RHEUMATOID ARTHRITIS: NOT JUST AN ARTHRITIS!!

Dr Femi Adelowo, FMCP, FWACP, FACR,FRCP EdinProfessor of Medicine and Consultant Rheumatologist,Olabisi Onabanjo University Teaching Hospital,Sagamu, Ogun State, Nigeria. Presently LASUCOM, LASUTH. Ikeja

Email: femiadelowo2003@yahoo.com

PREAMBLE

Arthritis is not just one disease It is a manifestation or clinical presentation of many diseases,

just like Headaches!! There are more than 200 types or causes of Arthritis Rheumatoid Arthritis (RA) is one of the most destructive The deformities of Swan neck, Boutonniere, e.t.c are a result of

long standing and poorly managed RA Such should not occur again!! Rheumatologists, are ideally, in the best position for the

Medical Management

Cont

RA is a chronic, debilitating, progressive autoimmune disease

Onset can be abrupt/acute; gradual/insidious; or sub acute

Affects synovial joints primarily Other structures– bone, cartilage, ligaments,

tendons Secondarily Organs and structures affected– kidneys, eyes,

lungs, heart, CNS, CVS, Skin etc All age groups are affected, especially 35-50yrs Prevalence 1% of population. Urban>Rural

Cont.

Constitutes 15% of all rheumatological cases seen in a Private Practice Rheumatology Clinic in Lagos

Female: Male ratio 2.5:1 Characterized by chronic inflammation of synovium Resultant joint damage, pains and disability Life expectancy reduced by 3-18yrs!! 50% off work within 10yrs Comparable mortality and morbidity with Triple

Coronary Artery Disease; and Stage III Hodgkin´s Lymphoma

2-3ce normal myocardial infarction

Cont

Staggering financial costs-Direct and Indirect More hospital admissions vs non RA Very few reports from W.Africa-said to be uncommon

Lee DM, Weinblatt ME. Lancet 2001;358:903-911 Pincus T et al.Clin Trop Rheumatol.2004;22(Suppl.35); S2-S11 Fuchs HA et al. J Rheumatol 1989;16:585-591 Scott DL et al. Lancet 1987;329:1108-1111 Adelowo OO et al. Clinical Rheum.2010;29:593-597

AETIOLOGY

Unknown Possible interplay of infectious agent and

genetics,hormonal Infectious-EBV, Parvovirus,Rubella,

Clostridium spp, Mycoplasma Genetic– shared epitope of HLA DR4/DR1

PATHOGENESIS Complex process of immune reaction, inflammation, cytokines and

destructive enzymes Mechanism-autoimmune response, resulting in proliferation of synovial

cells Release of pro-inflammatory cytokines- IL-1,2,6,8,15,17; TNF-α,

Growth factors, Interferon gamma(IFN-γ), Fibroblast growth factor, Platelet derived growth factors

Cytokines mediate and perpetuate inflammatory signs and symptoms Thickening of synovium(pannus), disintegration of cartilage and bone Collagenases, elastases, metalloproteinases,Cathepsin D

Gravallese DM, Golding SR. Arthritis Rheum. 2000;43:2142-2151 Harris ED Jr. N Eng J Med 1990;322:1277-1289 Hirth A et al. Arthritis Res 2002;4:117-125

DIAGNOSIS

American College of Rheumatology Criteria for RA (ACR) 1-Morning stiffness-in and around joints lasting at least 1 hr 2-Arthritis of 3 or more joint areas 3-Arthritis of hand joints-wrists, MCP, PIP 4-Symmetrical arthritis-bilateral involvement of PIP, MCP, MTP

considered positive even in absence of symmetry 5-Rheumatoid nodules-subcutaneous, over bony prominences 6-Rheumatoid factor by Latex Fixation Technique 7-Radiographic changes-erosions, bony decalcification Presence of 4 or more diagnostic criteria, 1-4 must be present for at

least 6 weeks

Arnett FC et al. Arthritis Rheum 1988;31:315-324

NEW ACR CRITERIA( Sept 10,2010)

Presence of synovitis at least one joint Absence of alternative diagnosis Achievement of total of 6 or more( of 10) in 4

Domains– 1.Number/site joints(0-5)– 2.Serologic(0-3)– 3.Elevated Acute phase response(0-1)– 4. Symptom Duration( 0-1)

