Rheumatoid Arthritis. Rheumatoid Arthritis: Definition Progressive, systemic, inflammatory disorder...

Rheumatoid Arthritis

Rheumatoid Arthritis: Definition Progressive, systemic, inflammatory disorder Unknown etiology Characterized by

u Symmetric synovitisu Joint erosionsu Multisystem extra-articular manifestations

RA - Epidemiology * RA has a worldwide

distribution with an estimated prevalence of 1-2%.

Prevalence increases with age, including 5% in women over age 55.

The average annual incidence in the US is about 70 per 100,000 annually.

Both incidence and prevalence of RA are two to three times greater in women than in men.

Although rheumatoid arthritis may present at any age, patients most commonly are first affected between the ages of 30 and 60 years.

RA – Epidemiology Continue RA is among the

oldest diseases. Arthritis and

osteoarthritis are the most prevalent conditions.

RA affects all races. Older age and

overweight are risk factors for arthritis.

Patients with RA have a shortened life span.

For women over 45 years, arthritis is the leading cause of activity limitation.

The most frequent cause of death is cardiovascular disease.

Other mortality conditions result from septicemia, pneumonia, etc.


Pathologic finding: chronic synovitis with pannus formation. The pannus erodes cartilage, bone, ligament and tendons. In the acute phase effusion and other manifestations of inflammation are evident; in the later stages ankylosis of the joint may set in. In both the acute and chronic phase, there may be widespread inflammation of the tissues around the joint that can lead to significant joint destruction.

RA – Immunologic Manifestations continue

Pannus is an organized mass of cells that grows into the joint space and invades the cartilage.

Pathology

Normal jointu synovial

membrane (macrophage and fibroblast-like cells)

u fibrous joint capsule

u synovial fluidu cartilage covers

articular surface

RA jointu SM hyperaemic, congestedu synovial cell proliferation and villous

hypertrophyu SM infiltration by lymphocytes,

macrophagesu Vascular pannus at cartilage-synovium

junctionu increased volume and cellularity of SFu atrophy of supporting musclesu osteopaenia of surrounding bone

Immunopathology

Aggregates of T-cells, macrophages and plasma cells in SMu Activated phenotype

SF contains mainly neutrophils Pro (TNF, IL1, IL6) and anti-inflammatory (IL10,

TGF) cytokines within joint Interplay between immune cells and cytokines

generates inflammation and joint damage

What initiates the process and why doesn’t it resolve?

Nobody knows the answer.

Pathogenesis of Rheumatoid Arthritis

B cell

T cell

Antigen-presenting

cells

B cell ormacrophage Synoviocytes

Pannus

Articularcartilage

Chondrocytes

Macrophage

HLA -DRother cytokines

IFN- &

Production of collagenase and otherneutral proteases

Osteoclast

TNFIL-1

RheumatoidFactors, anti-CCP

Immune complexes

Bone

Complement

Neutrophil

Mast cell

Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15

Current Treatment Targets

Chronic Inflammation: Imbalance Between Mediators

Proinflammatory

Anti-inflammatory

TNFIL-1

IL-8IL-6

IFNIL-4/IL-13

IL-1RaTGF

IL-10

RA – Signs and Symptoms It is a highly

variable disease that ranges from a mild illness of brief duration to a progressive destructive polyarthritis associated with a systemic vasculitis.

RA – Signs and Symptoms cont. The joints involved

most often are the proximal interphalangeal and metacarpophalangeal joints of the hands, the wrists, shoulders, elbows, knees, ankles, and metatarsophalangeal joints. The spine except in late disease is usually not affected.

Rheumatoid Arthritis: PIP Swelling Swelling is confined to

the area of the joint Synovial thickening

feels like a firm sponge

RA – Signs and Symptoms cont.

Morning stiffness, persisting more than one hour but often lasting several hours is especially characteristic of RA.

Its duration is a useful gauge of the inflammatory activity of the disease.

Rheumatoid Arthritis: Ulnar Deviation and MCP Swelling

An across-the-room diagnosis

Prominent ulnar deviation in the right hand

MCP and PIP swelling in both hands

Synovitis of left wrist

RA – Signs and Symptoms cont. Nonspecific systemic

symptoms primarily fatigue, malaise, and depression , may commonly precede other symptoms of the disease by weeks to months.

