etc.

Functional Status In the Rheumatology Clinic we use a Health Assessment Questionnaire (HAQ) Dressing, Bathing, Grooming Cooking, Cleaning, Shopping Mobility – Walking and Standing Working Social Activities & Sports Rank the Functional Status (IMPORTANT) Mild, Moderate, or Severe

Pleasure Work Cooking Cleaning Shopping Dressing Bathing Grooming

Rheumatoid Arthritis is … Usually insidious in onset Adds joints over time Has a predilection for the small joints of the hands and feet Joints become warm and swollen but not red Morning stiffness is greater than 1 hour Patients are often tired and don’t sleep properly Can result in significant disability very quickly

Doesn’t just affect the joints EXTRA-ARTICULAR MANIFESTATIONS

Xerophthalmia (Dry Eyes)

Xerostomia (Dry Mouth)

Raynaud’s Phenomenon

Carpal Tunnel Syndrome

Pleural Effusion

Rheumatoid Nodules

Rheumatoid Nodules

Rheumatoid Vasculitis

Extra-Articular Manifestations Sicca Features: Xerostomia & Xerophthalmia Raynaud’s Phenomenon Neuropathy: Carpal Tunnel Syndrome Rheumatoid Nodules Pleural Effusions Rheumatoid Vasculitis

INVESTIGATING A PATIENT WITH SUSPECTED RA Tests, Tests, Tests INVESTIGATING A PATIENT WITH SUSPECTED RA

CASE SUMMARY Has a 4 month history of an inflammatory polyarthritis Nothing else on history or physical examination to suggest an associated connective tissue disorder or seronegative spondyloarthropathy.

INFLAMMATION Complete Blood Count (CBC) Hemoglobin: May be anemic (normocytic) WBC: Should be normal Platelets: May be normal to elevated Erythrocyte Sedimentation Rate (ESR) C-Reactive Protein (CRP)

TO MAKE SURE MEDS WILL BE SAFE ORGAN FUNCTION TO MAKE SURE MEDS WILL BE SAFE Renal Function Creatinine + Urinalysis Liver Enzymes AST, ALT, ALP, ALB Hepatitis B & C Testing Consider baseline Chest X-Ray

ANTIBODIES Rheumatoid Factor Anti-Nuclear Antibody

Rheumatoid Factor IgG Molecule Fc Portion Autoantibodies (IgM) directed against the Fc Fragment of IgG An Antibody to an Antibody Their Role in RA is not understood IgM Molecule Antigen Binding Groove

Non- Rheumatic Disease Rheumatoid Factor Rheumatic Disease Sjogren’s syndrome Rheumatoid Arthritis SLE MCTD Myositis Cryoglobulinemia Non- Rheumatic Disease Normal Aging Infection Hepatitis B & C SBE Tb HIV Sarcoidosis Idiopathic Pulmonary Fibrosis

Rheumatoid Factor (RF) Question: What Percentage of New Onset RA will have a positive RF? Answer: 30-50% Question: What Percentage of Established RA will have a positive RF? Answer: 70-85% NOT USEFUL FOR DIAGNOSIS OF RA

Pearls about RF in RA Asymptomatic people with a positive RF are unlikely to go on to develop RA The higher the value the greater the likelihood of rheumatic disease USEFUL for PROGNOSIS Patients who are RF +ve are more likely to have aggressive disesase NOT USEFUL to FOLLOW TITRES Not predictive of flare Not predictive of improvement

RADIOGRAPHIC FINDINGS IN RA

Periarticular Osteopenia Joint Space Narrowing Erosions Mal-Alignment

SYNOVIAL FINDINGS IN RA

Rheumatoid Synovium A non-suppurative (no pus) inflammatory infiltrate in the synovium Due to the aggregation of lymphocytes and plasma cells

Rheumatoid Synovium

PRINCIPLES OF TREATMENT

90% of the joints involved in RA are affected within the first year The Big Bang 90% of the joints involved in RA are affected within the first year SO TREAT IT EARLY

Disability in Early RA Inflammation Fatigue Potentially Reversible Swollen Stiff Sore Warm Fatigue Potentially Reversible

Disability in RA Most of the disability in RA is a result of the INITIAL burden of disease People get disabled because of: Inadequate control Lack of response Compliance GOAL: control the disease early on!

A Fire in the Joints If there’s a fire in the kitchen do you wait until it spreads to the living room or do you try and put it out?

