Biologic DMARDs Included in the Comparative Effectiveness ReviewThe biologic disease-modifying anti-rheumatic drugs (DMARDs) that have been studied for treatment of rheumatoid arthritis and were included in the comparative effectiveness review are:The biologic DMARDs that target tumor necrosis factor-alpha (TNF-α) include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).Other biologic DMARDs included in the review target immune system components other than TNF-α. They are:Abatacept (Orencia): Its target of activity is CD28.Anakinra (Kineret): Its target of activity is interleukin 1. Rituximab (Rituxan): Its target of activity is CD20.Tocilizumab (Actemra, RoActemra): Its target of activity is the interleukin-6 receptor.Reference:Donahue KE, Jonas D, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55 (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-10056-I). Rockville, MD: Agency for Healthcare Research and Quality; April 2012. AHRQ Publication No. 12-EHC025-EF. Available at www.effectivehealthcare.ahrq.gov/dmardsra.cfm.
Rheumatoid Arthritis (RA): Definition Progressive, systemic, Autoimmune inflammation Often aggressive, devastating consequences Unknown etiology (auto immune, ?infection, smoking) Characterized bySymmetric synovitis – Chronic PolyarthritisJoint erosions, cartilage and bone destructionMultisystem - extra-articular manifestationsOnset usually slow & insidious over monthsIn 15 to 20% may have rapid or acuteAggressive management leads to good control
Rheumatoid Arthritis (RA): Epidemiology Prevalence of - 0.8% to 2.1% of the population Gender predilection ratio – Women: Men – 3:1 Prevalence increases with age – Juvenile RA About 40-60% have severe disease – 3 fold mortality Median life expectancy is shortened by 3 to 7 years Onset mostly between ages of 35 – 60 years Genetic – HLA-DRB1 – Class II HCA Exact etiology is not known
Risk FactorsGenderWomen are more predisposed toRA than men1GeneticHLA-DRB1 and PTPN22 genepolymorphisms3Family historyEnvironmentLow level of education, exposureto manual labour, socio-economic status and geographiclocation (living in lower latitudes)2BehaviourSmoking is strongly associatedwith RA pathogenesis2Caffeine?1. Goronzy JJ & Weyand CM. Arthritis Research and Therapy. 2009.2. Liao KP, Alfredsson L & Karlson EW. Curr Opin Rheumatol. 2009.3. Costenbader KH, Chang S-C & De Vivo I, et al. Arthritis Research & Therapy. 2008.? Bacterial or Viral Agent– Parvovirus, Hepatitis, Lyme, and Rubella
Rheumatoid Arthritis: Pathogenesis5Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15B cellT cellAntigen-presentingcellsB cell ormacrophage SynoviocytesPannusArticular cartilageChondrocytesMacrophageothercytokinesIFN- &Production of collagenase and otherneutral proteasesOsteoclastTNFIL-1RheumatoidFactors, anti-CCPImmune complexesBoneComplementNeutrophilMast cellCurrentTreatmentTargets
The Mediators of Joint DestructionImmunedestructionCytokinesTNF ChemokinesIL-1, IL-6MMPVEGF
IL-6 Has Numerous Articular Effects in RA1,2SynoviocytesOsteoclast activationbone resorptionEndothelial cellsVEGFPannus formationJoint destructionMediation of chronicinflammationIL-6MacrophageT-cellB-cellNeutrophilAntibodyproductionAdapted from 1 Choy E. Rheum Dis Clin North Am. 2004;30:405–415.2 Gabay C. Arthritis Res Ther. 2006;8(suppl 2):S3.
Complications of RheumatoidArthritisRheumatoid Arthritis: Diagnosis-Stage-Functional ClassesCurrent Management of RheumatoidArthritis11Aims
Rheumatoid nodules• Painless firm lumps thatappear beneath theskin, often single ormultiple, and range insize from millimeters tocentimeters indiameter occur on theunderside of theforearm and on theelbow.
