1987 Revised Criteria for classification of RA 1.Morning stiffness * 2.Arthritis ≥ 3 joints * 3.Arthritis of PIP, MCP or Wrist * 4.Arthritis is Symmetric* 5.Subcutaneous nodules 6.RF 7.Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks

What is rheumatoid arthritis ? It ‘s a chronic systemic autoimmune inflammatory disease affecting all joints covered by synovium leading to destructive polyarthritis

causes severe joint destruction is a systemic disease with systemic damage leads to disability Is associated with significant costs Is an immune mediated disease driven by inflammatory cytokines RA is the most common inflammatory arthritis

Incidence, prevalence & morbidity World wide prevalence: 1-3% Age distribution: 4F:1M Peak onset: (35-50) It can affect any age from childhood up to the age of 75 Life expectancy is reduced by approximately 7 yrs ( ♂) 3 yrs ( ♀ ) Due to : Cardiovascular disease Infection Renal disease Respiratory disease Vasculitis Malignancy GI disease

Etio-pathogenesis of RA No clear aetiology Multi-factorial Genetic factors Auto-Immunity

A- Genetics HLA class II is strongly linked to RA. HLA DR4 is the major halo-type in ethnic group, HLA DR1 in Indians and HLA DW15 in Japanese. N.B : % of caucasian RA patients are HLA DR4, Compared to % of the population at large. 1 st degree relatives of RA patients are 4x. 25 % F frequency in identical twins 5 % Frequency in non-identical twins

B- Auto-Immunity There is substantial evidence that the initiation of RA is T-cell mediated. Antigen Specific Process Once T-Lymphocyte recognize antigens (Arthritogenic antigen) Therefore: Auto Immunity Cascade Started

Arthritogenic Antigen Exogenous EBV Mycoplasma Hepatitis MycoBacterium Paro Virus B19 Yarsenia Streptococcus Endogenous Citrullinated Peptide viral Bacterial

Pathogenesis of Rheumatoid Arthritis (RA)

The Inflammatory Cascade in RA Activation of T cells triggers a series of intercellular reactions 1 Lymphocytes, monocytes/ macrophages, and synovial fibroblasts are stimulated to release proinflammatory cytokines 2 Cytokines induce synovial proliferation and release of destructive enzymes 1-3 B Cell T Cell Macrophage Pannus Cartilage TNF IL-1

Mechanisms of Structural Damage in Rheumatoid Arthritis 1 CD4+ T lymphocyte Macrophage Endothelial cell Osteoclasts Bone destruction Joint erosion Synoviocytes Cartilage destruction Joint-space narrowing Chondrocytes Adhesion molecule expression TNF  IL-1 TNF  IL-1 Adapted from Arend WP. J Rheumatol Suppl. 2002;65: Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend.

Cytokine Disequilibrium in the Disease Process of RA 1,2 Proinflammatory TNF IL-8 IL-1 IFN-  IL-2 LT  IL-6 Anti-inflammatory IL-4 IL-10 sIL- 1R IL-11IL- 1Ra TGF-  sTNFR

TNF – A Logical Target Helps drive events in the inflammatory cascade 1-3 Triggers production of other cytokines, including IL-1 1,2 Proinflammatory IL-6, IL-8, GM-CSF IL-1 TNF Anti-inflammatory IL-10, sTNFR, IL-1Ra,

Three Destructive Effects of TNF 1-5 Inflammation Activates monocytes/macrophages Bone resorption and erosions Activates osteoclasts, suppresses osteoblasts Cartilage breakdown Activates chondrocytes, releasing collagenases

16 The role of B cells in the pathophysiology of RA

17 B cells: key players in RA pathophysiology For the past 20 years, RA has been considered a T cell-mediated disease Recently, the important role of B cells in the pathophysiology of RA has been revealed This new discovery has led to a breakthrough in the management of RA (Dörner & Burmester, 2003)

18 B cells: key players in RA pathophysiology (cont ’ d) There is an abundance of B cells in the synovium of RA-affected joints – These lymphocytes can be organised into lymphoid structures Three critical roles of B cells in RA pathogenesis: – Antigen presentation and T cell activation – Autoantibody production – Cytokine production

19 Role of B cells in RA: (1) antigen presentation leading to T cell activation B cells are highly efficient antigen-presenting cells (APCs) Antigen presentation leads to T cell activation Activated T cells produce cytokines that activate macrophages to produce pro-inflammatory cytokines Results in inflammation and joint destruction

