rheumatoid arthritis (ra)

RHEUMATOID ARTHRITIS (RA)

OVERVIEW

Definition Immuno-pathogenesisClinical findings (articular and systemic

manifestations) InvestigationsAssessment & monitoringManagement

RHEUMATOID ARTHRITIS

• Chronic multisystemic inflammatory disease of unknown etiology

• Affects the synovial membranes of multiple joints (diarthrodial joints)

• Female : Male ratio 3:1• Most frequent during 4th and 5th decade• Affects approximately 1% of the adult population

worldwide

DEFINITION chronic immune inflammatory disorder, with still

unknown aetiology, characterized by: Articular manifestations: chronic destructive and

deforming arthritis affecting small joints in a bilateral and symmetrical pattern;

Systemic manifestations: cardio-vascular, respiratory, renal, neurologic, ocular;

Progressive irreversible articular damage;

Significant functional disability and impaired quality of life

IMMUNO-PATHOGENESIS

Immune factors Autoimmunity

proinflammatory cytokines (TNF)

Environmental factors

Viral infectionssmoking

Genetic susceptibi

lityHLA DR4HLA DR1

Proliferative synovitis (pannus) Inflammation, (neo)angiogenesis,

tissue damage

NORMAL SYNOVIAL JOINT

Articular cartilage

Synovium Membrane

Lamellar bone

Subchondral bone

Type A cell: mphage like, protective role

Type B cell: fibroblast like, produce matrix and synovial fluid

Vessel

Synovial Membrane:only 1-2 cells thick

DESTRUCTION OF JOINT CARTILAGE AND BONE

Proliferating synovial lining => Pannus

Proliferating synovial lining comes in contact with the cartilage matrix and bone there is degradation of the cartilage and erosion of the bone surface (by matrix metalloproteinases and other proteases produced by synovial cells)

Chondrocytes themselves

IL-1 and TNF-alpha also stimulate production of metalloproteinase by Chondrocytes of the articular cartilage. In response to these cytokines, chondrocytes decrease type II collagen and proteoglycan synthesis and increase synthesis of metalloproteinases that contribute to the degradation of collagen and proteoglycans.

Neutrophils in Synovial Fluid

The main inflammatory cells of the synovial fluid are neutrophils.

Cytokines such as transforming growth factor beta (TGF-beta) and interleukin 8 (IL-8) attract neutrophils.

Neutrophils may undergo degranulation and cause some damage to surrounding tissues.

Osteoclasts

Osteoclasts may be activated by inflammatory mediators including IL-1, TNF and PGE2

bone

cartilage

CENTRAL ROLE OF TNFα IN RA

Kirwan JR. J Rheumatol. 1999;26:720-725.

Thickened Synovium

Lymphocytic Infiltrate

Neovascularization

EARLY CHANGES IN RA

Major type of cells in synovium are T-cells and macrophages whereas in synovial fluid are neutrophils

RA IS CHARACTERISED BY SYNOVITIS AND JOINT DESTRUCTION

NORMAL RA

Synovial membrane

Cartilage

CapsuleSynovial fluid

Inflamed synovial

membrane

Pannus

Major cell types:• T lymphocytes• macrophages

Minor cell types:• fibroblasts• plasma cells• endothelium• dendritic cells

Major cell type:• neutrophils

Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.

Cartilage thinning

PANNUS FORMATION

Articular findings: rheumatoid hand and foot; C1-C2 subluxation

Extra-articular findings: cardio-vascular (rhythm troubles, early accelerated atherosclerosis, vasculitis), respiratory (diffuse interstitial fibrosis, nodules, pleurisy), ocular (sicca syndrome), neurologic (peripheral & entrapment neuropathy), renal (amyloidosis), rheumatoid nodules, myositis, osteoporosis

Chronic evolution with flares

CLINICAL MANIFESTATIONS

ACR 1987 Diagnostic CriteriaACR and EULAR 2010 Classification

CriteriaACR, American College of Rheumatology

EULAR, European League Against Rheumatism


• Clinical presentation– usually presents insidiously;– prodromal syndrome of malaise, weight loss and

vague periarticular pain and stiffness may be seen– less commonly, the onset is acute, triggered by a

stressful situation such as infection, trauma, emotional strain or in the postpartum period.

– the joint involvement is characteristically symmetric with associated stiffness, warmth tenderness and pain


• Clinical Features– the stiffness is characteristically worse in the

morning and improves during the day; its duration is a useful indicator of the activity of the disease.

