2 AcknowledgementsDr. Andrew Thompson, rheumatologist at SJHC and developer of the UWO rheumatology medical school program
3 Objectives Gain a basic understanding of Rheumatoid Arthritis Understand the presentation of Rheumatoid Arthritis (Inflammatory Arthritis)Understand the current treatment paradigm and medications used
4 Case Presentation 43 yo woman, has been healthy apart from: C-Section forMild depressionHer current medications areSertraline 100 mg per day (depression)Naproxen 500 mg twice a day (recent joint pain)
5 Case Presentation4 months ago developed pain in the left knee with some mild swelling.The episode lasted a few days and then went away.
6 Case PresentationAbout a week later the right knee began to swell and become soreThen 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.
8 Case PresentationShe feels stiff when she wakes up in the morning and this stiffness lasts for at least 3 hoursShe has no energy and has missed the last week of workHer sleep is difficult because she is uncomfortableShe isn’t running because it “hurts too much”
9 Differential Diagnosis INFLAMMATORY POLYARTHRITISInfectionRheumatoid ArthritisSeronegative Arthritis (Psoriatic)Connective Tissue Disease (SLE etc)Associated with another Systemic Disease
10 Who gets RA? ANYONE CAN GET RA Common Age to Start: 20’s to 50’s From babies to the very oldCommon Age to Start: 20’s to 50’sSex: Females more common than males 3:1
11 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 PresentationRACECAR, RADAR, MOM, DAD
12 How does RA start?Initially, most patients notice stiffness of the joints which seems more pronounced in the morningSome fatigueSome pain
13 What Joints are affected? RA usually begins as an oligoarticular process (<5 joints) and progresses to polyarticular involvmementHas a predilection for the small joints of the hands and feet!
18 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?”
19 Morning Stiffness Inflammatory fluid increases in and around the joint As patients get moving the fluid gets resorbedStiffness can occur after rest “gelling”
20 Constitutional Features Fever – UnusualWeight Loss – Can be seen with severe polyarticular disease (again not common)Anorexia – UnusualFatigue – VERY COMMONSleep Disturbance – VERY COMMONMusculoskeletal ReasonsNeurologic Reasons – Carpal TunnelPsychological Reasons – Worry about illness, finances, job, family etc.
21 Functional StatusIn the Rheumatology Clinic we use a Health Assessment Questionnaire (HAQ)Dressing, Bathing, GroomingCooking, Cleaning, ShoppingMobility – Walking and StandingWorkingSocial Activities & SportsRank the Functional Status (IMPORTANT)Mild, Moderate, or Severe
23 Rheumatoid Arthritis is … Usually insidious in onsetAdds joints over timeHas a predilection for the small joints of the hands and feetJoints become warm and swollen but not redMorning stiffness is greater than 1 hourPatients are often tired and don’t sleep properlyCan result in significant disability very quickly
24 Doesn’t just affect the joints EXTRA-ARTICULARMANIFESTATIONS
34 INVESTIGATING A PATIENT WITH SUSPECTED RA Tests, Tests, TestsINVESTIGATING A PATIENT WITH SUSPECTED RA
35 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.
36 INFLAMMATION Complete Blood Count (CBC) Hemoglobin: May be anemic (normocytic)WBC: Should be normalPlatelets: May be normal to elevatedErythrocyte Sedimentation Rate (ESR)C-Reactive Protein (CRP)
37 TO MAKE SURE MEDS WILL BE SAFE ORGAN FUNCTIONTO MAKE SURE MEDS WILL BE SAFERenal FunctionCreatinine + UrinalysisLiver EnzymesAST, ALT, ALP, ALBHepatitis B & C TestingConsider baseline Chest X-Ray
41 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
42 Pearls about RF in RAAsymptomatic people with a positive RF are unlikely to go on to develop RAThe higher the value the greater the likelihood of rheumatic diseaseUSEFUL for PROGNOSISPatients who are RF +ve are more likely to have aggressive disesaseNOT USEFUL to FOLLOW TITRESNot predictive of flareNot predictive of improvement
50 90% of the joints involved in RA are affected within the first year The Big Bang90% of the joints involved in RA are affected within the first yearSO TREAT IT EARLY
51 Disability in Early RA Inflammation Fatigue Potentially Reversible SwollenStiffSoreWarmFatiguePotentially Reversible
52 Disability in RAMost of the disability in RA is a result of the INITIAL burden of diseasePeople get disabled because of:Inadequate controlLack of responseComplianceGOAL: control the disease early on!