20 Role of B cells in RA: (2) autoantibody production Auto reactive B cells produce auto anti-bodies, including RF. Formation of RF immune complexes in the synovium leads to production of pro-inflammatory cytokines through: – Complement activation – Macrophage activation (Abrahams et al, 2000; Silverman & Carson, 2003; Sutton et al, 2000)

21 Role of B cells in RA: (3) cytokine production Activated B cells produce cytokines (e.g. TNF-α, interleukin [IL]-6, lymphotoxin) which are known to promote inflammation and joint damage in RA Lymphotoxin promotes the formation of new lymphoid structures in the synovium, thus helping to perpetuate autoimmune reactions (Duddy et al, 2004; Lund et al, 2005)

22 Steps in the maturation of B cells CD20 only expressed in a subset of B cells (Roitt et al, 2002; Sell & Max, 2001; Silverman & Weisman, 2003)

Pro-inflammatory Cytokines Stimulate the secretion of: MMP: degrade matrix and complement protein MTP “ Acute phase protein” Prostaglandins “ O2 free radicals” Heat shock proteins and others! And these are the major That mediate tissue destruction

Conclusion of Pathogenesis Whatever the initiating stimulus ….. RA is characterized by : 1.Persistent cellular activation 2.Genetically susceptible host 3.Auto-immunity At the site of articular and extra-articular tissue chronic inflammation (PANUS) and (JOINT DESTRUCTION(

presentation 70% insidious onset (weeks to mnths) 10% acute (fulminant onsent) 20% sub acute onset

Patterns of joints involvement Oligoarticular 45% Polyarticular 35%  60% small joints 30 % large joints 10 % Both Monoarticular 20%  50% knee only 50%  wrist elbow shoulder ankle hips

1987 Revised Criteria for classification of RA 1.Morning stiffness * 2.Arthritis ≥ 3 joints * 3.Arthritis of PIP, MCP or Wrist * 4.Arthritis is Symmetric* 5.Subcutaneous nodules 6.RF 7.Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks

Precipitating factors? Emotional stress Infection Immunization Pregnancy Fibromyalgia Reynaud's phenomenon Family history (of autoimmune disease )

Extraarticular manifestation of RA Skin Pulmonary Cardiovascular Hematological Ocular CNS Bone Amyloidosis Filty’s Syndrome

Skin Palmer erythema Reynaud's phenomena Rheumatoid nodules up to 25 % of patients (firm,nontender,single or multiple) Vasculaitis 1%  PAN like vasculitis lekuocytoclastic vasculitis cryoglobulonemia

pulmonary Manifistaions Pleurisy (with or without effusion) (frequent- often mild-) 25% bilateral Rheumatoid pleural nodules 5%  caplan syndrome (coin shape lesions) Diffuse interstitial fibrosis –Rare-- Cricoartynoid involvment (hoarsness,dysphagia,inspiration dificulty)

Cardiovascular Pericarditis 10%, Myocarditis 5%, Valvulitis (aortic incompitance)<1% Coronary artery disease (40% of RA have prematue atherosclerosis) Nodule formation Amylodosis

Hematological complications Lymph node enlargment 50 % Anemia of chronic disease Iron defficency anemia Autoimmune heamolytic anemia(uncommon) Drug induced marrow supression anemia Thrombocytosis Cytopenia secondary filty’s syndrome splenomegaly

Ocular keratocongunctivitis Sicca (xeropthalmia) secondary to sjögren’s syndrome xerostomia,dyspareunia Episcleritis benign Scleritis  scleromalcia 1% Nodules <2%  scleromalcia perforance Uveitis &Congunctivitis are rare

Bone Osteoperosis AVN(avascular necrosis) osteoarthritis

CNS Carpal tunnel syndrome (common) Tarsal tunnel syndrome(rare) Mono neuritis multiplex Atlantoaxial subluxation 1/3 of patients (usually assymptomatic chronic cases) CNS Vasculitis Depression, Psychosis FMS

Secondary amyloidosis Renal is the most common Skin,liver,GI can be affected

Bad Prognostic Factors Early onset Fulminant course Seropositive RF Anti CCP positve Rheumatoid nodules Sjogron’s syndrome Feltty syndrome Vasculitis Limtation of biologics

Unlikely to be RA Asymmetric Arthritis Migratory pattern Predominantly large joints DIP involvement Rash, High fever Back complain RF Negative status-CCP negative No erosions in X rays if more than 2 years since presentation.

Are you a safe physician? Is the patient with RA fit for the OR? Can the Patient get pregnant? How to asses activity of the disease by : history physical exam lab When to start DMARDS When to start Anti TNF When to start Anti B-cell How to follow up a patient

Managing RA – Therapeutic Goals Control symptoms Minimize loss of function Reduce progression of disease

RA Disease Management

Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Radiographic Scores Kirwan J. J Rheumatol. 1999;26:720-5.

