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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
RHEUMATOID ARTHRITIS
• 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
RHEUMATOID ARTHRITIS
• 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.
RHEUMATOID ARTHRITIS
• 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
RHEUMATOID ARTHRITIS
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
RHEUMATOID ARTHRITIS
• 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
RHEUMATOID ARTHRITIS
• 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.
RHEUMATOID ARTHRITIS
• 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
RHEUMATOID ARTHRITIS
• 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
RHEUMATOID ARTHRITIS
• Treatment– goal of treatment
• reduce inflammation and pain, • preservation of function, and • prevention of deformity.
RHEUMATOID ARTHRITIS
• 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)
RHEUMATOID ARTHRITIS
• 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.
RHEUMATOID ARTHRITIS
• 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
Common Adverse Effects of the Biologic Drugs
• 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
Common Adverse Effects of the Biologic Drugs