– the usual joints affected by rheumatoid arthritis are the metacarpophalangeal joints, the PIP joints, the wrists, knees, ankles and toes.

– Entrapment syndromes may occur especially carpal tunnel syndrome

RHEUMATOID HAND

DEVIERE CUBITALA DEGETEPOLICE “IN Z”

1. Swelling of the RC, MCF, PIP joints

2. Fusiform swelling fingers: synovitis of PIP joints, causing them to appear spindle-shaped.


• After months to years, deformities can occur; the most common are– ulnar deviation of the fingers– swan neck deformity, which is hyperextension of

the distal interphalangeal joint and flexion of the proximal interphalangeal joint

– boutonniere deformity, which is flexion of the distal interphalangeal joint and extension of the proximal interphalangeal joint

– valgus deformity of the knee

RHEUMATOID HAND

RHEUMATOID HAND

Boutonniere deformityRheumatoid nodules

Artritis mutilans

DEGETE “IN GAT DE LEBADA”

Swan-neck deformity”

Fingers in “swan-neck”

Fingers in “ boutonniere”

artritis mutilans


Saurabh Garg

RHEUMATOID FOOTHammer toes Complex deformity of the foot

Subluxation of the metatarsal headsTriangular foot

EXTRA-ARTICULAR MANIFESTATIONS• General: fever, lymphadenopaty,weit loss, fatigue

• Dermatologic: rheumatoid nodules, vasculitis• • Ocular manifestations: Keratoconjunctivitis sicca, episcleritis, scleritis, choroid and retinal

nodules

• Pulmonary manifestations: pleural involvement, fibrosing alveolitis , obliterative bronchiolitis• Felty’s Syndrome: RA with splenomegaly and neutropenia

• Cardiac involvement: Constrictive pericarditis, myocarditis, coronary vasculitis, nodules on valves

• Renal involvement: secondary amyloidosis

• Neurologic manifestations: Mononeuritis multiplex, entrapment neuropathies, peripheral neuropathies

• Hematologic manifestations: anemia, thrombocytosis

RHEUMATOID NODULESSubcutaneus nodules

Occur 20-35% of RA patients in severe, active disease with RF positive

localisation: on the extensor surface of the forearms, in the olecranon bursa, over joints, and over pressure points, like sacrum and occiput

characteristic histology: central area of fibrinoid necrosis surrounded by a zone of palisades of elongated histiocytes and a peripheral layer of cellular connective tissue

VASCULITIS

In RA patients with long standing disease, significant joint involvement, high titers RF, and nodules

Clinical aspects: palpable purpura, small infarcts of digital pulp, visceral arteritis

OCULAR MANIFESTATIONS

keratoconjunctivitis sicca (30%)

iritis/iridociclitis

episcleritis/scleritis

scleromalacia perforans

retinian vasculitis

EPISCLERITIS SCLERITIS

SCLEROMALACIA PERFORANS

INVESTIGATIONS

Inflammatory

syndrome (ESR, CRP

level)

Immune syndrome

Rheumatoid factor

Anti-CCP antibodies,

etchematologicpulmonary, renal,

cardio-vascular

assessment

Imagistic Radiologic

Hand and foot ultrasonograp

hyIRM


• Labs: inflammatory syndrome:– The ESR is elevated both in the acute and chronic

phases of the disease– C reactive protein

– a moderate anemia is often present which is usually hypochromic normocytic

– the white count is normal or slightly increased but leukopenia may occur, often in presence of splenomegaly (e.g., Felty’s syndrome)

– the platelet count is often elevated in proportion to the degree of joint inflammation


• Labs: immune syndrome:– Rheumatoid factor is an autoantibody directed against the constant

region (Fc) of IgG. High titers of rheumatoid factor are associated with severe disease.

Rheumatoid factor is also found in other diseases like syphilis, sarcoidosis, infective endocarditis, TB, leprosy, parasitic,SLE, hepatitis, infections; in advanced age and in asymptomatic relatives of patients with rheumatoid disease.

– Antinuclear antibody are seen in 20% of patients with rheumatoid arthritis, though their titer is lower than in SLE

– Anticyclic citrullinated peptide antibody are the most specific for RA; they are correlate strongly with erosive disease.


• Labs – joint fluid examination is valuable. The fluid is

translucent to opaque and has between 3000 and 50,000 WBCs /microL. There are 50% or more polymorphonuclear leukocytes. The culture is negative.