Current RA Treatment Strategy for 2009 DMARD (Step-up/triple therapy ) MTX SSZ Biologic 1 Anti-TNF Etanercept Infliximab Adalimumab Biologic 2 Rituximab Abatacept DAS28 driven

ACR Goals of Therapy in RA Symptom relief Improvement in physical function Reduce physical disability Slowing/arresting progression of structural damage Guidelines for the Management of RA. Arthritis Rheum. 1996; 39:

For early aggressive treatment we need the following Early referal Reliable diagnosis Effective & safe therapies Prognostic predictors Disease activity measures Decrease disease activity & prevent joint damage

Progress in management of RA in recent years DrugsObjectivesConcepts 1985 MTX/SSZSigns & symptoms 1995 Combination Leflunomide  joint damage 2000 TNF blockers Stop joint damage Early treatment Prevent joint damage Tight control Early intensive ttt 2008Remission

Traditional Therapies Wilske and Haeley. J Rheumatol 1989 Exp methods MTX, axathioprine Penicillamine, gold, hydroxychloroquine Physcial medicine, rehabilitation Salicylates, NSAIDs Patient education, rest, application of heat or cold Surgery Glucocorticoid (systemic or intra-articular)

Treatment of RA With DMARDs Traditional DMARDs 1 MTX Hydroxychloroquine Sulfasalazine Leflunomide “Biologics DMARDs” 2-5 Etanercept Infliximab Adalimumab Anakinra Abatacept Rituximab Combination Treatment ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46: Combe B, et al. Ann Rheum Dis. 2007;66: Kineret ® (anakinra) Prescribing Information, Amgen Corporation. Thousand Oaks, Calif. 4. Orencia ® (abatacept) Prescribing Information, Bristol-Myers Squibb Company, Princeton, NJ. 5. Rituxan ® (rituximab) Prescribing Information, Genentech, Inc., South San Francisco, Calif.

The Famous Combination Studies ARC low dose glucocorticoid study group trial Methotrexate-Cyclosporin combination study RAIN study of Methotrexate + SSP + HCQ: (triple therapy) COBRA study: SSP + MTX + Prednisolone or SSP alone Fin-RACo Trial: SSP+MTX+HCQ+Prednisolone vs single drug +/- Prednisolone

Key Anti-TNF Trials Late ARMADAAdalimumab ATTRACTInfliximab TEMPOEtanercept Early ASPIREInfliximab ERAEtanercept PREMIERAdalimumab

When to use anti-TNF? Straight away After DMARD failure DAS28 >5.1 or less Late

Key Messages Set clear disease activity targets TICORA TEAR CAMERA Earlier treatment PROMPT COMET Therapeutic memory BeST B cell targeting

Definition of Remission Clinical Remission – ACR/DAS criteria, or normal acute phase response, no clinical synovitis Imaging Remission – No radiographic damage progression – No significant synovitis on sensitive imaging True Remission – A state of low disease activity with no progression of structural damage

Clinical Remission by DAS28 Based on VAS of 100mm Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26: DAS28 Score Severe Moderate Low Remission Disease Activity DAS28 <2.6

Remission in RA Importance of Structural Damage Determinants of Structural Damage – Interrelationship synovitis and damage Remission Clinical and Imaging – Impact of DMARDs – Effect of TNF antagonists

Remission on DMARDs DMARDs frequently produce clinical remission DMARDs rarely produce imaging remission Hence DMARDs rarely produce true remission Explains progression of damage in patients in clinical remission on DMARDs? What happens with TNF antagonists?

Early RA: Early DMARD therapy MTX dose mg/week (within 1-2 months) + glucocorticoid Cobra? Long-standing RA: If previosuly inadequate dose: Optimize DMARD (MTX) dose + glucocorticoid DAS28 improvement >1.2 or HAQ improvement >0.5 within 3-4 months Smolen, Sokka, Pincus, Breedveld, Clin Exp Rheumatol 2003 Switch to another DMARD + glucocorticoid Add a biologic agent (eg, TNF- antagonist) or NO Add another DMARD + glucocorticoid Add a biologic agent (eg,TNF- antagonist) or NO SDAI <3.3 or DAS28 < 2.4 or HAQ <0.5 within 4 months by adjusting dosages X-rays YES Continue DMARD therapy, lower corticosteroids YES Algorithm for Achieving Therapeutic Success in RA