Rheumatoid nodules• But they can also occuron other pressurepoints, including theback of the head, thebase of the spine, theAchilles tendon, and thetendons of the hand
Rheumatoid nodules• Occur in about 25% ofpatients• More common in menthan women
Rheumatoid nodules• These nodules maymove easily whentouched or they may befixed to deeper tissuesand cause pressure onsurrounding nerves orcan rupture, causingpain and discomfort insurrounding tissue.
Rheumatoid nodules• Although nodules aremostlybenign, complicationssuch asinfection, ulceration, and gangrene can occurfollowing breakdown ofskin overlying thenodules.
Rheumatoid nodules• Usually no treatment isnecessary unlessnodules becomedebilitating, ulcerated,or infected. Surgicalremoval may beperformed.
Skin complications of RA• Skin and muscles becomeatrophic (thin andwrinkled), making it fragileand easy to bruise .
Skin complications of RA• Skin on the back of thehands may become paleor even translucent• Nails may becomebrittle and split length-wise
Skin complications of RA• The palms becomereddened (palmererythema)
Skin complications of RA• A rare, seriouscomplication, usually withlong-standing rheumatoiddisease, is blood vesselinflammation (Vasculitis).Vasculitis can impair bloodsupply to tissues and lead totissue death (necrosis). Thisis most often initially visibleas tiny black areas aroundthe nail beds or as legulcers.• Atrophic skin
Skin complications of RA• Dark purplish areas onthe skin (purpura) arecaused by bleeding intothe skin from bloodvessels damaged byrheumatoid arthritis.
Skin complications of RA• Rheumatoid Vasculitis cancause many internalsymptoms, , hepatomegaly(enlargedliver), splenomegaly(enlarged spleen), bowelulcers, and haematuria(blood in urine).
Skin complications of RA• Skin ulcers (usually legulcers) may be extensiveand painful• Petechiae (purplish spots)or purpura• Nail fold or edge breakdown• Gangrene
Skin complications of RA• Neutrophilic dermatoses• Neutrophils are a type ofwhite blood cell(leucocyte). They arepresent in bacterialinfections. They are theprominent cell seen onskin biopsy of someuncommon inflammatoryskin diseases known asneutrophilic dermatoses.
Skin complications of RA• Sweet disease andpyodermagangrenosum are otherneutrophilic disorderssometimes seen inassociation withrheumatoid arthritis.• Pyodermagangrenosum
Skin complications of RA• Interstitial granulomatousdermatitis.• also known as‘rheumatoidpapules’, interstitialgranulomatous dermatitispresents as skin colouredor red papules often onthe trunk. It is rare.
Skin complications of RA• RA can affect the glandslocated near the eyes andmouth, resulting in acondition called secondarySjogrens syndrome• Decreased tear and salivaproduction can cause drymouth, and dry eyes.• Sjogrens syndrome
GASTRO-INTESTINAL COMPLICATIONS• Dry mouth, related to Sjogren syndrome, is the mostcommon symptom of gastrointestinal involvement.• Gastritis (stomach inflammation) or stomach ulcercaused by NSAID therapy.
Urinary complications of RA• The kidneys are not usually affected directlyby rheumatoid arthritis. Kidney problems inrheumatoid arthritis are much more likely tobe caused by medications used to treat thecondition.
Hematological complications of RA• Anemia• Low white blood cell count (leukopenia) canoccur from Feltys syndrome, a complicationof rheumatoid arthritis that is alsocharacterized by enlargement of the spleen.
Hematological complications of RA• Immune thrombocytopenic purpura caused byan autoimmune reaction against platelets.• drug induced neutropenia;thrombocytopenia, particularly autoimmuneand drug induced thrombocytopenia; andhematological malignancy.
Carpel Tunnel Syndrome Due to compression of the medial nerve byswelling around the wrist. Atlanto-Axial Subluxation Erosion of the odontoid process and/or transverseligaments in the cervical spine’s connection to theskull.▪ Vertebrae begin slipping over one another and compressthe spinal cord.▪ Clumsiness is initially experienced, but without due care this canprogress to quadriplegia. Quadriplegia :: paralysis of all four extremities.
