Update in Rheumatoid Arthritis - PowerPoint Presentation

Slide1

Update in Rheumatoid Arthritis

Gregory Gardner, M.D.Gilliland-HendersonProfessor of MedicineDivision of RheumatologyUniversity of Washington

Slide2

Outline of DiscussionPathophysiologyClinical FeaturesTreatment UpdatePerioperative Management

Slide3

Rheumatoid Arthritis

Pathophysiology

Slide4

Rheumatoid arthritis demographicsAutoimmune disease

Affects 1-2% of US population1st degree relative has double the riskWomen:Men 3:1Occurs in two peaks:-Women during child bearing years-Men and women after age 60

Slide5

Treating RA: think BoleroEarly 1990 RA immunologically staged by Harris (modified)Stage 0 -1 - Benign autoimmunity to early RA; antigen processed/presented to T-cells; autoantibody production Stage 2 - T cells proliferate & induce B cell proliferation. New blood vessels develop as a scaffold for proliferating

synovitis. Acute inflammation in synovial fluidStage 3 - Marked synovial proliferation and inflammation develop with production of of cytokinesStage 4 - Synovitis polarized into aggressively invasive front of macrophages and synovial cells that begins irreversible destruction of cartilage, ligaments and boneStage 5 - Progressive loss of articular cartilage & bone; tendon/ligamenous attenuation and loss; joint deformity

N Engl J Med. 1990;322:1277–1289

J Rheumatol. 1996;239(suppl 44)2-4

Slide6

Genetic issues in RAGenetic factors account for 50-60% of RA riskand environmental factor account for 40-50%Shared epitope (SE) on 3rd hypervariable region on the HLA DR beta 1 chain, amino acid sequences 67-74, associated with susceptibility and severity of RA

The presence of anti-citrullinated peptide antibodies (ACPA ie anti-CCP) is the strongest predictor of developing rheumatoid arthritis; ACPA are also prognosticCitrulline results from deimination of arginine; peptides with citrulline are immunogenicIn high risk populations, a long period of benign autoimmunity can proceed the onset of active RAAnti-CCP antibodies my be present before RA develops

Slide7

Structure/functionof HLA molecule

Figure 1 is representation of structure of the HLA class II molecule present on and antigen presenting cells. Figure 2 shows the position of the shared epitope on the HLA DR molecule. Figure 3 illustrates the function of the class II molecule

Fig 1

Fig 2

Fig 3

ACR and Hochberg 2008

Slide8

Benign autoimmunity: Specific auto-antibodies may precede the symptoms of rheumatoid arthritisNielen et al. Arthritis Rheum 2004;50:380 Study of 79 RA pts who had donated blood several times prior to onset of RA

67% RF + 6 yrs after Dx; no data for CCP2100 control sera: 1.1% + for RF; 0.6% + for CCP

Slide9

Environmental issues in RAAre genetic mechanism responsible for the development of the benign autoimmune state and the inability to control the immune activation once initiated?Are environmental factors responsible for initiating citrullination of peptides that genetic factors then react to?Current environmental risk factors that appear to play a role in RA include by leading to

citrullination of proteinsSmokingPeriodontal disease

Slide10

Is rheumatoid arthritis caused by an environmental agent from the New World?

?

Rothschild BM, et al: Semin Arthritis Rheum 1992;22:181

Slide11

Antiquity of rheumatoid arthritisPaucity of reports of RA in medical literature prior to the 1800’s; first clear case reported in 1676 by Sydenham

Rothschild et al examined 35,000 European skeletal remains without finding an example of RA-like DzGout, osteoarthritis, ankylosing spondylitis etc. commonRA found in Pre-Colombian skeletons in N AmericaEspecially in Tennessee, Ohio, Alabama, and KentuckyPrevalence: 7% female, 3% males

Rothschild BM, et al: Semin Arthritis Rheum 1992;22:181

Slide12

RA in European art: Siebrandus Sixtius, Dutch Priest 1631J Dequeker Ann Rheum Dis. 1992 April; 51(4): 561–562

Slide13

European contact with North American RA

Dutch

English

Spanish

French

French

Numerous NW Tribes with RA

Yakama

Makah

Tlingit

Etc.

