Rheumatoid Arthritis

Dr. Rajesh Padhi, MD,FCCP Asso Prof Internal medicine and Critical care

Goals

General Approach to Arthritis Rheumatoid Arthritis

Diagnostic Criteria Pathophysiology Therapeutic Approach Disease Severity and Course

Approach to Arthritis

Joint Pain

most common symptom Pain (arthralgia) vs. Inflammation Inflammation:

(fibromyalgia)

(arthritis)

heat, redness, pain, swelling, loss of function inflammatory arthritis (RA, SLE) vs. pain syndrome

Number of Joints Affected Inflammatory vs. Non-Inflammatory

Number of Joints Affected

Monoarticular

Oligo/Polyarticular

Crystal-induced Infection Reactive Arthritis Hemarthrosis OA: joint effusions Autoimmune disease

Monoarticular causes RA SLE Viral infection

B19

Psoriasis, IBD, AS, Behet's

Acute Serum Sickness Untreated Crystal-induced Vasculidities

Inflammatory vs. Non-Inflammatory

Inflammatory: i.e. RA

Generalized AM stiffness > 30 min Resolves with movement Classic signs of inflammation

Non-Inflammatory: i.e. Osteoarthritis

Localized AM stiffness < 30 min

Arthrocentesis

Confirm diagnoses Differentiate between inflammatory & noninflammatory Therapeutic/Adjunct to Antibiotics Labs:

cell count w/diff crystal analysis Gram stain & Culture WBC >2000/L indicates inflammatory arthritis

Arthroscopy

Evaluate ligamentous & cartilaginous integrity Biopsy Infectioun: aspirate thick or loculated fluid

Rheumatoid Arthritis

RA

Systemic inflammatory autoimmune disorder ~1% of population Onset: 52 years

25 to 55 years of age <60 - 3-5:1 female predominance

Genetics

Increased incidence among Pima & Chippewa Native American tribes (5%)

Genetic & Environmental

HLA-DRB1*0401 & HLA-DRB1*0404

Increased risk Increased joint damage Increased joint surgery

Pathophysiology

Immunology

Macrophages:

Produce cytokines Cytokines (TNF-) cause systemic features Release chemokines recruit PMNs into synovial fluid/membrane

TH-1 cells:

Mediate disease processes Activate B cells

B cells:

Release cytokines Plasma cells that produce Ab

TNF- & IL-1:

Proliferation of T cells Activation of B cells Initiates proinflammatory/jointdamaging processes

Osteoclasts:

Bone erosion Juxta-articular & Systemic osteoporosis

Pathophysiology

Swelling of Synovial lining

Angiogenesis

Rapid division/growth of cells = Pannus

Synovial thickening/hyperplasia Inflammatory vascularized tissue Generation of Metalloproteinases

Cytokine release

Infiltration of leukocytes Change in cell-surface adhesion molecules & cytokines Destruction of bone & cartilage

Bottom Line

Proliferation Destruction of joints Disability

Disease Trigger

Subclinical vs. Viral trigger

Lab manifestations up to 10 yrs before clinical RF & anti-CCP (anticyclic citrullinated peptide) Ab Increased CRP subclinical inflammatory disease

ADLs:

> 50% of pts stop working w/i 5-10 years of disease onset ~ 80% disabled to some degree > 20 years Life expectancy: decreased by 3-18 years

Clinical Presentation

Gradual onset Stiffness & Swelling Intermittent or Migratory involvement Extraarticular manifestations Myalgia, fatigue, low-grade fever, wt loss, depression

Stiffness & Swelling

Pain with pressure to joint Pain with movement of joint Swelling due to hypertrophy Effusion Heat Redness

Physical Exam

Decreased grip strength Boxing glove edema Carpal tunnel Ulnar deviation Boutonniere/Swan neck deformities Extensor tendon rupture

Extraarticular Involvement

Anemia Rheumatoid nodules Pleuropericarditis Neuropathy

Episcleritis, Scleritis Splenomegaly Sjogrens Vasculitis

Differential

Seronegative polyarthritis Erosive inflammatory OA Psoriatic arthritis Reiters Crystal-induced Enteropathic arthritis Tophaceous gout SLE Pseudogout Paraneoplastic syndrome