• X-ray– of all the laboratory tests, x-ray changes are most

specific for rheumatoid arthritis. However, they are not sensitive and usually are negative during the first 6 months of the disease


• X-rays– The earliest changes occur in the wrist or feet and

consist of soft tissue swelling and juxta-articular demineralization.

– Later, diagnostic changes consisting of joint space narrowing and erosions develop. The erosions are first seen at the ulnar styloid and at the juxta-articular margin, where the bony surface is not protected by cartilage.

– Diagnostic changes also occur in the cervical spine with C1-2 subluxation, but this can take several years to develop.

Juxta-articular osteoporosis

Bony erosions

erosiongeodes

erosion

juxta-articular osteoporosismarginal erosionsnarrow joint space

Serial X-rays of a knee in RA

C1-C2Subluxation

Pulmonary rheumatoid nodules

Caplan syndrome

RHEUMATOID ARTHRITIS• 1987 American College of Rheumatology Revised criteria for

the diagnosis of Rheumatoid Arthritis:– At least four of the following

• 1. Morning stiffness > 1hour• 2. Synovitis in three joints simultaneously• 3. Synovitis in wrist or hand, MCP or PIP joints• 4. Symmetrical arthritis (some joint areas on both sides of

the body)• 5. Rheumatoid nodules• 6. Serum rheumatoid factor• 7. Radiographic changes typical of Rheumatoid Arthritis

(erosions are the patognomonical signes)

To be classified as having RA a patient must meet 4 or more criteria

PROBLEMS WITH OLD ACR CRITERIA

• Work best in longstanding RA– But DMARDs work best in early RA and the goal is

to prevent development of damage• Need criteria addressing earlier diagnosis

given the benefits of early treatment• Need to include ACPA (CCP)

– Balance with need for use in low resource settings where CCP not available

• Goal of new criteria: predict who should be treated with DMARDs

NEW ACR/EULAR PROPOSED CRITERIA

• Initial screen:– 1+ swollen joints (if no, not RA)– Better explained by other dz? (if yes, not RA)– Typical RA erosion on X-ray? (if yes, RA)

• Next step:– Pattern of joint involvement (more points for more

joints and small joints)– Serology (RF and/or CCP, negative, low, high)– Duration (<6 wk, 6+ wk)– ESR and/or CRP (both normal vs. one abnormal)

2010 ACR/EULARClassification Criteria for RA

JOINT DISTRIBUTION (0-5)1 large joint 0

2-10 large joints 1

1-3 small joints (large joints not counted) 2

4-10 small joints (large joints not counted) 3

>10 joints (at least one small joint) 5

SEROLOGY (0-3)Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

SYMPTOM DURATION (0-1)<6 weeks 0

≥6 weeks 1

ACUTE PHASE REACTANTS (0-1)Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

≥6 = definite RA

What if the score is <6?

Patient might fulfill the criteria…

Prospectively over time (cumulatively)

Retrospectively if data on all four domains have been adequately recorded in the past

ASSESSMENT AND MONITORING

RA activity: Disease Activity Score, DAS28 Disability and quality of life: Health

Assessment Questionnaire, HAQ Response to treatment: EULAR, ACR criteria Remission Negative prognostic factors

ACR GUIDELINES FOR MANAGEMENT

• Summarize evidence for DMARDs and biologics in different settings

• Incorporate the following in treatment decisions– Disease duration (<6mo, 6-24, >24 mo)– Disease activity (low, moderate, high)– Features of poor prognosis

Saag KG et al. Arthritis Rheum 2008;59:762

MEASUREMENT OF DISEASE ACTIVITY: DAS28 AS EXAMPLE

DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH

• Includes:

– Tender joint count– Swollen joint count– ESR (or CRP in different version)– GH: Patient global disease activity assessment

• Categorized: as low (<3.2), moderate (3.2-5.1), or high (>5.1)

28 joints counted

DAS 28

POOR PROGNOSTIC FACTORS IN RA

• Presence of RF and/or CCP antibodies• Radiographic erosions• Functional limitation• Extraarticular disease

REMISSION CRITERIA

• 5 or more must be fulfilled for at least 2 consecutive months:– Morning stiffness not exceeding 15 minutes– No fatigue– No joint pain (by history)– No joint tenderness or pain on motion– No soft tissue swelling in joints or tendon sheaths– ESR (W) < 30 mm/h (f); < 20 mm/h (m)