Slide14

Can we treat earlier?Klareskog et al. Nature Clinical Practice Rheumatology 2006;2:425

Slide15

Rheumatoid Arthritis

Clinical Features

Slide16

2010 ACREULAR/RA CriteriaJoint involvementScore

1 large joint02-10 large joints11-3 small joints24-10 small joints3> 10 small joints5Serology

Score

Negative RF ACPA

0

Low positive RF ACPA

2

High level RF ACPA

3

Acute

phase reactants

Score

Normal CRP or ESR

0

Abnormal CRP or ESR

1DurationScore

< 6 weeks0> 6 weeks1

6/10 points Needed forclassificationSmall joints:MCPsPIPsWrists2-5 MTPs

High RF/ACPA

> 3x ULN

Slide17

DDx of Inflammatory PolyarthritisRheumatoid arthritisSLE - systemic features, + ANA/ENAPsoriatic arthritis - rash, dactylitisViral arthritis ie parvovirus - more pain than swelling, rash, seasonPolyarticular goutOther CTD - other systemic features ie Raynaud

’s, myositis, etc…

Slide18

Joint DistributionCervical spineShouldersElbowsWrists

HandsPIPsMCPsSPARES DIPsHipsKneesAnklesTibiotalar

Subtalar

Feet

MTPs

Slide19

Earliest RA

Slide20

Slide21

RA Hands Late

Slide22

RA Feet

Slide23

Rheumatoid Arthritis:Extra-Articular Disease

Pulmonary Nodules

Scleritis in RA

Rheumatoid Vasculitis

Slide24

Nodules

RA nodule or gouty tophus?

Slide25

Other complication of RAFelty’s syndromeLeukopenia, splenomegaly, RAInfections, leg ulcersC1-C2 subluxation

Neck pain, myelopathyC spine flexion/extension views, MRISeptic arthritisLarge joints, fewer systemic symptomsStaph > Strep > gram negativesMorbidity/mortality highTendon rupturesEspecially ring/little finger extensor tendons

Slide26

Rheumatoid Factor

Rheumatolgic Disease

RA, SLE, Sjogren

’

s, MCTD, PM/DM, Cryoglobulinemia

Infectious Disease

SBE, TB, Syphilis,

Hep C

Other

Aging, IPF, Cirrhosis, Sarcoidosis, Waldenstrom

’

s

IgM Rheumatoid

Factor

IgG Fc Region

Points to remember!

-High level; worse prognosis

-May take months to appear

-20-30% of RA Pts never develop

-Not specific for RA

Slide27

Anti-CCP (ACPA)Antibodies to Cyclic Citrullinated Peptide (CCP) have a sensitivity of 78% and specificity of 96% for RA40% of “seronegative RA” are anti-CCP +

Level of CCP is directly correlated with the development of erosionsNegative , low-moderate (35-200) or high CCP (>200)OR of radiographic progression vs CCP negative RA pts after10 yrsNegative 1.0Low-moderate 3.2High 15.2Other ACPA being investigated for utility in diagnosis and prognosis

Schellekens. Arthritis Rheum 2000;43:155

Slide28

Imaging in RA5th MTP may show earliest changes in RA

RA X-ray findings:OsteopeniaMarginal erosionsJnt space narrowingUltrasoundMRI

Slide29

Progressive X-ray changes in RA

Joint Erosions in RA: From Bad to Worse

Slide30

Prediction Model for Erosive vs Nonerosive RA Early in Disease Course

CriterionOdds Ratio

Score

Symptom duration ≥ 6 wk but < 6 mo

≥ 6 mo

0.96

1.44

0

0

Morning stiffness ≥ 1 hour

1.96

1

Arthritis in ≥ 3 joint groups

1.73

1

Bilateral compression pain in MTP joints

3.78

2

IgM-RF ≥ 5 IU/mL

2.99

2

Anti-CCP ≥ 92 IU/mL

4.58

3

Erosions on hand or foot x-ray

Infinite

Infinite

524 consecutive patients with early arthritis; total score corresponds to predictive value for erosive vs nonerosive arthritis given the presence of persistent RA. Visser H et al.

Arthritis Rheum.

2002;46:357-365; Visser H.

Best Pract Res Clin Rheumatol.

2005;19:55-72.

Slide31

Rheumatoid Arthritis

Treatment Issues

Slide32

Therapy for Rheumatoid Arthritis circa 1989MedicationsGoldPenicillamineHydroxychloroquineSulfasalazineNew drug, methotrexateTreatment philosophyPyramid with sequential DMARD monotherapy“

Rheumatoid arthritis is a disabling but otherwise benign disease”

Slide33

Rheumatoid Arthritis Circa 1989Frequent complicationsRheumatoid vasculitisC1-C2 subluxationFelty’s syndromeExtensor tendon rupture

Septic arthritisPathophysiology of RAMacrophage mediated disease

Slide34

Outcome of RA over 20 years in 112 consecutive patients by functional class and mortality Scott DL et al. Lancet 1987;1108-1111 “The concept of remission-inducing drugs is fallacious. Early treatment may be advantageous, but the prognosis of RA in not good

”