Clinical Course of RA Type 1 = Self-limited—5% to 20% Severity of Arthritis Years Type 1 = Self-limited—5% to 20% Type 2 = Minimally progressive—5% to 20% Type 3 = Progressive—60% to 90% Pincus. Rheum Dis Clin North Am. 1995;21:619. 7

Why is Early Treatment Important? Joint Damage Occurs EARLY 93% of patients with less than 2 years of disease have radiographic abnormalities Rate of radiographic progression is higher in the first 2 years of disease Disability Occurs EARLY 50% out of work at 10 years Increased MORTALITY With severe disease

Why is Early Treatment Important? EARLY Treatment has Long-Term Beneficial Effects WINDOW OF OPPORTUNITY Delay of 4 months can have long-term effects

Disability in Late RA (Too Late) Damage Bones Cartilage Ligaments and other structures Fatigue Not Reversible

Induce Remission Maintain Remission

DMARDs Disease Modifying Anti-Rheumatic Drugs Reduce swelling & inflammation Improve pain Improve function Have been shown to reduce radiographic progression (erosions)

DMARDs Methotrexate Sulfasalazine Hydroxychloroquine (Plaquenil) Leflunomide (Arava) Gold Azathioprine (Imuran)

Combining DMARDs DMARDs all work slightly differently Never truly know how a patient will respond to an individual DMARD Most clinicians now agree that combinations of DMARDs are more effective than single agents This is now supported by some research

Combination therapy (using 2 to 3) DMARDs at a time works better than using a single DMARD

Common DMARD Combinations Triple Therapy Methotrexate, Sulfasalazine, Hydroxychloroquine Double Therapy Methotrexate & Leflunomide Methotrexate & Sulfasalazine Methotrexate & Hydroxychloroquine Methotrexate & Gold Sulfasalazine & Plaquenil

Case Study Began therapy with Methotrexate, Sulfasalazine, & Plaquenil Initially responded well and took them for 4 months On a friends “advice”, stopped all DMARDs in favour of “natural” therapy “Natural” therapy was a dismal failure Triple therapy re-instituted – difficulty obtaining adequate control

Case Study Change DMARDs – Add leflunomide Biologic Therapy

BIOLOGIC THERAPY

Tumour Necrosis Factor (TNF) TNF is a potent inflammatory cytokine TNF is produced mainly by macrophages and monocytes TNF is a major contributor to the inflammatory and destructive changes that occur in RA Blockade of TNF results in a reduction in a number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)

How Does TNF Exert Its Effect? TNF Receptor How Does TNF Exert Its Effect? Any Cell Trans-Membrane Bound TNF Macrophage Soluble TNF

Destructive effects of TNF TNF triggers multiple destructive effects in RA. In part, it stimulates osteoclasts to resorb bone, ultimately resulting in bone erosions visible on x-ray.1 TNF also induces the proliferation of synoviocytes, which in turn produces inflammation due to the release of inflammatory mediators.2,3 As depicted here, inflammation not only causes pain and swelling but also has been shown to precede joint damage.2,4 Chondrocytes are a third target of TNF activation, producing collegenase that degrades cartilage and eventually causes joint space narrowing.1,5 In addition to these effects, TNF plays an early role in the inflammatory process by stimulating activation of T cells by foreign antigens.2,3 TNF also induces expression of adhesion molecules, thereby promoting the migration of macrophages and lymphocytes into the synovium.5   References: 1. Goronzy JJ, Weyand CM. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, ed. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:155-174. 2. Carpenter AB. Immunology and inflammation. In: Wegener ST, ed. Clinical Care in the Rheumatic Diseases. Atlanta, Ga: American College of Rheumatology; 1996:9-14. 3. Albani S, Carson DA. Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. Vol 1. 13th ed. Baltimore, Md: Williams & Wilkins; 1997:979-992. 4. McGonagle D, Conaghan PG, O'Connor P, et al. The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum. 1999;42:1706-1711. 5. Rosenberg AE. Skeletal system and soft tissue tumors. In: Cotran RS, ed. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1994:1213-1271.

How Are the Effects of TNF Naturally Balanced? TNF Receptor How Are the Effects of TNF Naturally Balanced? Any Cell Trans-Membrane Bound TNF Macrophage Soluble Receptor Soluble TNF

Strategies for Reducing Effects of TNF Monoclonal Antibody (Infliximab & Adalimumab) Trans-Membrane Bound TNF Macrophage Soluble TNF

Infliximab (Remicade®) & Adalimumab (Humira®) Chimeric (murine & human) monoclonal antibody directed against TNF-α

Strategies for Reducing Effects of TNF Soluble Receptor Decoy (Etanercept) Trans-Membrane Bound TNF Macrophage Soluble TNF

Etanercept (Enbrel®) 2 soluble p75receptors attached to the Fc portion of the IgG molecule

Biologics Monoclonal Antibodies to TNF Soluble Receptor Decoy for TNF Infliximab (Remicade®) Adalimumab (Humira®) Soluble Receptor Decoy for TNF Etanercept (Enbrel®) Receptor Antagonist to IL-1 Anakinra (Kineret®) (rarely used) Monoclonal Antibody to prevent T-Cell Signaling Abatacept (Orencia®) Monoclonal Antibody to CD-20 Rituximab (Rituxan®)

Infection Common (Bacterial) Side Effects Opportunistic (Tb, Histo) Demyelinating Disorders Malignancy Worsening CHF Blood Counts

Do they work? Resounding YES! Outcome measured by ACR20 20% reduction in swollen & tender joints Plus 20% reduction in at least 3 of the following: Patient VAS pain Physician global VAS Patient global VAS HAQ ESR or CRP

SUMMARY Rheumatoid Arthritis is a chronic potentially debilitating illness Early treatment can have a PROFOUND effect on this disease Treatment is multidisciplinary