Arthritis and Rheumatism Vol 62 Issue 9 pg 2569-2581 Sept 2010

NON SPECIFIC CONSTITUTIONAL FEATURES

Fatigue Weight loss Malaise Fever Anaemia of chronic illness Reduced quality of life

EXTRA ARTICULAR MANIFESTATIONS

Skin-non tender subcutaneous nodules on extensor surfaces, particularly in the forearms or at pressure points

Heart-Pericardial effusions, pericarditis Lungs-Pleurisy, pleural effusion, nodules in lung tissue-

cavitations, calcification Vasculature-vasculitis of small vessels, causing infarction of the

digits, gut, nerves, atherosclerosis Eyes-scleritis, keratoconjunctivitis sicca, Sjogren´s Syndrome Nerves-entrapment syndromes-carpal tunnel, tarsal tunnel;

peripheral neuropathy

DIFFERENTIAL DIAGNOSIS

SLE Polyarticular OA Polyarticular Gout Psoriatic arthritis Fibromyalgia Syndrome Spondyloarthropathies Benign Hypermobility Syndrome Sarcoidosis Hypothyroidism Sjogren´s Syndrome

MARKERS OF INFLAMMATION

C-Reactive Protein– fluctuates with disease activity

ESR-- correlates with bone erosion rate Rheumatoid factor- IgM usual method but not

specific, IgG-specific for RA Anti-Cyclic Citrullinated Peptides-useful in

initial diagnosis. Specific and Sensitive

PROGNOSTIC FACTORS- POORER OUTCOMES

1-Insidious onset 2-Large joint involvement 3-Smoking 4-Rheumatoid factor positivity 5-Subcutaneous nodules 6-Higher swollen joint score 7-Higher tender joint counts

Weinblatt ME. Ann Intern Med 1996;24:773-774

MANAGEMENT

Pharmacologic Non pharmacologic Early referral to Rheumatologist Window of opportunity- initial 2 years

Objectives of Management

Prevention/control of structural damage to joints Pain relief Prevention or reversal of disability Improvement in quality of life Ultimately, Remission, not achieved spontaneously

Symptomatic treatment with NSAIDs does NOT STOP disease, it relieves pain, but destruction and disability continue

Standard treatment-Disease Modifying Anti Rheumatic Drugs (DMARD).Within 3-6months

CONT

Methotrexate alone or in combination Methotrexate + Hydroxychloroquine + Sulfasalazine Leflunomide alone or combination MTX Azathioprine, Cyclophosphamide Gold salts, D Penicillamine not commonly used again Corticosteroids in LOW dose-10mg or less; Intra-articular

steroids NSAIDs when in pains Narcotic analgesics NOT indicated

Strand V et al. Arch Intern Med 1999;159:2542-2550

NON PHARMACOLOGIC

Education Physical Therapy Exercise Occupational Therapy Good nutrition Assistive Devices- walking sticks,frames,in

soles

BIOLOGICS: THE FUTURE IS HERE!!!

UNMET NEEDS- Inadequate response,drug toxicity,contraindications to medications DMARDs,Steroids

Drugs that target specific molecule in the inflammatory cascade Recent developments, but have made a lot of differences to

patients in terms of pain, swelling, stiffness, deformity, quality of life, morbidity and mortality

Used variously in Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis/Psoriasis,

Behcets, Juvenile Arthritis, Crohn´s Disease, SLE,Vasculitis(Churg Strauss,PAN),Polymyositis etc

INFLIXIMAB(IFX)

Inhibits TNF alpha BeST study-less progression of joint damage

in patients treated early Initial treatment of early onset RA with MTX

and IFX more effective than reserving IFX for failed DMARD

van der Kooij SM et al. 71st ACR Meeting Nov 2007. Abstract #697

DRUGS THAT TARGET TNF alpha

ETANERCEPT(ETN)-antagonist to soluble TNF receptors. Given subcutaneously at a dose of 50mg weekly(single or double dose)

1-TEMPO study-(ETN/MTX) radiographic progression of disease halted and improved clinical outcomes after 3yrs

2-COMET—Early RA(3months-2yrs). Two arms study, MTX alone and MTX+ETN, at week 52, 48% of patients on combination achieved ACR 70 compared with 28% on MTX alone

van der Heijde D et al. TEMPO data 71st ACR Meeting Nov 2007. Abstract #256

Emery P et al. COMET data 71st ACR Meeting Nov 2007. Abstract #L17

ADALUMIMAB(ADA)

