NSAIDs, Rheumatoid Arthritis, & Osteoarthritis:

A Case Approach

Bobo Tanner MD

Rheumatology & Allergy

Monday Feb 19, 2007 VMS IV

AGENDA

• Differentiate RA & OA

• Therapeutic Choices

• Case based examples

• Treat Early & Monitor

• Monitor for Benefit & Side Effects

Case 165-year-old man: knee pain that began

insidiously about a year ago. No other rheumatic symptoms.

PMHx: PUD, ischemic heart dz, sulfa allergy

• What further questions should you ask?

• What are the pertinent physical findings?

• Which diagnostic studies are appropriate?

Inflammatory vs. Mechanical RA

History & PE• AM stiffness >1 hr.• Symmetrical swelling,

tenderness: wrists, MCPs, PIPs

Labs• 45-85% +RF, +CCP Ab

ESR,C-RP, Hct

X-rays• JSN • erosions

OAHistory & PE• Worse pain w/activity• DIPs, 1st CMC,

wt.bearing jts.Labs• Medication monitoring CBC,BMP,UA

X-rays• Osteophytes, asymmetry,

sclerosis

Therapeutic Options

RANSAIDsCorticosteroidsDMARDsBiologic DMARDsAlso:Joint InjectionsPT/OTSurgery SLESteroidsAnti-malarialImmunosuppressive

OAAnalgesics

NSAIDs

Also:

Joint injections

PT/OT

Surgery

Nutritional supplements

Case 1: Radiographic Features• Asymmetric joint

space narrowing

• Marginal osteophytes

• Subchondral cysts

• Bony sclerosis

• Malalignment

• NAILS THE DIAGNOSIS

OA: Risk Factors• Why did this patient develop

osteoarthritis?

OA: Risk Factors (cont’d)• Age: 75% of persons over age 70 have OA

• Female sex

• Obesity

• Hereditary

• Trauma

• Neuromuscular dysfunction

• Metabolic disorders

Case 1: Cause of Knee OA

• On further questioning, patient recalls a serious knee injury during high school football

• Therefore, posttraumatic OA is most likely diagnosis

Pharmacologic Management of OA

• NSAIDs

• Non-opioid analgesics

• Topical agents

• Opioid analgesics

• Intra-articular agents

• Unconventional therapies

NSAIDs

• Inhibit prostaglandin synthesis & other• Account for ½ the Rx in the elderly• If no response to one may respond to

another• Lower doses may be effective• Do not retard disease progression

NSAIDs (cont’d)

• Side effects: GI, renal, cardiac, edema

• Severe side effects <5%, but large numbers of users

• Gastroprotection increases expense

• Antiplatelet effects may be hazardous

• GI tolerance much better with COX-2

• C-V events overshadow COX-2

Non-opioid Analgesic Therapy• Acetaminophen

• Pain relief comparable to NSAIDs, less toxicity

• Beware of toxicity from use of multiple acetaminophen-containing products

• Maximum safe dose = 4 grams/day• Lifetime dose & toxicity?

* P<.05

Bradley, et al. N Engl J Med. 1991;325:87–91.

Ibuprofen vs Acetaminophen for

Knee OA—Equivalent Benefit

0 0.2 0.4 0.6 0.8

HAQ Pain

Walking Pain

Rest Pain*

50 Ft Walk

HAQ Disability

Change in Score

2400 Ibuprofen1200 IbuprofenAcetaminophen

Celecoxcib vs Acetaminophen for Hip & Knee OA—Pincus data

PACES trial

Patient preferences:

• 53% celecoxib (200mg) vs

24% acetaminophen(4 gm) PACES-a (p<0.001)

• 37% acetaminophen v

28% placebo in PACES-a (p = 0.340)

Ann Rheum Dis. 2004 Aug;63(8):931-9

OA: Nutritional Supplements

• Polysulfated glycosaminoglycans—nutriceuticals • Glucosamine +/- chondroitin sulfate:

Symptomatic benefit, no known side effects, long-term controlled trials pending

Knee Injection

• Knee fully extended

• Junction upper third and lower two thirds of the patella

• Insert needle under patella and aim superiorly

© ACR

OA: Intra-articular Therapy• Intra-articular

steroids• Pain relief • Up to q 3 mo• Risks: infection,

worsening diabetes, or CHF

• Joint lavage• Symptomatic benefit

demonstrated

• Hyaluronate injections*• Synvisc ® , Hylgan®• Symptomatic relief • Improved function• $$$$$$$• Series of injections, fail

steroids first?• No evidence of long-

term benefit• Knees, other?

* Altman, et al. J Rheumatol. 1998;25:2203.

