Update in Rheumatoid Arthritis

Gregory Gardner, M.D.Gilliland-Henderson

Professor of MedicineDivision of RheumatologyUniversity of Washington

Outline of Discussion

Pathophysiology

Clinical Features

Treatment Update

Perioperative

Management

Rheumatoid Arthritis

Pathophysiology

Rheumatoid arthritis demographics

Autoimmune disease Affects 1-2% of US population 1st degree relative has double the risk Women:Men 3:1 Occurs in two peaks:

-Women during child bearing years-Men and women after age 60

Treating RA: think Bolero

Early 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 fluid

Stage 3 - Marked synovial proliferation and inflammation develop with production of of cytokines

Stage 4 - Synovitis polarized into aggressively invasive front of macrophages and synovial cells that begins irreversible destruction of cartilage, ligaments and bone

Stage 5 - Progressive loss of articular cartilage & bone; tendon/ligamenous attenuation and loss; joint deformity

N Engl J Med. 1990;322:1277–1289J Rheumatol. 1996;239(suppl 44)2-4

Genetic issues in RA

Genetic 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 prognostic Citrulline results from deimination of arginine; peptides

with citrulline are immunogenic In high risk populations, a long period of benign

autoimmunity can proceed the onset of active RA Anti-CCP antibodies my be present before RA develops

Structure/function

of HLA moleculeFigure 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 3ACR and Hochberg 2008

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 CCP

2100 control sera: 1.1% + for RF; 0.6% + for CCP

Environmental issues in RA

Are 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 proteins Smoking Periodontal disease

Is rheumatoid arthritis caused by an environmental agent from the

New World?

?

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

Antiquity of rheumatoid arthritis

Paucity 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 Dz Gout, osteoarthritis, ankylosing spondylitis etc.

common

RA found in Pre-Colombian skeletons in N

America Especially in Tennessee, Ohio, Alabama, and

Kentucky

Prevalence: 7% female, 3% males

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

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

European contact with North American RA

Dutch

English

Spanish

French

French

Numerous NW Tribes with RAYakamaMakahTlingitEtc.

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

Rheumatoid Arthritis

Clinical Features

2010 ACREULAR/RA

Criteria

Joint involvement Score

1 large joint 0

2-10 large joints 1

1-3 small joints 2

4-10 small joints 3

> 10 small joints 5

Serology 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 1

Duration Score

< 6 weeks 0

> 6 weeks 1

6/10 points Needed forclassification

Small joints:MCPsPIPsWrists2-5 MTPs

High RF/ACPA> 3x ULN

DDx of Inflammatory Polyarthritis

Rheumatoid arthritis SLE - systemic features, + ANA/ENA Psoriatic arthritis - rash, dactylitis Viral arthritis ie parvovirus - more pain

than swelling, rash, season Polyarticular gout Other CTD - other systemic features ie

Raynaud’s, myositis, etc…

Joint Distribution

Cervical spine Shoulders Elbows Wrists Hands

PIPs MCPs SPARES DIPs

Hips Knees Ankles

Tibiotalar Subtalar

Feet MTPs

Earliest RA

RA Hands Late

RA Feet

Rheumatoid Arthritis:Extra-Articular Disease

Pulmonary Nodules

Scleritis in RA

Rheumatoid Vasculitis

Nodules

RA nodule or gouty tophus?

Other complication of RA Felty’s syndrome

Leukopenia, splenomegaly, RA Infections, leg ulcers

C1-C2 subluxation Neck pain, myelopathy C spine flexion/extension views, MRI

Septic arthritis Large joints, fewer systemic symptoms Staph > Strep > gram negatives Morbidity/mortality high

Tendon ruptures Especially ring/little finger

extensor tendons

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 RheumatoidFactor

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

Anti-CCP (ACPA) Antibodies to Cyclic Citrullinated Peptide (CCP) have a

sensitivity of 78% and specificity of 96% for RA 40% of “seronegative RA” are anti-CCP + Level of CCP is directly correlated with the development

of erosions Negative , low-moderate (35-200) or high CCP

(>200) OR of radiographic progression vs CCP negative RA

pts after10 yrs Negative 1.0 Low-moderate 3.2 High 15.2

Other ACPA being investigated for utility in diagnosis and prognosis

Schellekens. Arthritis Rheum 2000;43:155

Imaging in RA

5th MTP may show earliest changes in RA

RA X-ray findings: Osteopenia Marginal erosions Jnt space narrowing

Ultrasound MRI

Progressive X-ray changes in RA

Joint Erosions in RA: From Bad to Worse

Prediction Model for Erosive vs Nonerosive RA Early in Disease Course

Criterion Odds Ratio Score

Symptom duration ≥ 6 wk but < 6 mo ≥ 6 mo

0.961.44

00

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.

Rheumatoid Arthritis

Treatment Issues

Therapy for Rheumatoid Arthritis circa 1989

Medications Gold Penicillamine Hydroxychloroquine Sulfasalazine New drug, methotrexate

Treatment philosophy Pyramid with sequential DMARD monotherapy “Rheumatoid arthritis is a disabling but

otherwise benign disease”

Rheumatoid Arthritis Circa 1989

Frequent complications Rheumatoid vasculitis

C1-C2 subluxation

Felty’s syndrome

Extensor tendon rupture

Septic arthritis

Pathophysiology of RA Macrophage mediated disease

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”

Business as usual was not working

> 90% of RA patients have erosions after 2 yrs

Fuchs HA, et al: J Rheumatol 1989;16:585-591

5 - 10% of RA patients become disabled each yr

Kushner I: J Rheumatol 1989;16:1-4

Only 18% of RA patients achieve a period of remission during the course of their disease.