Diagnostic Criteria

1. Morning stiffness EMS > 1 hour 2. Arthritis of 3 joint areas 3. Arthritis of hand joints 4. Symmetric arthritis 5. Rheumatoid nodules Subcutaneous nodules over bony prominences or extensor surfaces, or in juxta-articular regions, observed by a physician 6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method that has been positive 7. Radiographic changes Changes typical of RA on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

Diagnostic Criteria

Symmetric peripheral polyarthritis AM Stiffness >1 hour Rheumatoid nodules Laboratory features Radiographic bone erosions

Symmetric Peripheral Polyarthritis

3 or more Joints for >6 weeks Small Joints

Hands & Feet Peripheral to Proximal

MCP and PIP Joints

SPARES DIP

MTP & Plantar subluxation

Leads to Deformity & Destruction of Joints

Erosion of cartilage and bone

Stiffness

AM or after Prolonged Inactivity Bilateral In/Around Joints > 1 hours

Reflects severe joint inflammation

Better with movement Present >6 weeks

Rheumatoid Nodules

Extensor surfaces

elbows

Very Specific Only occur in ~30% Late in Disease

Laboratory Features

RF

70-80% of pts Overlap with HCV/Cryoglobulinemia

Anti-Cyclic Citrulline Peptide (anti-CCP)

Rare overlap with HCV

Acute Phase reactants

ESR, CRP monitoring disease activity

Rheumatoid Factor

IgM against IgG IgM+ pts: more severe disease & poorer outcome Non-specific

SLE, Sjgren's, Sarcoidosis, Chronic infections

Anti-CCP

IgG against synovial membrane peptides damaged via inflammation

Value in IgM-RF negative

Sensitivity (65%) & Specificity (95%)

Predictive of Erosive Disease

Disease severity Radiologic progression Poor functional outcomes

Other Lab Abnormalities

AOCD Thrombocytosis Leukocytosis ANA

30-40%

Inflammatory synovial fluid Hypoalbuminemia

Radiology

Evaluate disease activity & joint damage Bony decalcification Baseline AP views Initiation of DMARDs

Radiological Studies

Plain Films

Bilateral hands & feet Only 25% of lesions Less expensive Through bone cortex around joint margins

Color Doppler U/S & MRI

Early signs of damage i.e. Erosions Bone Edema - even with normal findings on radiography

Disease Severity

Mild Disease

Arthralgias >3 inflamed joints Mild functional limitation Minimally elevated ESR & CRP No erosions/cartilage loss No extraarticular disease i.e. anemia

Moderate Disease

6-20 Inflamed joints Moderate functional limitation Elevated ESR/CRP Radiographic evidence of inflammation No extraarticular disease

Severe Disease

>20 persistently inflamed joints Rapid decline in functional capacity Radiographic evidence of rapid progession of bony erosions & loss of cartilage Extraarticular disease:

AOCD, Hypoalbuminemia

Prognostic Features

RF & Anti-CCP antibodies Early development of multiple inflamed joints and joint erosions Severe functional limitation Female HLA epitope presence Lower socioeconomic status & Less education Persistent joint inflammation for >12 weeks

CV Disease

Leading cause of death ~50%

2x more likely to develop MI

chronic, inflammatory vascular burden premature atherosclerosis MTX: elevated homocysteine levels

Control inflammatory process = Decreased atherosclerosis/morbidity

Lipid screening & treatment Control of obesity, Hyperhomocystinemia, DM, HTN ASA

Other diseases

70% more likely to have a stroke 70% higher risk for developing infection

Likely 2/2 treatment

44x more likely to develop NHL

Staging

Early

<3 months

Established/Persistent

6-12 months

End-stage

Significant joint destruction Functional disability

Management

Early and aggressive disease control

Rheumatologist Referral

Early/Undiagnosed: NSAIDs, short course Corticosteroids Late/Uncontrolled: DMARD therapy

depends on the presence or absence of joint damage, functional limitation, presence of predictive factors for poorer prognosis

Goals

achieve NED & inflammation no treatment to resolve erosions once they occur

Treatment Strategies

KEY POINTS

Employ aggressive treatment with disease-modifying antirheumatic drugs Combination therapies, particularly using methotrexate as the cornerstone Biologic agents, particularly when used in combination with methotrexate, offer the greatest ability to slow structural damage

Therapy

Non-Pharmacologic:

Pharmacologic:

