Rheumatoid Arthritis

By Dr. Nate Josephson

Case Presentation

32 year old WF presents to PCP with a 3 month history of progressive pain and stiffness of several joints, notably the wrists, hands, feet, and ankles. She feels worse in the morning and t a k e s s e v e r a l h o u r s t o l o o s e n u p .

On your exam you think there may be some mild swelling in her MCP joints and wrists, but you are not absolutely sure. You are concerned that s h e m a y e a r l y r h e u m a t o i d a r t h r i t i s .

Questions

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2.

3.

How do you confirm the diagnosis of rheumatoid arthritis?

If she does have rheumatoid arthritis, is it okay to see how she does for a while on NSAIDS +/- corticosteroids?

Is it important to refer to rheumatology early?

Rheumatoid Arthritis

A symmetric, peripheral polyarthritis of unknown etiology that, untreated or if unresponsive to therapy, typically, leads to deformity and destruction of joints through the er osion of cartilage and bone.

Epidemiology of RA

Prevalence ranges from 0.5 to 1.0%, affecting more than 2 million Americans Age of onset typically between 20 and 45 years but over 25% cases start over 60 years old Female to male ratio is nearly 3:1 Annual incidence: 36 cases per 100,000 women

Initial Clinical Presentation - Classic Insidious onset of symmetric polyarthritis, particularly MCPs, MTPs, PIPs, wrists Morning stiffness lasting more than one hour Constitutional symptoms such as fatigue common

Initial Clinical Presentations – Less Common Acute polyarthritis with prominent myalgias and constitutional symptoms Palindromic rheumatism – one or several joints acutely involved for hours to few days with symptom free intervals lasting days to months Persistent monoarthritis as herald of disease

Key Physical Findings

Symmetrical soft tissue swelling / tenderness in peripheral joints >20 joints in severe disease Most common are MCP and MTP joints MCP and MTP squeeze test

Confirmation of Synovitis

Synovitis needs to be confirmed by reliable examiner since it is essential requirement for diagnosis If synovitis is equivocal on exam *May need to follow patient *Occasionally imaging techniques such as MRI helpful

Clinically Useful Biologic Markers

Rheumatoid factor Anti-CCP antibody ESR / CRP

Rheumatoid Factor(s)

Found in 75-80% of RA patients Positivity lower at onset but peaks by 6-12 months High levels associated with more aggressive disease Nonspecific – can occur in chronic infections (such as HCV) and other autoimmune disease

Anti-Cyclic Citrullinated Peptide (CCP) Antibodies

Found in 50-75% of RA patients May precede clinical symptoms Confers increased risk of progressive disease More specific than RF

Testing for both RF and anti-CCP antibodies RF Anti-CCP Both positive Sensitivity Specificity 73% 82% 56% 90% 48% 96%

Remember:

higher the specificity, higher the positive predictive value (more likely to have disease)

Acute Phase Reactants – ESR/CRP Not specific, but fairly sensitive Elevation of both: stronger indication of radiographic progression Correlate with disease activity and used in various metrics to follow disease activity

Imaging

Plain film radiography: unlikely to reveal erosive disease in very early disease but may serve as baseline MRI: much more sensitive for erosive disease How often is MRI needed for diagnosis and as a guide to therapy – remains controversial given cost

Rheumatoid Arthritis - Diagnosis

Based on a constellation of compatible features and exclusion of other causes of chronic (>6 weeks) inflammatory arthritis

Other Causes of Chronic Inflammatory Arthritis

SLE and other connective tissue diseases Psoriatic arthritis Reactive arthritis and undifferentiated spondyloarthropathy Polyarticular gout / pseudogout Inflammatory (erosive) interphalangeal OA Polymyalgia rheumatica/RS3PE syndrome in elderly

Natural History & Prognosis of RA

(Prior to DMARDS) At 20 years 70% of RA patients severely disabled Although disease activity (inflammation) varies, structural damage is cumulative and irreversible Up to 90% of patients < 2 years disease show radiographic damage Poor outcomes, including life expectancy, associated with early adverse prognostic factors – functional limitation, extraarticular disease, positive RF or anti-CCP, bony erosions

Aims of Therapy

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Relief of signs and symptoms.