Wolfe F, Hawley DJ:J Rheumatol 1988;12:245-252

Median life expectancy decreased 4 yrs for men and 10 yrs for women with RA

Mitchell DM, et al: Arthritis Rheum 1986;29:706-713

“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

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.”

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

RA treatment themes 2011

Early recognition, early institution of therapy especially with those with poor prognostic markers Presence of erosions High 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/week

Consider early institution of biologic therapy Strategies for using biologics under study ie initial

therapy with subsequent withdrawl vs add (discussed below)

Non-Biologic DMARDs for RA Methotrexate

7.5-25 mg/week po or sc ETOH restriction, avoid pregnancy, folic acid

Leflunomide 10-20 mg po qd Avoid pregnancy, liver toxicity

Sulfasalazine 500 mg 2 po bid Sulfa allergies, agranulocytosis, azospermia

Hydroxychloroquine 200-400 mg po qd (6.5mg/kg) Rash, retinal toxicity

Biologic Therapies 2011 Anti-TNF agents

Etanercept Adalimumab Infliximab Certozilumab Golimumab

Anti-B cell agent Rituximab

Anti-T cell agent Abatacept

Anti-IL-6 receptor antagonist Tocilizumab

Coming attractions Jak-2 inhibitors Anti-IL-17

therapy

Monitoring DMARDS Hydroxychloroquine

Baseline eye exam, repeat at 5 yrs then every yr Sulfasalazine

Baseline CBC LFTs; repeat q month time 3 then every 3 mo

Methotrexate Baseline CBC, creatinine, LFTs, CXR, Hep B &C; CBC LFTs

q mo x 6 mo then every 1-3 mos thereafter Leflunomide

Baseline 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

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 treatmentgroup (n = 55)

Routine case group (n = 55)

Dis

ease

Act

ivit

y S

core

Months

0

1

2

3

4

6

5

0 3 6 9 12 15 18

Total Sharp Score ProgressionRoutine Rx 8.5Intensive Rx 4.5

COMETEmery. Lancet 2009;372:375-382

MTX vs MTX plus etanercept

in early RA; Rx 52 wks

542 pts with early RA (<2

yrs) and MTX naïve

MTX alone vs MTX+ETN with

remission being primary

endpoint

SAE is 12% combo vs 13%

MTX alone

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

Unit

s

TEMPO Study: Mean Change in Total Sharp Score From Baseline at 2 Years1

Mean C

han

ge F

rom

Base

line

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

InhibitionBaseline

Healing of Erosions

1998

2005

42 y/o woman with 10 yr Hxof RA. On etanercept since1999. Note filling of erosionsOn 3rd an to a lesser extent4th MTP heads

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 withdrawn Drug free remission more likely to be males, sero-negative,

shorter symptom duration before starting therapy

GroupNo X-ray progressi

on

1 Mono DMARD 48%

2 Combo DMARD 46%

3 COBRA 62%

4 MTX & INF 69%

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

Treatment Observations 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

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.”

Rheumatoid Arthritis

Perioperative Management

Perioperative concerns in RA Postoperative MI

RA patients at increased risk of CVD; SMR 2x general population and similar to DM

Particularly important in pts with poorly controlled or long standing disease

Pulmonary disease Mild asymptomatic abnormalities common Rheumatoid lung disease – fibrosis, bronchiolitis,

pleuritis Cricoarytenoid arthritis

Up to 75% of patients may be affected via bronchoscopy May affect intubation or cause postop airway obstruction

TM jointsBandi V, Munnur U, Braman SS. Airway problems in patients with rheumatologic disorders. Crit Care Clin 2002;18:749-65

Perioperative Concerns Cervical spine disease:

Three types: C1-C2 subluxation Atlantoaxial impaction Subaxial disease

Patients undergoing orthopaedic surgery are a group to worry about. 38% of 154 patients undergoing surgery had evidence of cervical spine disease

All 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)

NSAIDs Not utilized as intensely as in years gone

by Use puts patient at risk for intraop

bleeding and postop GI bleeding Sponge 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 surgery

ASA should be stopped 10-14 days before surgery What about primary and secondary

prophylaxis? Hi risk?

Methotrexate Continue for most surgeries

Grennan demonstrated fewer infections and flares in group of RA patients who continued Mtx perioperatively

Consider temporary stop for: Rising creatinine Post op infection Long period of NPO Patients over 70 yrs

Toxiciy: bone marrow suppression, severe stomatitis Rx with folinic acid po or IV

Other Non-Biologic DMARDs Leflunomide

Half-life of 2 weeks 2 studies with opposite conclusions regarding

wound healing issues Consider stopping 1 month before surgery

where large wounds expected Sulfasalazine – no reason to stop except

for NPO May be protective against infection

Hydroxychloroquine – no reason to stop Used as postop anticoagulant in years gone by

TNF Agents Suggest holding for now TNF agent for

moderate to intense procedures; continue for minor

Hold based on half-life; hold at least 2 half lives Etanercept – half life 3.5-5.5 days Adalimumab – half life10-20 days Infliximab – half life 9.5 days Certolizumab– half life14 days Golumimab – half life14 days

Restart 10-14 days postop

Summary Exciting changes in the treatment of RA

over the last 20 years; most patients will never know how sick they could be!

Remember themes Early recognition, early therapy Treat to objective – low disease

activity/remission Early institution of biologics/combination

therapy Treatments and treatment schemes

evolving