Strengthening Exercise for OA• Decreases pain and increases function• Physical training rather than passive therapy• General program for muscle strengthening

• Warm-up with ROM stretching• Step 1: Lift the body part against gravity, begin

with 6 to 10 repetitions• Step 2: Progressively increase resistance with

free weights or elastic bands• Cool-down with ROM stretching

Rogind, et al. Arch Phys Med Rehabil. 1998;79:1421–1427.Jette, et al. Am J Public Health. 1999;89:66–72.

Surgical Therapy for OA• Arthroscopy

• May reveal unsuspected focal abnormalities

• Results in tidal lavage• Expensive, complications possible

• Osteotomy: May delay need for TKR for 2 to 3 years

• Total joint replacement: for severe pain and function significantly limited

Case 2: Rheumatoid Arthritis• 53-year-old woman with 6 months history

of RA sx

• Morning stiffness = 30 minutes

• Synovitis: 1+ swelling of MCP, PIP, wrist, and MTP joints

• Normal joint alignment

• Rheumatoid factor positive, anti-CCP +

• No erosions seen on x-rays

Rheumatoid Arthritis: Treat Early &Prevent Damage & Dysfunction

• Ulnar deviation of R hand

• MCP & PIP swelling

• synovitis of left wrist

• Joint space narrowing & erosions on x-ray

• Synovial thickening feels like a firm sponge

Case 2 (cont’d)• Assessment

• Rheumatoid Arthritis• No sign of damage

• Treatment• NSAID, steroid, DMARD • Education + ROM, conditioning, and

strengthening exercises

Which DMARD would you choose?

Rheumatoid Arthritis: Drug Treatment Options

• NSAIDs – Symptomatic relief, improved function– No change in disease progression

• Low-dose prednisone (10 mg qd) – If used long term, consider prophylactic treatment for

osteoporosis

• Intra-articular steroids – Useful for flares

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

Rheumatoid Arthritis: • Disease modifying drugs (DMARDs)

– Hydroxychloroquine (Plaquenil®)• Modest effect, low toxicity

– Sulfasalazine• Moderate effect, monitor like MTX

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

– Leflunomide (Arava®)• Effect & side effects similar to MTX

• Combinations

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

Rheumatoid Arthritis: Monitoring Treatment With DMARDs

• These drugs need frequent monitoring

• Blood, liver, lung, kidney,skin are frequent sites of adverse effects

• √ CBC,LFTs, creatinine, urine

• Lab intervals: 4 to 12 weeks commonly

• Most patients need to be seen 3 to 6 times a year

Biologic DMARDs

Anti-TNF – Etanercept (Enbrel®) 50mg SQ weekly– Infliximab (Remicade®) IV q 8 weeks– Adalimumab (Humira®) 40mg SQ QOW– Rapid onset, effective in refractory patients with

and w/o MTX, halts bone erosions– Screen for Tb, infections, expensive

Also– Anakinra (Kineret®), daily SQ, inj. anti-IL-1– Abatacept (Orencia®), IV monthly , T cell 2nd sig.– Rituximab ( Rituxan®) IV x 2, TNF failure, B cells

Fleischmann. Rheum Dis Clin North Am. 2006;32(1):21-28.

Early Intervention Is Effective in RAEarly Intervention Is Effective in RA

• Several studies collectively provide clear evidence that delayed use of DMARD therapy in RA may adversely affect clinical and radiographic outcomes

• Treatment should be initiated within months of the diagnosis, not years

Short Delay of Therapy Affected Joint Damage

Lard LR, et al.Lard LR, et al. Am J Med. Am J Med. 2001;111:446-451 2001;111:446-451..

Time (months)Time (months)

00

22

44

66

88

1010

1212

1414

00 66 1212 1818 2424

Early Treatment = median 15 daysEarly Treatment = median 15 days

Delayed Treatment = median 123 daysDelayed Treatment = median 123 days

JointJoint

DamageDamage

Percentage improvement

Percentage deterioration

Ritchie articular index

Morning stiffness

Radiological score

VAS = 10 cm visual analogue scale.VAS = 10 cm visual analogue scale.

HemoglobinPain VAS

Grip strength

Sedimentation rate

75

50

25

0

–25

–50

–75

Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268.

Clinical Parameters Don’t Correlate with Bone Damage

Case 2

• Which DMARD would you choose?