DIFFERENTIAL DIAGNOSIS

– Rheumatic fever: migratory arthritis, elevated ASLO and dramatic response to Aspirin

– Systemic Lupus Erythematosus: Butterfly rash, discoid lupus erythematous, photosensitivity, alopecia, high titers of Anti Ds-DNA, renal and CNS disease

– Osteoarthritis: no constitutional manifestations and no evidence of joint inflammation

– Gouty Arthritis: usually monoarticular initially but can become polyarticular in the later years

DIFFERENTIAL DIAGNOSIS– Pyogenic arthritis: usually monoarticular, fever and chills,

abnormal joint fluid– Chronic Lyme disease: commonly monoarticular and

associated with positive titers of anti Borrelia antibodies– Human Parvovirus infection: arthralgia more common than

arthritis, rash may be present, serologic evidence of parvovirus B19 infection

– Polymyalgia rheumatica is associated with proximal muscle weakness and stiffness

– several cancers produce paraneoplastic syndromes including polyarthritis; e.g., hypertrophic pulmonary osteoarthropathy produced by lung and gastrointestinal cancers. Diffuse swelling of the palmar fascia has been associated with several cancers including ovarian cancer.

MANAGEMENT

Objectives

Obtaining remission/ minimal activity status– Inhibition of radiologic

damage– Improve pain and

inflammation– Maintain/improve

articular function

Drugs• Pathogenic: Disease Modifying

Anti-Rheumatic Drugs DMARDs (methotrexate, leflunomide, sulfasalazine, hidroxicloroquine, azathioprine, cyclosporine); biological agents: (infliximab, etanercept, adalimumab, golimumab, certolizumab), anti-CD20 (rituximab), anti-IL6 (tocilizumab), anti-costimulation molecules (abatacept)

• Corticosteroids (systemic & local)

Surgery: Synovectomy, total joint replacement)

Rehabilitation: Physical & kynetotherapy

DMARDs (Disease-Modifying Anti-Rheumatic Drugs)

• Hydroxychloroquine (Plaquenil)

• Sulfasalazine• Methotrexate• Leflunomide (Arava)

• Less commonly used:– Azathioprine– Gold, PO or IM– Cyclosporine

• Etanercept (Enbrel)• Infliximab (Remicade)• Adalimumab (Humira)• Golimumab (Simponi)• Certolizumab Pegol (Cimzia)• Anakinra (Kineret)• Rituximab (Rituxan)• Abatacept (Orencia)• Tocilizumab (Actemra)

Traditional Biologics


• Treatment– goal of treatment

• reduce inflammation and pain, • preservation of function, and • prevention of deformity.


• Treatment NSAIDs: Ibuprofen, naproxen, sulindac and

other NSAIDs may also be effective though they are associated with a number of side effects including

• GI irritation and peptic ulcers (misoprostol can reduce the incidence of peptic ulcers associated with NSAIDs)

• Kidney damage• Liver damage

BENEFITS OF EARLY DETECTION AND DMARD THERAPY

• Decreased RA severity, disability and mortality with DMARDs

• Less need for joint replacement surgery• May decrease risk of cardiovascular disease

and mortality

RHEUMATOID ARTHRITIS• Treatment (Disease Modifying Agents (DMARDs)

– Methotrexate: the gold standard for RA.– It produces a beneficial effect in 2-6 weeks and is given

once weekly.– The usual dose is 10-25 mg once a week. The most

common side effect is gastric irritation and stomatitis. Other side effects are hepatotoxicity, pancytopenia and interstitial pneumonitis

.

• Combine with folic acid (at least 1 mg per day)


• Treatment– Antimalarials such as hydroxychloroquine sulfate is

effective in 25-50% of patients and in most cases after 3-6 months of therapy. It is reserved for mild disease. Doses: 200-400 mg/day.

– Sulfasalazine: 2-3 g daily– Leflunomide: 20 mg daily; side effects: diarrhea,

hepatotoxicity, hypertension.


• Treatment.– Corticosteroids produce immediate and dramatic

anti-inflammatory benefit but are limited by their many side effects

– “bridge therapy” to shut off the inflammation rapidly– Prednison 10mg daily.

• Consider using low-dose corticosteroids, if necessary

LIMITATIONS OF TRADITIONAL DMARDS

• Lack of efficacy in some patients• May not slow radiographic progression• Toxicity (less common reason for

discontinuation)

BIOLOGICS IN RA

• All recommended with methotrexate• Biologic agents target:

– Tumor necrosis factor-a (TNF-a)– Co-stimulation between B and T cells– B cell surface proteins– Interleukin-6 (IL-6)– More likely to come soon….