Nervous complications of RA• Entrapment ofnerves. Carpaltunnel syndromeor ulnar nerveneuropathy• including sensoryor motorneuropathy (lossof sensation)
Nervous complications of RA• Formation of a Bakerscyst (a cyst filled withjoint fluid and located inthe hollow space at theback of the knee).• Its herniation ofposterior capsule
RESPIRATORY COMPLICATIONS OF RA• CAPLANS SYNDROME• The combination of RA and exposure to coaldust produces the condition. It developsespecially in miners working in anthracitecoal-mines and in persons exposed to silicaand asbestos.
RESPIRATORY COMPLICATIONS OF RA• CXR showsmultiple, round, welldefined nodules, usually0.5 - 2.0 cm indiameter, which maycavitate and resembletuberculosis. CTscanning gives a betterpicture of cavitation.
RESPIRATORY COMPLICATIONS OF RA• well definednodules, usually 0.5 -2.0 cm indiameter, which maycavitate and resembletuberculosis.
RESPIRATORY COMPLICATIONS OF RA• The syndrome is namedafter Dr. AnthonyCaplan, a physician onthe CardiffPneumoconiosis Panel.
RESPIRATORY COMPLICATIONS OF RA• Fibrosis of lungscattered all over lung
• Myocardial Infarction– Commonly known as a heart attack.• Occurs when the blood supply to part of the heart isinterrupted causing some heart cells to die.• Disambiguation– Stroke.• The rapid loss of brain function(s) due to disturbance inblood supply to the brain.• Atherosclerosis– The abnormal narrowing of an artery.• The condition in which an artery wall thickens due to abuild up of fatty materials such as cholesterol.
• Other conditions of the heart caused by RA:– Pericarditis• Inflammation of the pericardium – the sac that containsthe heart and the roots of the great vessels.– Endocarditis• Inflammation of the inner layer of the heart.– Left Ventricular Failure• Commonly known as heart failure.– Valvulitis• Inflammation of one or more of the heart valves.
OCULAR COMPLICATIONS OF RA• RA can also cause inflammation of the sclera (whitepart of the eye), which may make the sclera appearred or bluish in color.
OCULAR COMPLICATIONS OF RA• Keratoconjunctivitissicca
Bow string sign• The tendons on the back ofthe hand may become veryprominent and tight, calledthe bow string sign.• Ulnar deviation• The direction of prominenttendons is like bow string
Complications of RheumatoidArthritisRheumatoid Arthritis: Diagnosis-Stage-Functional ClassesCurrent Management of RheumatoidArthritis64Aims
Clinical Manifestations of RA• Chronic and progressive inflammatorydisorder, characterised by synovitis and severe jointdestruction, if left untreatedFeldmann M, Brennan FM & Maini RN. Cell. 1996.Recent – Onset RAModerately AdvancedRA*Severely Advanced RA
1987 AMERICAN COLLEGE OFRHEUMATOLOGY CRITERIA FOR RA• Patients must have 4 of the 7 criteria:1. Morning stiffness lasting at least 1 hour*2. Swelling in three or more joints*3. Swelling in hand joints*4. Symmetric joint swelling*5. Erosions or decalcification on x-ray of hand6. Rheumatoid nodules7. Abnormal serum rheumatoid factor.[*Must be present at least six weeks]
American Rheumatology AssociationRemission Criteria for RA (Eberhardt a Fex 1998)• 4 or more of the following criteria must be fulfilled for at least2 consecutive months:1. Duration of morning stiffness not exceeding 15 min2. No fatigue3. No joint pain (by history)4. No joint tenderness or pain on motion5. No soft tissue swelling in joints or tendonsheaths6. ESR<30mm after 1 hour for a female or <20mm after 1 hour for a male
Blood Parameters in RA Acute Phase Reactants (APR ) C-Reactive Protein (CRP) - > 4 mg% - It is the single most useful marker ESR is raised > 30 mm – other confounders Ceruloplasmin Haptoglobin (Hp) Leukocytosis, Nutrophilia Normocytic normochromic anemia Thrombocytosis69