Anti TNF Subcut administration Inhibition of radiographic progression,and sustained

clinical response and physical function, in patients with RA for 5 years(ADA+MTX)

Early treatment of aggressive RA leads to remission in 49%(ADA+MTX) vs 25%(ADA) vs 25%(MTX)

Keystone et al. Arthritis Rheum 2004;50:1400-11 Breedveld F et al, Arthritis Rheum 2006;54:26-37

BIOLOGICS TARGETTING B-CELL

RITUXIMAB Indications-Failed or Refractory Rx to Anti TNF alpha 25-50% of RA fail to achieve ACR 20% improvement with Anti TNFs Anti TNF Non Responders-30-40% Rituximab enables remission and low disease activity RTX+MTX superior to RTX alone Genetically engineered chimeric murine/human monoclonal antibody Depletes CD20 positive B cells for 6-8months. Acts at multiple levels disrupting the inflammatory response

Edwards JC et.al N Engl J Med. 2004;350:2572-81

Cont. Acts through THREE mechanisms-: complement mediated B

cell lysis; cell mediated cytotoxicity and induction of apoptosis Optimal clinical response at 24-48 weeks Two intravenous injections of 1000mg, two weeks apart Well tolerated, no increased serious infections, TB or

Lymphoproliferative disorders compared ADA,ETN

Emery P et al. Ann Rheum Dis 2006;65:(Suppl.2)58 Keystone EC et al. Ann Rheum Dis 2006;(Suppl.2)323-324 Cohen S et al. Arthritis Rheum 2006;54:2793-2806 Keystone E. Arthritis Rheum 2008;59:785-793

EMERGING BIOLOGICS!!!

ABATACEPT-Recombinant fusion protein, binds CD80/86 and inhibits T cell activation.

TOCILIZUMAB-Anti Interleukin-6 receptor, IL-6 is important in activation of osteoclasts, proliferation of fibroblasts, induction of matrix metalloproteinases, differentiation of B cells and T cells.Useful in failed Anti TNF

CERTOLIZUMAB OFATUMUMAB OCRELIZUMAB

RHEUMATOID ARTHRITIS:NIGERIAN EXPERIENCE

6 YEAR AUDIT OF 200 RHEUMATOID ARTHRITIS PATIENTS SEEN IN A PRIVATE RHEUMATOLOGY CLINIC PRACTICE IN LAGOS, NIGERIA

RHEUMATOID ARTHRITIS DATA

15% OF ALL RHEUMATOLOGICAL CASES

Total mean 46.9 SD 12.9 Mean for males 47.9 SD 13.7 Mean for females 46.5 SD 12.5 Sex Distribution Females 141- 70.5% Males 59- 29.5% Ratio F:M 2.4:1% Morning Stiffness 77.7%

DATA CONTD

Subcutaneous nodules 29.5% Rheumatoid positivity 38.6% Duration before presentation Mean

50.15months(range 1-360months) Percentage by joint involvement PIP--79.9%MCP—72.0% Knees--69.9% Ankle—61.9% Shoulders--60.3% Wrist—57.7%

DATA CONTD

Elbows--57.7% MTP--29.1% Hip--6.9% Neck--2.6% Temporomandibular joint 0.5% ESR Greater than or equal to 100mm/hr-

9.2% 60-99mm/hr-30.1% Less than 60mm/hr-60.7%

DATA CONTD

WBC Greater than 11000 cells/ul-3.6% 4000-11000cells/ul-89.3% Less than 4000cells/ul-7.1%

DATA CONTD

Treatment Methotrexate-63% Sulfasalazine-6.5% Lefllunomide-5% Methotrexate+HCQ-4.5% Methotrexate+sulfasalazine-12.5% Methotrexate+sulfasalazine+HCQ-6.5% Methtotrexate+HCQ+Leflunomide-1% Eternercept+Methotrexate-1% RITUXIMAB+Methotrexate-2%

CONCLUSION RA NOT uncommon Early Diagnosis and Referral to

Rheumatologist Morbidity and Mortality High if untreated DMARDS, BIOLOGICS- TREATMENT

MAINSTAY.NSAIDs symptom relief Supportive therapy

THANK YOU