Patients have complained of severe fatigue 4-6 hours after wakening.

Fever occasionally occurs and is almost always low grade.

It is typical of patients with RA that their symptoms vary, often making diagnosis and treatment difficult.


Erosions, seen on x-ray, occur within the first 2 years. These changes result in limitation in range of motion.


Typical visible changes in the joints.

Rheumatoid Arthritis:Key Features

• Symptoms >6 weeks’ duration• Often lasts the remainder of the patient’s life

• Inflammatory synovitis• Palpable synovial swelling• Morning stiffness >1 hour, fatigue

• Symmetrical and polyarticular (>3 joints)• Typically involves wrists, MCP, and PIP joints • Typically spares certain joints

• Thoracolumbar spine • DIPs of the fingers and IPs of the toes

Rheumatoid Arthritis:Key Features (cont’d)

• May have nodules: subcutaneous or periosteal at pressure points

• Rheumatoid factor• 45% positive in first 6 months• 85% positive with established disease

• Marginal erosions and joint space narrowing on x-ray

Adapted from Arnett, et al. Arth Rheum. 1988;31:315–324.

Clinical Course of RA

Type 1 = Self-limited—5% to 20%Type 2 = Minimally progressive—5% to 20%Type 3 = Progressive—60% to 90%

0

1

2

3

4

0 0.5 1 2 3 4 6 8 16

Type 1Type 2Type 3

Years

Sev

erity

of

Art

hriti

s

Pincus. Rheum Dis Clin North Am. 1995;21:619.

Pincus, et al. Rheum Dis Clin North Am. 1993;19:123–151.

Rheumatoid Arthritis: Typical Course

• Damage occurs early in most patients • 50% show joint space narrowing or erosions in

the first 2 years• By 10 years, 50% of young working patients

are disabled• Death comes early

• Multiple causes• Compared to general population

• Women lose 10 years, men lose 4 years

Investigations

Haematologyu Hb, wcc, plts, ESR

Biochemistryu CRP

Microbiologyu viral titres

Immunologyu RhF, ANA, SSP

Radiologyu XR, bone scan, MRI

possible features

clinical

• arthritis / arthralgia• vasculitis• fever• Raynaud's phenomenon• fatigue• various renal diseases

laboratory

• increased ESR, CRP• anaemia • leukopenia•ANA• trombopenia

systemic autoimmune diseases

not specific

for

one single disease

not specific

for

one single disease

people

how do you recognize them ?

each person

has a face

each autoimmune disease

has its own "face"

how do you recognize it?

RA

Anti-Cyclic Citrullinated Peptide Antibody

Specificity Sensitivity

RF + 75% 60%

Anti-CCP + 96% 75%

Anti-CCP + RF +

99% 80%

* High titer anti-CCP may predict aggressive erosive disease.

Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71

Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of IgG, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process

Citrulline is a non-standard amino acid, created by de-imination of arginine residues in several proteins by the action of peptidylarginine deiminase (PAD). There are several isotypes of this enzyme; in the inflammatory RA synovium, PAD 2 and PAD 4 are abundant These enzymes cause the local citrullination of synovial proteins, such as fibrin. Citrullinated extracellular fibrin in the RA synovium may be one of the major autoantigens driving the local immune response, suggested by the discovery of local production of anti-CCP and anti-citrullinated filaggrin antibodies in the joint. Also, functional haplotypes of PADI4 may be associated with RA.