Synovial Fluid in RA No need in general for joint aspiration Required to exclude other causes of arthritis Inflammatory arthritis picture Turbid fluid with reduced viscosity Increased protein content Decreased glucose content WBC count from 2,000 to 50,000/l PMNLs predominate Total compliment, C3 and C4 are markedly 70
Rheumatoid Factor (RA Factor) Developed by Eric Waller in 1937 – Rose Waller Test Agglutinating Abs - Latex particle agglutination assay Isotype specific enzyme immunoassays – New technique Antibodies to Fc portion of our own IgG - These Abs are IgM Positive in 5% of normal persons and in only 70-80% of RA Low specificity (false +ves) & low sensitivity (false –ves.) It is not a screening or Dx. tool – More a prognostic tool It is negative in 30% cases of RA – Sero negative RA RF are commonly seen other disease – see next slide71
Anti-CCP Antibody Test in RA (ACPA) Antibodies to Cyclic Citrullinated Peptides (anti-CCP) Similar sensitivity for RA (70%) Specificity for RA (>95%) better than RA Factor In early polyarthritis anti-CCP are useful for Dx. Anti-CCP are associated with more severe disease They spell a poor prognosis and rapid progression They may be positive in asymptomatic patients yearsbefore the onset of symptoms73
Serology in Rheumatoid Arthritis74TestRA Factor is IgM Antibody to the Fc portion of the IgGAnti CCP: Antibodies to Cyclic Citrullinated Peptides
Pathology RA is generalized disorder of connective tissueaffecting Articular structure & Extra articular structures
Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.UndifferentiatedPolyarthritisEarly RA – MildDiseaseSevere RA withDeformitiesThe Natural Course of RA
Progressive changes in joints Stage I: Inflammation of the synovial membrane spreads to articularcartilage & other soft tissues. Limitation of joint movt with pain & muscle spasm
Stage II: Granulation tissue formation within synovial membrane& spread to periarticular tissue. Cartilage disintegration & joint filled with granulation Thickening of joint capsule, tendon (with sheaths) &impaired joint movt permanently.
Stage III: Granulation tissue converted into fibrous tissue withadhesion formation between tendon, joint capsule &articular surface. Articular surface cover partly by cartilage & partly byfibrous tissue.
Stage IV: Permanent joint damage and deformity disability
Rheumatoid Arthritis – ACR Functional ClassesClassification Specifications of activity levelsClass IComplete ability to perform daily activitiesself-care, vocational and avocationalClass IIAbility to perform usual self-care and vocationalactivities; limited avocational activitiesClass IIIAbility to perform usual self-care activities;limited vocational or avocational activitiesClass IVLimited ability to perform usual self-care orvocational or avocational activities
DAS28 (Disease Activity Scoring) for RA - EULAR Calculated using a formula that includes Counts for tender and swollen joints – (28 joints) General health by the patient (on a scale of 0 to 100) A measurement of ESR or CRP Score > 5.1 – High disease activity, Score 5.1 to 3.2 – Moderate disease activity Score < 3.2 – Low disease activity Score < 2.6 – Being in Remission Response to Rx. – of ≥ 1.2 – Good and < 0.6 – PoorEuropean League Against Rheumatism (EULAR)
Extra articular changes Nodule formation: In the pressure area & may besubcutaneous or intracutaneous. They may present in organs such aslung & heart. Vascular changes: It constitute inflammation of all sizearteries. The lumen of small vessels canbecome obliteration.