Improvement in patient reported outcomes Inhibition of structural damage These 3 interrelated aims best achieved by rapid and sustained suppression of disease to remission or low disease activity with DMARDs.

Disease Modifying Antirheumatic Drugs (DMARDS)

Traditional DMARDS Hydroxychlroquine Sulfasalazine Doxycycline Methotrexate Leflunomide Biologic agents – targeting the immune system

Biologic Agents for RA

Target

TNF B cells T cell 1L-6 receptor

Drug

etanercept infliximab adalimumab golimumab certolizumab rituximab abatacept tocilizumab

What Emerges from Randomized Clinical Therapeutic Trials in Early RA Clearly the earlier the therapy the better the outcome The tighter the control the better the outcome Combinations employing biologic agents are more effective in controlling symptoms and radiographic progression than traditional DMARDs

Measures of Disease Activity

A metric utilizing several parameters to assess activity Used to initially stage disease Can evaluate response to therapy – adequate (tight) or not Can be used to define remisson

Assessment of Disease Activity in Early RA

Semi Quantitative

# joints Extraarticular Erosions RF/CCP+ ESR/CRP

Quantitative

DAS 28

Mild

< 6 No No +/ +/ 2.4-3.6

Moderate

6-20 No +/ + + 3.7-5.5

Severe

> 20 Common ++ ++ ++ > 5.5

Treatment of Mild Disease in Early RA NSAIDS and traditional DMARDs may suffice – *hydroxychloroquine *sulfasalazine (HCQ) (SSA) *methotrexate *leflunomide *doxycycline (MTX) (LEF) Combination of traditional DMARDS sometimes used Corticosteroids – not at all or sparingly

Treatment of Moderate/Severe Early RA Goal: Remission of low disease activity A. MTX (or LEF) monotherapy for 8-12 week trial B. Inadequate responders to A: MTX + anti-TNF C. Inadequate responders to B: TNF switching or MTX + other traditional DMARDs or MTX + newer biologic agent tocilizumab (Actemra) rituximab (Rituxin) abatacept (Orencia) NSAIDS and Corticosteroids adjunctive

Role of Corticosteroids in Early RA

If patient systemically ill or experiencing rapid decline in function, prednisone 10 mgm/daily Once patient responds sufficiently, dose should be tapered to 5 mgm/day or less Intraarticular route very effective and may bypass systemic use Also consider protection for osteoporosis if prednisone used at >5 mgm/day for greater than 3 months

Safety Issues - NSAIDS

Toxicity increases with dose escalation regardless of agent Gastroprotection in patients with risk factors for gastropathy – age > 65, past history of ulcer

Safety Issues - Methotrexate

Hepatotoxicity Pulmonary toxicity Bone marrow suppression Teratogenecity Although not nephrotoxic lower doses with reduced renal function

Potential Safety Issues with TNF Inhibitors

Target Related (general immunomodulatory / TNF Specific) Infectious / serious infections Opportunistic infections (eg, TB) Malignancies (lymphoma, skin, etc) Demyelinating conditions Hematologic abnormalities Congestive heart failure Autoantibodies (>40% het ANA+, 10% anti-DNA; ACL also seen: however, few other autoantibodies, and lupus-like syndromes rare) Hepatotoxicity Skin reactions / psoriasis Agent related Administration reaction Immunogenicity

Tuberculosis & TNF Antagonists

Latent TB (LTBI): +PPD/-Sxs/-CXR All TNF inhibitor Rx patients should be evaluated for LTBI with a tuberculin skin test prior to initiation Obtain CXR? Not routinely advocated in USA. Do: *If PPD positive *If signs/Sxs present *Recent known TB contact If latent TB (no signs/Sxs): initiate INH prior to or with TNF inhibitor therapy If active TB infection, treat 4 drugs, delay initiation of TNF inhibitor therapy

Prevention While on TNFi

General precautions *General infection control *Manage comorbidities (alcohol and smoking cessation, DM control, minimize steroid dose) 2006 ACIP Guidelines on Immunizations *Influenza vaccine every year *Pneumococcal vaccine *Meningococcal, Hepatitis B where exposure is likely *Avoid live-attenuated vaccines (oral polio*, MMR, varicella, shingles)

Conclusions

Early diagnosis important, which leads to – Early treatment, aggressive if necessary, which leads to – Better outcomes Communication important between PCP and rheumatologist