53 A Fire in the JointsIf 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?
54 Clinical Course of RA Type 1 = Self-limited—5% to 20% Severity of ArthritisYearsType 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
55 Why is Early Treatment Important? Joint Damage Occurs EARLY93% of patients with less than 2 years of disease have radiographic abnormalitiesRate of radiographic progression is higher in the first 2 years of diseaseDisability Occurs EARLY50% out of work at 10 yearsIncreased MORTALITYWith severe disease
56 Why is Early Treatment Important? EARLY Treatment has Long-Term Beneficial EffectsWINDOW OF OPPORTUNITYDelay of 4 months can have long-term effects
57 Disability in Late RA (Too Late) DamageBonesCartilageLigaments and other structuresFatigueNot Reversible
61 Combining DMARDs DMARDs all work slightly differently Never truly know how a patient will respond to an individual DMARDMost clinicians now agree that combinations of DMARDs are more effective than single agentsThis is now supported by some research
62 Combination therapy (using 2 to 3) DMARDs at a time works better than using a single DMARD
64 Case Study Began therapy with Methotrexate, Sulfasalazine, & Plaquenil Initially responded well and took them for 4 monthsOn a friends “advice”, stopped all DMARDs in favour of “natural” therapy“Natural” therapy was a dismal failureTriple therapy re-instituted – difficulty obtaining adequate control
65 Case StudyChange DMARDs – Add leflunomideBiologic Therapy
67 Tumour Necrosis Factor (TNF) TNF is a potent inflammatory cytokineTNF is produced mainly by macrophages and monocytesTNF is a major contributor to the inflammatory and destructive changes that occur in RABlockade of TNF results in a reduction in a number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)
68 How Does TNF Exert Its Effect? TNF ReceptorHow Does TNF Exert Its Effect?Any CellTrans-Membrane Bound TNFMacrophageSoluble TNF
69 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.1,5In 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.5References: 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: Carpenter AB. Immunology and inflammation. In: Wegener ST, ed. Clinical Care in the Rheumatic Diseases. Atlanta, Ga: American College of Rheumatology; 1996: 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: 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: 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:
70 How Are the Effects of TNF Naturally Balanced? TNF ReceptorHow Are the Effects of TNF Naturally Balanced?Any CellTrans-Membrane Bound TNFMacrophageSoluble ReceptorSoluble TNF
71 Strategies for Reducing Effects of TNF Monoclonal Antibody (Infliximab & Adalimumab)Trans-Membrane Bound TNFMacrophageSoluble TNF
73 Strategies for Reducing Effects of TNF Soluble Receptor Decoy (Etanercept)Trans-Membrane Bound TNFMacrophageSoluble TNF
74 Etanercept (Enbrel®)2 soluble p75receptors attached to the Fc portion of the IgG molecule
75 Biologics Monoclonal Antibodies to TNF Soluble Receptor Decoy for TNF Infliximab (Remicade®)Adalimumab (Humira®)Soluble Receptor Decoy for TNFEtanercept (Enbrel®)Receptor Antagonist to IL-1Anakinra (Kineret®) (rarely used)Monoclonal Antibody to prevent T-Cell SignalingAbatacept (Orencia®)Monoclonal Antibody to CD-20Rituximab (Rituxan®)
76 Infection Common (Bacterial) Side Effects Opportunistic (Tb, Histo) Demyelinating DisordersMalignancyWorsening CHFBlood Counts
77 Do they work? Resounding YES! Outcome measured by ACR20 20% reduction in swollen & tender jointsPlus 20% reduction in at least 3 of the following:Patient VAS painPhysician global VASPatient global VASHAQESR or CRP
78 SUMMARYRheumatoid Arthritis is a chronic potentially debilitating illnessEarly treatment can have a PROFOUND effect on this diseaseTreatment is multidisciplinary