Rheumatoid Arthritis: Typical Involvement Wrist joints and MCP joints - very commonly involved Index and middle Metacarpophalangeal joints Proximal interphalangeal joints (PIP) Metacarpophalangeal joints (MCP) Metatarsophalangeal joints (MTP) Elbows, Shoulders Knees, Ankles, Hips. Lumbosacral area is not involved Spine: only Atlanto-axial joint (C1– C2), subluxation Terminal interphalangeal (TIPS) joints are not involved91
Rheumatoid Arthritis: Predictors of Prognosis Presence of > 20 inflamed joints Markedly elevated ESR Radiographic evidence of bone erosions Presence of rheumatoid nodules High titers of RA Factor and anti CCP Higher class of functional disability Persistent inflammation; comorbidities Advanced age of onset Low socio-economic status, low education level HLA-DR*0401 or DR*04049540%-85% of RA pts unable to work in8-10 years
Complications of RheumatoidArthritisRheumatoid Arthritis: Diagnosis-Stage-Functional ClassesCurrent Management of RheumatoidArthritis96Aims
Goals of Therapy1. Relief of pain2. Reduction of inflammation3. Protection of articular structures4. Maintenance of functional activity5. Control of systemic involvement6. Slow the progression of disease7. Increase the over all quality of life
Non Pharmacological Management Rest Exercise Flexibility/stretching Muscle conditioning Cardiovascular/aerobic Diet Weight management Physical and occupational therapy
Therapeutic Window of Opportunity Erosive changes occur early in disease Even a brief delay of therapy can have a significantimpact on disease parameters years later Early DMARD treatment to arrest progression MTX is the sheet anchor – Combination of DMARDs Bridge the gap initially with NSAID and GC Biologics only for refractory case – with caution; cost Surgical treatment options in selected patientsO’Dell JR. Arthritis Rheum. 2002;46:283-285.Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Early RA: The Window ofOpportunity to Intervene
Therapeutic Window of Opportunity Erosive changes occur early in disease Even a brief delay of therapy can have a significantimpact on disease parameters years later Early DMARD treatment to arrest progression MTX is the sheet anchor – Combination of DMARDs Bridge the gap initially with NSAID and GC Biologics only for refractory case – with caution; cost Surgical treatment options in selected patientsO’Dell JR. Arthritis Rheum. 2002;46:283-285.Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.Surgical Treatment will be mandated in25%
MANAGEMENT OF R.A. Medications are divided into three main classes 1.NSAIDs 2.corticosteroids 3.DMARDs 4.BIOLOGICS 5.Surgery
Medical Management – Drug ClassesClasses NSAIDs – Cox-1 & Cox-2 inhibitorsGlucocorticoids – Prednisolone, MPIAS – Intra articular steroidsDMARDs – MTX, SSZ, HCQ, CQImmunosuppressive Rx.– AZT, Leflunomide, CSCytotoxic agents – CyclophosphamideBiologics – TNF-antibodies, IL-1 R antagonistOld drugs – Gold salts, D-Penicillamine
NSAIDS in RANSAIDsCOX 1 COX2 Selective COX 2 Inhibitors Improved GI tolerability Reduced effects on RBF No effect on platelets Called as COXIBs May have adverse effecton heart Celecoxib Etoricoxib MeloxicamConstituent pathwayRenal and GIhomeostasisInduciblepathwayInflammation
NSAID Class of DrugsNon Selective Ibuprofen Ketoprofen Diclofenac Aceclofenac Piroxicam Lornaxicam Naproxen IndomethacinNSAIDs used as analgesics Ketorolac Aspirin (NSAID)Selective COX-2 Celecoxib, Etoricoxib MeloxicamAnalgesics Tramadol Paracetamol
Pros and Cons of NSAID TherapyPROS Effective control ofinflammation and pain Effective reduction inswelling Improves mobility,flexibility, range of motion Improve quality of life Relatively low-costCONS Does not affect diseaseprogression GI toxicity common Renal complications(eg. Irreversible renalinsufficiency, papillarynecrosis) Hepatic dysfunction CNS toxicity
Pros and Cons of Corticosteroid TherapyPROS Anti-inflammatory andimmunosuppressive effects Can be used to bridgegap between initiationof DMARD therapy andonset of action Intra-articular steroid (IAS)injections can be used forindividual joint flaresCONS Does not conclusivelyaffect disease progression Tapering anddiscontinuation of useoften unsuccessful Low doses result in skinthinning, ecchymoses, andCushingoid appearance Significant cause of steroid-induced osteopenia