• Monitor :

Clinically

Labs

X-rays

Case 3• 68-year-old woman, 3-years of RA ,

squeezed into your schedule as a new patient

• 4 weeks of increasing fatigue, dizziness, dyspnea, and anorexia

• Joint pain and stiffness: mild & unchanged

• Meds: flare up 4 mos. ago ,switched to naproxen and prednisone

Case 3 (cont’d)• Past history: Peptic ulcer 10 years ago,

mild hypertension

• Exam: thin, pale apathetic woman with Temp 98.4ºF, BP 110/65, pulse 110 bpm

• Symmetrical 1+ synovitis of the wrist, MCP, PIP, and MTP joints

• Heart, lungs, and abdomen: unremarkable

Case 3 (cont’d)• The doctor is falling behind in the schedule

• What system must you inquire more about today?A. Cardiovascular

B. Neuropsychological

C. Endocrine

D. Gastrointestinal

Case 3 (cont’d)

• 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

Case 3 (cont’d)

• NSAID gastropathy is sneaky and can be fatal

Don’t Miss It

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

NSAID Gastropathy• Gastric ulcers are more common than

duodenal ulcers

• No reliable warning signs

• 80% of occur without prior symptoms

• Ulcers in RA 2.5- 5.5 times more than general population

• 107,000 hospitalized & 16,000 deaths annually due to NSAID-GI complications

NSAID Gastropathy: Key Points

Know the risk factors• The best way to treat it is to prevent it

• Avoid it: Use acetaminophen, salsalate,

(or ? selective COX-2 inhibitor)• Counteract it: PPI or prostaglandin analogue

• Antacids and H2 blockers are not the answer• May mask symptoms but do not prevent

serious events

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

GI Risk Factors : NSAID Ulcers

• Older age• Prior history of peptic ulcer or GI symptoms with

NSAIDs• Concomitant use of prednisone• NSAID dose• Disability level: The sicker the patient the higher

the risk

Balancing NSAID Efficacy and Safety

• Is NSAID therapy indicated?

• Can low dose relieve symptoms?

• Risk of complications ?

• Consider NSAID therapy with reduced GI toxicity or combination Rx with GI med

• Antiinflammatory activity

• Analgesia

• GI toxicity• Renal toxicity• Platelet effects

Selective COX-2 Medications

• VIOXX® :withdrawn from market 9/30/04

• Celebrex®

• Bextra® withdrawn 2005

also associated with cardiovascular dz, hypertension, edema and sulfa & skin rxns

COX-2 Selective NSAIDs• A replacement for non-selective NSAIDs?

• Pain relief equivalent to older NSAIDs• Less GI toxicity (rofecoxcib)• No effect on platelet aggregation or bleeding

time• Cost similar to generic NSAIDs plus proton

pump inhibitor or misoprostol• Side effects: Cardio-Vascular,BP,edema

Medical Letter. 1999;41:11–12.

COX-2 : CV events (rofecoxcib)

3.75 3.75

7.5

15

0

2

4

6

8

10

12

14

16

Events/ 1000 pts.

<18 months >18 months

VIOXX Polyp Trial

placebo

VIOXX

Time in studyWSJ 10/1/04

Case 4• 52-year-old man with destructive RA

• Rx NSAID & low-dose prednisone

• MTX & Remicade( anti-TNF) started 4 months ago

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

• Exam: Low-grade fever, fine rales in both lungs,• Labs: normal CBC ,LFTs, low alb• Chest xray: bilat.interstitial infiltrates

Case 4 (cont’d)

• What should be done?

A. Culture, treat with antibiotic for bacterial pneumonia

B. Place PPD, sputum for AFB

C. Give steroids for hypersensitivity pneumonitis and stop methotrexate

D. Give a high-dose steroids and increase methotrexate for rheumatoid lung

DMARDs & Biologics Have a Dark Side

Don’t Miss It

Methotrexate may cause serious problems

LungLiverBone marrow

Anti-TNF (Remicade, Enbrel, Humira) assoc. with TB reactivation and other infections

Case 5• A pre-op physical has been ordered for a

routine cholecystectomy on a 43-year-old woman with RA since age 20

• PMH: bilateral THR ,left TKR

• Meds: NSAID, 5 mg/d prednisone, MTX• General physical exam normal• MS exam, extensive deformities, mild synovitis• In addition to routine tests, what test should be ordered

before surgery?

Don’t Miss It

Subluxation of C1 on C2

RA can cause asymptomatic instability of the neckManipulation under anesthesia can cause spinal cord injury

Clues for C1-C2 Subluxation• Long-standing rheumatoid arthritis or JRA• May have NO symptoms• C2-C3 radicular pain in the neck and occiput• Spinal cord compression

• Quadriparesis or paraparesis• Sphincter dysfunction • Sensory deficits• TIAs secondary to compromise of the vertebral arteries

Anderson. Primer on Rheum Dis. 11th edition. 1997:161.

Summary

• Distinguish Inflammatory Disease (RA) from mechanical (OA)

• Treat RA early

• Know the medication side effects

• Know the complications of the disease

One Last Word:Unconventional Therapies

• Keep in touch with current information. The unconventional may become conventional• www.quackwatch.com• ACR Website

(www.rheumatology.org)• Arthritis Foundation Website

(www.arthritis.org)