TNFα INHIBITORS

• Generally accepted as first-line biologics• Add to methotrexate when disease

activity remains moderate to high (after adequate trial)

• Five different agents available

TNF INHIBITORSGeneric (Brand)

Class Route Dose Frequency

Etanercept (Enbrel)

Soluble TNFR SQ 50 mg Q week

Infliximab (Remicade)

Chimeric mAb IV 3-10 mg/kg At 0, 2, 6 weeks, then q 8 weeks

Adalimumab (Humira)

Humanized mAb

SQ 40 mg Q 2 weeks

Golimumab (Simponi)

Human mAb SQ 50mg Q month

Certolizumab pegol (Cimzia)

PEGylated fragment of humanized mAb

SQ 400 mg At wks 0, 2, 4, then 200 mg q 2 wk or 400 q 4 wk

APPROVED BIOLOGIC AGENTS

• Etanercept (Enbrel) is a fusion protein given as a weekly, 50-mg subcutaneous injection

• Infliximab (Remicade) is a chimeric monoclonal antibody given in doses of 3 mg/kg to 10 mg/kg every four to eight weeks

• Adalimumab (Humira) is a fully human monoclonal antibody given as a subcutaneous injection of 40 mg every 2 weeks

APPROVED BIOLOGIC AGENTS

• Certolizumab pegol (Cimzia) is a pegylated Fab’ fragment of a humanized monoclonal antibody, given in subcutaneous doses of 200 mg every other week or 400 mg a month, after a loading dose

• Golimumab (Simponi) is another human monoclonal antibody given subcutaneously in doses of 50 mg once a month

CHECK-LIST FOR THE ANTI-TNFα THERAPY

INCLUSION1. Certain diagnosis of RA

(ACR 1987)

2. Active, severe RA (DAS > 5,1): ≥ 5 NTJ si NSJ + 2 of: Morning stiffness ≥60 min ESR > 28 mm/1h CRP > 20 mg/l

3. Non-responder 2 DMARDs (> 12 sapt)

EXCLUSION

1. Severe infection:TB (binding screening !), sepsis

2. B, C Hepatitis, HIV

3. Chronic heart failure (class III/IV NYHA)

4. Neoplasia

5. Concomitant vaccination with living vaccine

6. Associated autoimmune phenomena (ANA, anti ds DNA antibodies)

HOW TO APPROACH FAILURE OF TNFα

• TNF inhibitors are not universally efficacious• Options after TNF inhibitor failure:

– Within-class switching– TNF to non-TNF class biologic switch

• Rituximab• Abatacept• Tocilizumab

• Future direction: biomarkers to direct choice

Buch MH. Curr Opin Rheumatol 2010;22:321

BIOLOGIC DRUGS FOR RA-2

• Abatacept (Orencia) is a selective costimulation

modulator of T cells given as a monthly intravenous

infusion in doses ranging from 500 to 1,000 mg

depending on patient body weight, after a loading

dose

• Tocilizumab (Actemra) is a humanized monoclonal

antibody that binds to the interleukin (IL)-6 receptor.

It is given by intravenous infusion every four weeks

in doses of 4 to 8 mg/kg

Biologic Drugs for RA-2

• Rituximab (Mabthera) is a chimeric monoclonal

antibody against the CD20 protein on the surface

of B cells. This drug is given as two 1,000 mg

infusions; the frequency of repeat therapy is at 24

weeks after the last infusion

Common Adverse Effects of the Biologic Drugs

• Etanercept: Infections and injection site reactions

• Infliximab: Upper respiratory tract infections, sinusitis, pharyngitis, infusion reactions, headache, and abdominal pain

• Adalimumab: Upper respiratory tract infections, sinusitis, injection site reactions, headache, and rash


• Certolizumab pegol: Upper respiratory tract infections, rash, and urinary tract infections

• Golimumab: Upper respiratory tract infections, nasopharyngitis

• Abatacept: Headache, upper respiratory tract infections, nasopharyngitis, and nausea

• Tocilizumab: Upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased alanine transaminase levels

• Rituximab: Upper respiratory tract infection, nasopharyngitis, urinary tract infection, bronchitis. Other potentially important events include infusion reactions, serious infections, cardiovascular events and, progressive multifocal leukoencephalopathy


rheumatoid arthritis (ra)

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