Methotrexate (MTX) MTX is given 10 to 30 mg orally, IM, or SC per week It is DHF reductase inhibitor – Supplemental folic acid The clinical improvement takes one to two months Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT Rare: low WBC & platelets; pneumonitis; sepsis; liver disease;EBV related lymphoma; CBC, creatinine, and LFTs monthly for six months, then every oneto two months; repeat AST or ALT in two to four weeks if initiallyelevated, and adjust dose as needed; Rapid onset (six to 10 weeks); tends to produce more sustainedresults over time than other DMARDs and lowers all-causemortality; Can be used when cause of polyarthritis uncertain; Often combined with other DMARDs like Leflunomide, SSZ, HCQ109
Methotrexate Adverse Events• GI - Mucositis, diarrhea, abdominal pain• Hematologic - Cytopenias, macrocytosis• Hepatic- Transaminitis, fibrosis, and cirrhosis• Pulmonary - Hypersensitivitypneumonitis, pulmonary fibrosis• Infections• Neoplasia - reversible lymphoproliferativedisorder, lymphoma, and leukemia• Accelerated nodulosis and vascultitis• Reproductive – abortifacient and teratogen– Must use birth control and d/c drug 2-6 months beforeplanned pregnancy
Changing Paradigm of Treatment•EarlyAggressive Rx.•Biological•CombinationtreatmentEvolvingparadigm111Current TreatmentTraditional DMARDs
New Treatment Paradigm for RA113Orthopedic surgeryHigher dose steroidsfor flares or extraarticular diseaseOccupational therapyPhysical therapyPatienteducationIntraarticular steroidsSimpleanalgesicWeaver AL, 2008.
Biological Agents in RA TNFα antagonists Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade) Interleukin-1 antagonist Anakinra (Kineret) Suppressors of T-Cell activation Abatacept (Orencia) Anti B-Cell monoclonal antibodyRituximab (Rituxan) IL-6 receptorTocilizumab114
Biologic DMARDs Included in the ComparativeEffectiveness ReviewDonahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.Biologic Disease-Modifying anti-rheumatic DrugsName Trade Name Target of ActivityAdalimumab Humira® TNF-αCertolizumab pegol Cimzia® TNF-αEtanercept Enbrel® TNF-αGolimumab Simponi® TNF-αInfliximab Remicade® TNF-αAbatacept Orencia® CD28Anakinra Kineret® IL-1Rituximab Rituxan® CD20Tocilizumab Actemra®RoActemra®IL-6 receptorAbbreviations: IL = interleukin; TNF-α = tumor necrosis factor-alpha
Agent Usual dose/route Side effects ContraindicationsInfliximab(Anti-TNF)3 mg/kg i.v infusion at wks0,2 and 6 followed bymaintainence dosing every8 wksHas to be combined withMTX.Infusion reactions,increased risk ofinfection, reactivation ofTB ,etcActive infections,uncontrolledDM,surgery(with hold for 2 wkspost op)Etanercept(Anti-TNF)Active infections,uncontrolledDM,surgery(with hold for 2 wkspost op)Adalimumab(Anti-TNF)40 mg s/c every 2wks(fornightly)May be given with MTX oras monotherapySame as that ofinfliximabActive infections.25 mg s/c twice a wkMay be given with MTXor as monotherapy.Injection sitereaction,URTI ,reactivation ofTB,development ofANA,exacerbationof demyelenatingdisease.
Abatacept(CTLA-4-IgG1 Fusionprotien)Co-stimulationinhibitor10 mg/ kg body wt.At 0, 2 , 4 wks & then4wklyInfections, infusionreactionsActive infectionTBConcomittant with other anti-TNF-αRituximab(Anti CD20)1000 mg iv at0, 2, 24 wksInfusion reactionsInfectionsSame as aboveTocilizumab( Anti IL-6)4-8 mg/kg8 mg/kg iv monthlyInfections, infusionreactions,dyslipidemiaActive infectionsAgent Usualdose/routeSide effects.Anakinra 100 mg s/c oncedailyMay be given withMTX or asmonotherapy.Injection sitepain,infections,neutropeniaActive infectionsContraindications(Anti-IL-1)
Biologics: Relative Contraindications118 Active Hepatitis B Infection Multiple sclerosis, optic neuritis Active serious infections Chronic or recurrent infections Current neoplasia History of TB or evidence of Koch’s Congestive heart failure (Class III or IV)