Slide35

Business as usual was not working> 90% of RA patients have erosions after 2 yrs

Fuchs HA, et al: J Rheumatol 1989;16:585-5915 - 10% of RA patients become disabled each yr Kushner I: J Rheumatol 1989;16:1-4Only 18% of RA patients achieve a period of remission during the course of their disease. Wolfe F, Hawley DJ:J Rheumatol 1988;12:245-252Median life expectancy decreased 4 yrs for men and 10 yrs for women with RA Mitchell DM, et al: Arthritis Rheum 1986;29:706-713

Slide36

“What we need in RA is a drug for which one does not need a statistician to see the beneficial effects

”Irving Kushner, M.D.J Rheumatol 1989;16:1-4

Slide37

J Rheumatol. 1989;16:565-7

“

Time and comparative observations will be needed to show the optimum combination of drugs and whether step down bridge concept will achieve the sought for and presently unobtainable goal of early and sustained control of inflammation, improved quality of life and prevention of bone and joint damage.

”

Slide38

Changes in Treatment Approaches to RA

1900

1910

1920

1930

1940

1950

1960

1970

1980

1990

2000

Pyramid inversion

Early intervention

Combination therapy

Single-drug Rx

Treatment pyramid

Biologics

Slide39

RA treatment themes 2011Early recognition, early institution of therapy especially with those with poor prognostic markersPresence of erosionsHigh titer anti-CCP/RF

Treat to DAS (disease activity score) or some other measure of disease activity (SDAI, CDAI etc)Methotrexate mainstay in most pts; dose to 15-20 mg/weekConsider early institution of biologic therapyStrategies for using biologics under study ie initial therapy with subsequent withdrawl vs add (discussed below)

Slide40

Non-Biologic DMARDs for RAMethotrexate7.5-25 mg/week po or scETOH restriction, avoid pregnancy, folic acidLeflunomide

10-20 mg po qdAvoid pregnancy, liver toxicitySulfasalazine500 mg 2 po bidSulfa allergies, agranulocytosis, azospermiaHydroxychloroquine

200-400 mg

po

qd

(6.5mg/kg)

Rash, retinal toxicity

Slide41

Biologic Therapies 2011Anti-TNF agentsEtanerceptAdalimumabInfliximab

CertozilumabGolimumabAnti-B cell agentRituximab

Anti-T cell agent

A

batacept

Anti-IL-6 receptor antagonist

Tocilizumab

Coming attractions

Jak-2 inhibitors

Anti-IL-17 therapy

Slide42

Monitoring DMARDSHydroxychloroquineBaseline eye exam, repeat at 5 yrs then every yrSulfasalazine

Baseline CBC LFTs; repeat q month time 3 then every 3 mo MethotrexateBaseline CBC, creatinine, LFTs, CXR, Hep B &C; CBC LFTs q mo x 6 mo then every 1-3 mos thereafterLeflunomideBaseline CBC, creatinine, LFTs,

Hep

B&C; CBC LFTs monthly for 6

mos

then 1-3

mos

thereafter

TNF inhibitors

Baseline CBC LFTs,

Hep

B (ok for

Hep

C!), PPD; CBC q

mo x 3 then q 6 mos; consider monitoring for PPD (Quantaferon) conversion

Slide43

Treating to clinical goal results in better outcomes (TICORA) Grigor C, et al. Lancet. 2004;364:263-269

P

< 0.0001, intensive vs routine

after month 3.

Mean DAS Scores Over Time

Intensive treatment

group (n = 55)

Routine case

group (n = 55)

Disease Activity Score

Months

0

1

2

3

4

6

5

0

3

6

9

12

15

18

Total Sharp Score Progression

Routine Rx 8.5

Intensive Rx 4.5

Slide44

COMETEmery. Lancet 2009;372:375-382MTX vs MTX plus etanercept in early RA; Rx 52 wks542 pts with early RA (<2 yrs) and MTX naïveMTX alone vs MTX+ETN with remission being primary endpoint

SAE is 12% combo vs 13% MTX alone

Slide45

PREMIER study: radiographic changes of combination TNF+Mtx better than Mtx alone (RA pts with < 3 yrs of disease and MTX naïve) Breedveld FC, et al. Arthritis Rheum. 2006;54:26-37

Sharp Units

Slide46

TEMPO Study: Mean Change in

Total Sharp Score From Baseline at 2 Years1

Mean Change From Baseline

1 Year

2 Years

Klareskog

L, et al.

Lancet

. 2004;363:675-681.

*Total Sharp Score is based on combined scores of joint erosions in the hands on a scale of 0 to 5, feet on a scale of

0 to 10 (0=no damage), and joint space narrowing in hands and feet on a scale of 0 to 4 (0=no narrowing).