Stage I Early – no destruction

Stage II Moderate – no joint deformity, osteoporosis with bone and cartilage destruction

Stage III Severe – cartilage and bone destruction with osteoporosis, joint deformity

Stage IV Terminal – fibrous or bony ankylosis

Disease Activity Score

Frequent Assessments of Rheumatoid Arthritis (RA) Disease

Activities are:

DAS28 (Disease Activity Score)

DAS28=(0.56*TJC1/2)+(0.28*SJC1/2)+(0.7*ln[ESR])+(0.014* VAS, [in mm])

ІІ. Степень активности.1 Степень активности:Боль, ВАШ

(см)0до 3утренняя скованность (минуты)30-

60СОЕ (мм/час)менше 152 степень – ВАШ 4-6

утренняя скованность до 12 часов , СОЕ 31-45 мм/час;

3 степень: ВАШ больше 6, утренняя скованность на

протяженидня, СОЄбольше 45

Differential diagnosis Post viral condition Reactive arthritis SLE Polyarticular Gout Polyarticular OA

Factors Suggesting Poor Prognosis

>20 swollen joints High RF titer Elevated anti-

CCPs Elevated Sed Rate Elevated CRP Late

implementation of treatment

Joint erosions Presence of

rheumatoid nodules Socioeconomic

characteristics Smoking Poor functional status

RA – Signs and Symptoms cont.The American

Rheumatism Association’s criteria for diagnosis of RA.

1. Morning stiffness in and around the joints that lasts for at least 1 hour.

2. Arthritis of 3 or more joint areas; at least 3 joints have soft tissue swelling or fluid.

3. Arthritis of wrist, MPC, or PIP joint.

4. Symmetric involvement of joints

5. Rheumatoid nodules over bony prominences, or extensor surfaces, or in juxtaarticular regions

6. Positive serum RA factor 7. Radiographic changes,

including erosions or bony decalcification to the involved joints

2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis

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


>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

Algorithm to Classification of RA Including Radiographs

Longstanding inactive disease

suspected?

Longstanding inactive disease

suspected?

≥6/10 on the scoring system?

≥6/10 on the scoring system?

Not RA

RA

NoNo

Radiographsalready available

Radiographsalready available

Perform radiographic assessment

Perform radiographic assessment

YesYes Erosions typical forRA present?

Erosions typical forRA present?

YesYes≥1 swollen joint,

which is not best explained by another disease?

≥1 swollen joint, which is not best explained by

another disease?

NoNo

NoNo

NoNo

YesYes

Document result of the scoring system

Document result of the scoring system

YesYes

YesYes

NoNo

The 2010 Tree Algorithm for classifying definite RA (green circles) or for excluding its presence (red circles) among those who are eligible to be

assessed by the 2010 ACR-EULAR RA Classification Criteria

APR = acute-phase response. Serology: + = low-positive for rheumatoid factor (RF) or anti–citrullinated protein antibody (ACPA); serology: ++ = high-positive for RF or ACPA; serology: +/++ = serology either + or ++. Aletaha D, Neogi T, Silman A, Funovits J, Felson D, et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology / European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 2010;62:2569-81.

Definitions

≥6 = definite RA


1 large joint 0

2-10 large joints 1




SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




Definition of “JOINT INVOLVEMENT”

- Any swollen or tender joint (excluding DIP of hand and feet, 1st MTP, 1st CMC)

- Additional evidence from MRI / US may be used for confirmation of the clinical findings

DefinitionsJOINT 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


SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




≥6 = definite RA

Definition of “SMALL JOINT”

MCP, PIP, MTP 2-5, thumb IP, wrist

NOT: DIP, 1st CMC, 1st MTP

Definitions

≥6 = definite RA


1 large joint 0

2-10 large joints 1




SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




Definition of “LARGE JOINT”

Shoulder, elbow, hip, knee, ankles


1 large joint 0

2-10 large joints 1




SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




≥6 = definite RA

Definition of “>10 JOINTS”

- At least one small joint

- Additional joints include: temporomandibular, sternoclavicular, acromioclavicular, and others (reasonably expected in RA)

Definitions

Definitions

≥6 = definite RA


1 large joint 0

2-10 large joints 1




SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




Definition of “SEROLOGY”

Negative: ≤ULN (for the respective lab)

Low positive: >ULN but ≤3xULN

High positive: >3xULN

Definitions

≥6 = definite RA


1 large joint 0

2-10 large joints 1




SEROLOGY (0-3)





<6 weeks 0

≥6 weeks 1




Definition of “SYMPTOM DURATION”

Refers to the patient’s self-report on the maximum duration of signs and symptoms of any joint that is clinically involved at the time of assessment.