Referral to PT/OT Evaluate ADLs Assistive devices/splints Weight loss Smoking cessation

Anti-inflammatory Interrupt progression

Development of erosions Joint space narrowing

Pharmacologic Therapy

Analgesics NSAIDs Glucocorticoids SAARD/DMARD Anticytokine therapy

Analgesics

Topical Capsaicin Diclofenac

Oral Tylenol Opiods

NSAIDs

Pros:

Analgesic, Antipyretic, Antiinflammatory

Cons:

Dont alter disease progression Ineffective in Erosive disease

GI/Ulcers Hepatotoxicity Nephrotoxicity AIN Bleeding antiplatelet Rash Aseptic meningitis

Corticosteroids

Decrease cytokines

Slow Joint Inflammation

Insomnia Emotional lability Fluid retention Weight gain HTN Hyperglycemia Osteoporosis

Cataracts Avascular necrosis Myopathy Psychosis

Bisphosphonates: >5mg/d for >3months

Disease modification

SAARD slow acting antirheumatic drugs DMARD disease modifying antirheumatic drugs

Methotrexate

Dihydrofolate reductase inhibitor

Well tolerated, Mono/Combo Onset: 6-12 weeks

Nausea Mucosal ulcerations Fatigue & Flu-like symptoms BM Toxicity Hepatotoxicity Treat with Folic acid, 1 mg/d

Metabolism: Liver Clearance: Kidneys

Monitoring:

Baseline:CXR, PFTs, HIV, HBV/HCV CBC, LFTs Q4-8 weeks Caution with CRI

Leflunomide

Inhibits dihydrooratate dehydrogenase Dec. activated T-cells Onset: rapid Efficacy: 6 weeks

Derm - rash, alopecia Diarrhea BM toxicity Hepatotoxicity

Monitoring:

CBC, LFTs

Azathioprine

Corticosteroid-sparing Monitoring:

CBC Q1-2 months AST/ALT

Infection BM Toxicity Hepatitis Malignancy

Cyclophosphamide

Alkylating agent
Monitoring:

CBC, UA monthly Yearly UA +/- Cytology

Alopecia Nausea Infection BM suppression pancytopenia Infertility pretreat women with Leuprolide Renal: hemorrhagic cystitis, bladder malignancy treat with acrolein Oral more toxic than IV

Anticytokine therapy

Anti-TNF alpha agents

Etanercept Infliximab Adalimumab IL-1 receptor antagonist (Anakinra)

TNF-a Inhibitors

Anti-inflammatory Block TNF- (proinflammatory cytokine) Etanercept, Adalimumab (SQ), Infliximab (IV)

Injection site reaction Infection Reactivated TB Infliximab

infusion reaction

Very expensive: > $15,000/patient

Combo therapy with MTX

Pancytopenia Autoantibody/SLE-like Exacerbate CHF Malignancy lymphoma

Etanercept

First TNF alfa inhibitor S/c injection of 25 mg twice weekly or a single 50-mg injection once a week.

It is a fusion protein of the soluble portion of the human TNF p75 chain of the receptor and the fragment crystallizable (Fc) portion of human IgG1.

Infliximab

Infliximab is a chimeric monoclonal antibody against TNF

Iv 3 to 10 mg/kg. The recommended dosing regimen at weeks 0, 2, and 6, and every 8 weeks .

Adalimumab

Adalimumab is a fully human monoclonal antibody directed against TNF

It is delivered as a subcutaneous injection once every other week (20 to 80 mg)

INTERLEUKIN-1 RECEPTOR ANTAGONIST AND INTERLEUKIN-1 RECEPTOR: anakinra

Rituximab RTX is a chimeric monoclonal antibody targeting CD20+ B cells

Abatacept is a soluble, recombinant fusion protein composed of extracellular domain of cytotoxic T lymphocyteassociated antigen-4 (CTLA-4) and the modified Fc portion of IgG1

More aggressive approach Combo therapy Adjunctive therapy: TNF- antagonist

Disease Course

Long Remission

10%

Intermittent Disease

15-30%

Progressive Disease

Summary

Approach to Arthritis

Number of Joints Affected Inflammatory vs. Non-Inflammatory

Rheumatoid Arthritis

Diagnostic Criteria Pathophysiology Therapeutic Approach Disease Severity and Course

Questions?