‡

p

<0.05 vs.

etanercept

†

p

<0.05 vs. etanercept

-0.6

†

1.1

†

3.3

Inhibition

Baseline

Slide47

Healing of Erosions

1998

2005

42 y/o woman with 10

yr

Hx

of RA. On

etanercept

since

Note filling of erosions

On 3rd an to a lesser extent

4th MTP heads

Slide48

Can we stop therapy in RA?BeST remission/radiographic data at 4 yearsKooij et al. Ann Rheum Dis published online 28 Jul 2008

Pt with < 2 yrs of RA treated to DAS 44 score of <2.4 (remission <1.6)As patients went into remission, medications withdrawnDrug free remission more likely to be males, sero-negative, shorter symptom duration before starting therapy

Group

No X-ray progression

1 Mono DMARD

48%

2 Combo DMARD

46%

3 COBRA

62%

4 MTX & INF

69%

Slide49

RA Mortality and Current TherapyMichaud K, Wolfe F. Arthritis Rheum 2005;52(suppl)S145

TreatmentObservations

Hazard Ratio

95% CI

No MTX/TNF

35,309

1

Methotrexate

34,638

0.82

0.72 - 0.94

Etanercept

6,649

0.62

0.46 - 0.84

Infliximab

9,407

0.95

0.70 - 1.29

MTX+Etan

5,767

0.59

0.41 - 0.84

MTX+Inflix

21,397

0.69

0.55 - 0.87

19,580 Pts, 63,811 pt years of observation, Deaths: 33% CV, 22% malignancy, 19% lung

Slide50

DL Scott on Early Aggressive TherapyScott DL. British Medical Bulletin 2007 81-82(1):97-114 “At present, it seems sensible to focus on trying to rapidly identify patients with the most severe early RA, particularly patients who are sero-positive for rheumatoid factor and have early erosive damage, and give them intensive treatment. There is some evidence, albeit incomplete, that combination therapy using TNF-inhibitors is most effective.

”

Slide51

Rheumatoid Arthritis

Perioperative Management

Slide52

Perioperative concerns in RAPostoperative MIRA patients at increased risk of CVD; SMR 2x general population and similar to DMParticularly important in pts with poorly controlled or long standing diseasePulmonary diseaseMild asymptomatic abnormalities commonRheumatoid lung disease – fibrosis, bronchiolitis, pleuritisCricoarytenoid arthritis

Up to 75% of patients may be affected via bronchoscopyMay affect intubation or cause postop airway obstructionTM jointsBandi V, Munnur U, Braman SS. Airway problems in patients with rheumatologic disorders. Crit Care Clin 2002;18:749-65

Slide53

Perioperative ConcernsCervical spine disease:Three types:C1-C2 subluxationAtlantoaxial

impaction Subaxial diseasePatients undergoing orthopaedic surgery are a group to worry about. 38% of 154 patients undergoing surgery had evidence of cervical spine diseaseAll pt undergoing orthopaedic surgery for their disease, > 5 yrs of disease, or any neurologic abn warrant cervical spine films flexion/extension views (MRI if abn)

Slide54

NSAIDsNot utilized as intensely as in years gone byUse puts patient at risk for intraop bleeding and postop GI bleedingSponge weights and suction volumes indicate that NSAID use up to the time of surgery increase blood loss by factor of two and increases transfusion requirements (mortality?)

Recommendation is to stop NSAIDs 5 half-lives before surgeryASA should be stopped 10-14 days before surgeryWhat about primary and secondary prophylaxis? Hi risk?

Slide55

MethotrexateContinue for most surgeriesGrennan demonstrated fewer infections and flares in group of RA patients who continued Mtx perioperatively

Consider temporary stop for:Rising creatininePost op infectionLong period of NPOPatients over 70 yrsToxiciy: bone marrow suppression, severe stomatitisRx with folinic acid po or IV

Slide56

Other Non-Biologic DMARDsLeflunomideHalf-life of 2 weeks2 studies with opposite conclusions regarding wound healing issuesConsider stopping 1 month before surgery where large wounds expectedSulfasalazine – no reason to stop except for NPOMay be protective against infectionHydroxychloroquine – no reason to stopUsed as postop anticoagulant in years gone by

Slide57

TNF AgentsSuggest holding for now TNF agent for moderate to intense procedures; continue for minorHold based on half-life; hold at least 2 half livesEtanercept – half life 3.5-5.5 daysAdalimumab – half life10-20 daysInfliximab – half life 9.5 daysCertolizumab– half life14 daysGolumimab – half life14 daysRestart 10-14 days postop

Slide58

SummaryExciting changes in the treatment of RA over the last 20 years; most patients will never know how sick they could be!Remember themesEarly recognition, early therapyTreat to objective – low disease activity/remission Early institution of biologics/combination therapyTreatments and treatment schemes evolving