Evolving RA Treatment Paradigm

Initial

treatment:

traditional DMARDs

• Early aggressive treatment

• Biologics• Combination therapy

Current Approach Evolving Paradigm

Rheumatoid Arthritis:Treatment Principles

Confirm the diagnosis Determine where the patient stands in the

spectrum of disease When damage begins early, start aggressive

treatment early Use the safest treatment plan that matches the

aggressiveness of the disease Monitor treatment for adverse effects Monitor disease activity, revise Rx as needed

Critical Elements of a Treatment Plan: Assessment

• Assess current activity • Morning stiffness, synovitis, fatigue, ESR

• Document the degree of damage • deformities• Joint space narrowing and erosions on x-ray• Functional status

• Document extra-articular manifestations • Nodules, pulmonary fibrosis, vasculitis

• Assess prior Rx responses and side effects

Critical Elements of a Treatment Plan: Therapy

• Education • Exercise• Medications

• DMARDs : Immunosuppressive, cytotoxic, and biologic

• Analgesic and/or anti-inflammatory

Advantages of DMARDs Slow disease progression Improve functional disability Decrease pain Interfere with inflammatory processes Retard development of joint erosions

Rheumatoid Arthritis: Treatment Options

• Disease modifying drugs (DMARDs)• Sulfasalazine, hydroxychloroquine

• Moderate effect, low cost

Alarcon. Rheum Dis Clin North Am. 1998;24:489–499.Paget. Primer on Rheum Dis. 11th edition. 1997:168.

Paget. Primer on Rheum Dis. 11th edition. 1997:168.

Rheumatoid Arthritis: Treatment Options (cont’d)

• Immunosuppressive drugs• Methotrexate

• Most effective single DMARD• Good benefit-to-risk ratio

• Azathioprine • Slow onset, reasonably effective

• Cyclophosphamide• Effective for vasculitis, less so for arthritis

• Cyclosporine • Superior to placebo, renal toxicity

Selection of an Initial DMARD

Toxicities to monitorMyelosuppression, hepatotoxicity, lymphoproliferative Renal, hyperuricemiaMyelosuppression, rash,proteinuria, gastrointestinal

Myelosuppression, rashproteinuriaMacular damageHepatotoxicity, gastrointestinalHepatotoxicity, pulmonary, myelosuppressionMyelosuppression, proteinuriaMyelosuppression, gastrointestinal

Potential toxicityModerate

HighLow

Moderate

LowLow

Moderate

LowHigh

Low

Time to benefit2-3 months

4-8 weeks4-6 months

3-6 months

2-4 months4-8 weeks

1-3 months

3-6 months

1-3 months

AgentAzathioprine

CyclosporinGold, oral

Gold, parenteral

HydroxychloroquineLeflunomide

Methotrexate

D-Penicillamine

Sulfasalazine

Rheumatoid Arthritis: Monitoring Treatment With DMARDs

• These drugs need frequent monitoring• Blood, liver, lung, and kidney are frequent sites of

adverse effects• Interval of laboratory testing varies with the drug

• 4- to 8-week intervals are commonly needed • Most patients need to be seen 3 to 6 times a year

Treatment of Rheumatoid Arthritis: DMARDs

*Physicians’ Desk Reference, 1998. Recommended doses are not necessarily those utilized in clinical practice.

AgentAzathioprineCyclosporinGold, oralGold, parenteral

HydroxychloroquineLeflunomideMethotrexateD-Penicillamine

Sulfasalazine

Recommended Dose *1.0-2.5 mg/kg/d2.5-4.0 mg/kg/d6-9 mg/d

25-50 mg every 2-4 weeks following initial weekly titration doses

200-400 mg/d

100 mg x 3 days loading; 20

mg/q.d.

7.5-20 mg/wk125-750 mg/d

2-3.0 g/d

Selection of an Initial DMARD: Methotrexate

Pros Long-term clinical

experience Favorable rate of

continuation of therapy

Proven efficacy in moderate to severe RA

Cons Laboratory monitoring

every 4-8 weeks

Toxicities: hepatotoxicity, myelosuppression, pulmonary

Rheumatoid Arthritis: Unknown Case 3 52-year-old man with destructive RA treated with

NSAID and low-dose prednisone. MTX started 4 months ago, now 15 mg/wk

Presents with 3-week history of fever, dry cough, and increasing shortness of breath

Exam: Low-grade fever, fine rales in both lungs, normal CBC and liver enzymes, low albumin, diffuse interstitial infiltrates on chest x-ray

RA: Unknown Case 3 (cont’d) What would you do?

A. Treat with antibiotic for bacterial pneumonia

B. Give cough suppressant for viral pneumonia and watch

C. Give oral steroid for hypersensitivity pneumonitis and stop methotrexate

D. Give a high-dose oral pulse of steroid and increase methotrexate for rheumatoid lung

DMARDs Have a Dark Side

Don’t Miss It

DMARDs have a dark sideMethotrexate may cause serious problems

LungLiverBone marrow

Be on the look out for toxicity with all the DMARDs

Methotrexate Lung

• Dry cough, shortness of breath, fever• Most often seen in the first 6 months of MTX

treatment• Diffuse interstitial pattern on x-ray

• Bronchoalveolar lavage may be needed to rule out infection

• Acute mortality = 17%; 50% to 60% recur with retreatment, which carries the same mortality

• Risk factors: older age, RA lung, prior use of DMARD, low albumin, diabetes

Kremer, et al. Arth Rheum. 1997;40:1829–1837.

Cons Effective for mild-to-moderate RA Contraindicated in patients with sulfa

intolerance Toxicities: myelosuppression,

gastrointestinal, CNS Rate of AEs is dose-dependent CBC every 2-4 weeks for 3 months,

then every 12 weeks

Pros Clinical effectiveness

demonstrated in short-term use

Mild level of toxicity

Selection of an Initial DMARD: Sulfasalazine

Cons Lack of clinical

experience Toxicities:

hepatotoxicity, gastrointestinal

Selection of an Initial DMARD: Leflunomide

Pros Early onset of action (~ 4

weeks) Stabilized benefit for long-

term use Selectively targets

autoimmune lymphocytes to reduce untoward AEs

Cons High risk for severe leukopenia and/or

thrombocytopenia Other toxicities: hepatotoxicity, may increase

cancer risk, high risk for opportunistic infections, macrocytic anemia, severe bone marrow depression

Requires monitoring every 1-2 weeks with dosage change, every 1-3 months thereafter

Selection of an Initial DMARD: Azathioprine

Pros Effective in refractory

RA

Combination DMARD Therapy Combination DMARD regimen

u Does not increase toxicity levelsu Long-term outcome more favorableu Superior efficacy to single-DMARD regimen

Possible combinationsu Methotrexate/sulfasalazine/hydroxychloroquineu Cyclosporine/methotrexateu Leflunomide/methotrexate

Rheumatoid Arthritis: Treatment New Options—Combinations

Methotrexate, hydroxychloroquine, and sulfasalazine

Superior to any one or two alone for ACR 50% improvement response and maintenance of the response

Side effects no greater0

10

20

30

40

50

60

70

80

90

2-Year Outcome

Per

cent

With

50%

AC

R R

espo

nse

TripleRX

SSZ+HCQ

MTX

Rheumatoid Arthritis: Drug Treatment Options

• NSAIDs • Symptomatic relief, improved function

• No change in disease progression• Low-dose prednisone (10 mg qd)

• May substitute for NSAID • Used as bridge therapy!!!• If used long term, consider prophylactic

treatment for osteoporosis• Intra-articular steroids

• Useful for flaresPaget. Primer on Rheum Dis. 11th edition. 1997:168.

Cons

Does not affect disease progression !!!!

GI toxicity common Renal complications (eg, irreversible

renal insufficiency, papillary necrosis)

Hepatic dysfunction CNS toxicity

Pros

Effective control of inflammation and pain

Effective reduction in swelling

Improves mobility, flexibility, range of motion

Improve quality of life

Relatively low-cost

Pros and Cons of NSAID Therapy

RA: Unknown Case 1 68-year-old woman with 3-year history of RA She presents with 4 weeks of increasing fatigue,

dizziness, dyspnea, and anorexia Her joint pain and stiffness are mild and

unchanged Managed with ibuprofen and hydroxychloroquine

until 4 months ago, when a flare caused a switch to piroxicam and prednisone

RA: Unknown Case 1 (cont’d) Past history: Peptic ulcer 10 years ago and mild

hypertension Exam shows a thin, pale apathetic woman with

Temp 36.6ºC, BP 110/65, pulse 110 bpm Symmetrical 1+ synovitis of the wrist, MCP, PIP,

and MTP joints Exam of the heart, lungs, and abdomen is

unremarkable

RA: Unknown Case 1 (cont’d)

Which system in this patient is currently predominantly affected?

A. Cardiovascular

B. Neuropsychological

C. Endocrine

D. Gastrointestinal


Don’t Miss It

NSAID gastropathy is sneaky and can be fatal


• Clues of impending disaster• High risk for NSAID gastropathy• Presentation suggestive of blood loss

• Pale, dizzy, weak• Tachycardia, low blood pressure

• No evidence of flare in RA to explain recent symptoms of increased fatigue

Singh. Am J Med. 1998;105(suppl B):31S–38S.

Key Point: Know the Risk Factors for NSAID Ulcers

Older age Prior history of peptic ulcer or GI symptoms with

NSAIDs Concomitant use of prednisone NSAID dose: More prostaglandin suppression =

greater risk of serious events Disability level: The sicker the patient the higher

the risk

Cons

Does not conclusively affect disease progression!!!

Low doses result in skin thinning, ecchymoses, and Cushingoid appearance

Significant cause of steroid-induced osteopenia

Pros

Anti-inflammatory and immunosuppressive effects

Can be used to bridge gap between initiation of DMARD therapy and onset of action

Intra-articular injections can be used for individual joint flares

Pros and Cons of Corticosteroid Therapy

Therapeutic Window of Opportunity of DMARDs is limited

O’Dell JR. Arthritis Rheum. 2002;46:283-285.Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.

Biologic DMARD’s – Genetically Engineered Targeted Molecules Similar or Identical to

Naturally Occurring Molecules

TNFα antagonists:u Adalimumab (Humira)u Etanercept (Enbrel)u Infliximab (Remicade)

Interleukin-1 antagonistu Anakinra (Kineret)

Suppress T-Cell activationu Abatacept (Orencia)

Anti B-Cell monoclonal antibodyu Rituximab (Rituxan)

Characteristics of Biologics

Etanercept

Enbrel

Infliximab

Remicade

Adalimumab

Humira

Anakinra

Kineret

Abatacept

Orencia

Rituximab

Rituxan

Target TNF TNF TNFIL-1

ReceptorT-Cell

ActivationB-Cell

Half Life 3-5 Days 8-10 Days 10-20 Days 4-6 Hrs 13-16 Days 19 Days

Construct Human Chimeric Human Human Human Chimeric

DosingOnce

Biweekly-weekly

Once every 4-8 weeks

Once every 1-2 weeks

Once Daily Once Monthly

Twice every 6-12 months

Route Sub-Cut I.V. Sub-Cut Sub-Cut I.V. I.V.

Rituximab: Mechanism of Action

Rituximab initiates complement-mediated B-cell lysis

Rituximab initiates cell-mediated cytotoxicity via macrophages and natural killer (NK) cells

Rituximab induces apoptosis caspase-3,-9

CD20

Rituximab

Clynes RA et al. Nat Med. 2000;6:373-374; Reff ME et al. Blood. 1994;83:435-445.

B cell

B-cell lysis

Apoptosis

Complementcascade

Macrophage

B cell

CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals

Antigen Presenting Cell T Lymphocyte

TCRMHC II

Signal 1

CD80 CD28 Signal 2CD86 CD28

ClonalProliferation

CytokineProduction IL-2 IL-4 IL-5 TNF-

Full Activation

Antigen specific

Costimulation

CTLA4lg

Abatacept Fusion proteinFirst in the new class of “costimulation blockers” for treatment of RAPrevents T-cell activation via binding CD80 and CD86 on antigen-presenting cells

Safety Considerations with Biologic DMARD’s

Serious Infections Opportunistic

infections (TB) Malignancies/

lymphoma Demyelination Hematologic

abnormalities

Administration reactions

Congestive heart failure

Hepatic Autoantibodies and

drug induced lupus Vaccination

Biologics: Relative Contraindications

Active Hepatitis B Infection

Multiple sclerosis, optic neuritis

Active serious infections

Chronic or recurrent infections

Current neoplasia

History of TB or positive PPD (untreated)

Congestive heart failure (Class III or IV)

ACR Algorithm for Management of RA

ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-346.

Diagnosis• Establish early diagnosis of RA• Document baseline disease activity and damage• Estimate prognosis of patient

Initiate therapy• Patient education• Start disease-modifying agent within 3 months• Consider NSAID and/or local or low-dose steroids• Physical/occupational therapy

Subjective criteria

Physical exam

Laboratory tests

Radiography

DMARDs

Biologics

Periodically assess disease activity

ACR Algorithm for Management of RA

ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-346.

Periodically assess disease activity

Adequate response with disease activity

Inadequate response(ongoing disease activity)

Change or add disease-modifying drugs

Methotrexate naive

Methotrexate Othermonotherapy

Suboptimal methotrexate response

Combinationtherapy

Biologics

Rheumatoid Arthritis: Case 1 34-year-old woman with 5-year history of RA Morning stiffness = 30 minutes Synovitis: 1+ swelling of MCP, PIP, wrist, and

MTP joints Normal joint alignment Rheumatoid factor positive No erosions seen on x-rays

Rheumatoid Arthritis: Case 1 (cont’d)

• Assessment• Current activity—mild• No sign of damage after 5 years• Type 2 minimally progressive course

• Treatment• NSAID + safer, less potent drugs, eg,

• Hydroxychloroquine, or sulfasalazine• Education and exercises

Rheumatoid Arthritis: Case 2 34-year-old woman with 1-year history of RA Morning stiffness = 90 minutes Synovitis: 1+ to 2+ swelling of MCP, PIP, wrist,

knee, and MTP joints Normal joint alignment RF positive Small erosions of the right wrist and two MCP

joints seen on x-rays


Early erosion at the tip of the ulnar styloid

A. Soft-tissue swelling, no erosions

B. Thinning of the cortex on the radial side and minimal joint space narrowing

C. Marginal erosion at the radial side of the metacarpal head with joint space narrowing

How fast is joint damage progressing?


ACR Clinical Slide Collection, 1997.


• Assessment of case 2• Moderate disease activity• Many joints involved• Clear radiologic signs of joint destruction early

in disease course• Type 3 progressive course

• Treatment should be more aggressive• NSAID, MTX, SSZ, and hydroxychloroquine

would be a good choice

Rheumatoid Arthritis: Case 3

• 34-year-old woman with 3-year history of RA• Morning stiffness = 3 hours• 2 to 3+ swelling of MCP, PIP, wrist, elbow,

knee, and MTP joints• Ulnar deviation, swan neck deformities,

decreased ROM at wrists, nodules on elbows• RF positive, x-rays show erosions of wrists and

MCP joints bilaterally• Currently on low-dose prednisone + MTX, SSZ,

and hydroxychloroquine


• Assessment• Very active disease in spite of aggressive

combination therapy• Evidence of extensive joint destruction

• Treatment options are many• Step-down oral prednisone, 60 mg qd tapered

to 10 mg qd over 5 weeks, can be used for immediate relief of symptoms

• Use other cytotoxics or cyclosporine • Consider TNF inhibitor or leflunomide

Treatment Summary

Early appropriately aggressive intervention in patients with inflammatory arthritis: critical to best possible outcome.

The combination of a biologic plus MTX is frequently more effective than either agent alone.

Conclusion

Rheumatoid Arthritis is a serious disease Early diagnosis is key to good outcomes Advent of new therapies have major impact in

altering disease progression

Rheumatoid Arthritis. Rheumatoid Arthritis: Definition Progressive, systemic, inflammatory disorder...

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