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Update in Rheumatoid Arthritis. Gregory Gardner, M.D. Gilliland-Henderson Professor of Medicine Division of Rheumatology University of Washington. Outline of Discussion. Pathophysiology Clinical Features Treatment Update Perioperative Management. Rheumatoid Arthritis. Pathophysiology.

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Update in rheumatoid arthritis

Update in Rheumatoid Arthritis

Gregory Gardner, M.D.

Gilliland-Henderson

Professor of Medicine

Division of Rheumatology

University of Washington


Outline of discussion
Outline of Discussion

  • Pathophysiology

  • Clinical Features

  • Treatment Update

  • Perioperative Management


Rheumatoid arthritis

Rheumatoid Arthritis

Pathophysiology


Rheumatoid arthritis demographics
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
Treating RA: think Bolero

N Engl J Med. 1990;322:1277–1289

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

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


Genetic issues in ra
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 molecule
Structure/functionof HLA molecule

Fig 1

Fig 2

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 3

ACR and Hochberg 2008


Update in rheumatoid arthritis
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
Environmental issues in RA the symptoms of rheumatoid arthritis

  • 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
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
Antiquity of rheumatoid arthritis from the New World?

  • 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


Update in rheumatoid arthritis
RA in European art: Siebrandus Sixtius, Dutch Priest 1631 from the New World?J Dequeker Ann Rheum Dis. 1992 April; 51(4): 561–562


European contact with north american ra
European contact with North American RA from the New World?

Numerous NW Tribes with RA

Yakama

Makah

Tlingit

Etc.

French

Dutch

English

Spanish

French


Can we treat earlier klareskog et al nature clinical practice rheumatology 2006 2 425
Can we treat earlier? from the New World?Klareskog et al. Nature Clinical Practice Rheumatology 2006;2:425


Rheumatoid arthritis1

Rheumatoid Arthritis from the New World?

Clinical Features


2010 acr eular ra criteria
2010 ACR from the New World?EULAR/RA Criteria

6/10 points

Needed for

classification

Small joints:

MCPs

PIPs

Wrists

2-5 MTPs

High RF/ACPA

> 3x ULN


Ddx of inflammatory polyarthritis
DDx of Inflammatory Polyarthritis from the New World?

  • 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
Joint Distribution from the New World?

  • Cervical spine

  • Shoulders

  • Elbows

  • Wrists

  • Hands

    • PIPs

    • MCPs

    • SPARES DIPs

  • Hips

  • Knees

  • Ankles

    • Tibiotalar

    • Subtalar

  • Feet

    • MTPs


Earliest ra
Earliest RA from the New World?


Ra hands late
RA Hands Late from the New World?


Ra feet
RA Feet from the New World?


Rheumatoid arthritis extra articular disease
Rheumatoid Arthritis: from the New World?Extra-Articular Disease

Pulmonary Nodules

Scleritis in RA

Rheumatoid Vasculitis


Nodules
Nodules from the New World?

RA nodule or gouty tophus?


Other complication of ra
Other complication of RA from the New World?

  • 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
Rheumatoid Factor from the New World?

  • Rheumatolgic DiseaseRA, SLE, Sjogren’s, MCTD, PM/DM, Cryoglobulinemia

  • Infectious DiseaseSBE, TB, Syphilis, Hep C

  • OtherAging, 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


Anti ccp acpa
Anti-CCP (ACPA) from the New World?

  • 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
Imaging in RA from the New World?

  • 5th MTP may show earliest changes in RA

  • RA X-ray findings:

    • Osteopenia

    • Marginal erosions

    • Jnt space narrowing

  • Ultrasound

  • MRI


Joint erosions in ra from bad to worse

Progressive X-ray changes in RA from the New World?

Joint Erosions in RA: From Bad to Worse


Prediction model for erosive vs nonerosive ra early in disease course
Prediction Model for Erosive vs from the New World?Nonerosive RA Early in Disease Course

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 arthritis2

Rheumatoid Arthritis from the New World?

Treatment Issues


Therapy for rheumatoid arthritis circa 1989
Therapy for Rheumatoid Arthritis circa 1989 from the New World?

  • 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
Rheumatoid Arthritis Circa 1989 from the New World?

  • Frequent complications

    • Rheumatoid vasculitis

    • C1-C2 subluxation

    • Felty’s syndrome

    • Extensor tendon rupture

    • Septic arthritis

  • Pathophysiology of RA

    • Macrophage mediated disease


Update in rheumatoid arthritis
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
Business as usual was not working functional class and mortality

  • > 90% of RA patients have erosions after 2 yrsFuchs HA, et al: J Rheumatol 1989;16:585-591

  • 5 - 10% of RA patients become disabled each yrKushner 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 RAMitchell DM, et al: Arthritis Rheum 1986;29:706-713


Update in rheumatoid arthritis

functional class and mortality 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


Update in rheumatoid arthritis

functional class and mortality 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.”

J Rheumatol. 1989;16:565-7


Changes in treatment approaches to ra
Changes in Treatment Approaches to RA functional class and mortality

Biologics

Combination therapy

Early intervention

Pyramid inversion

Treatment pyramid

Single-drug Rx

1900

1910

1920

1930

1940

1950

1960

1970

1980

1990

2000


Ra t reatment themes 2011
RA t functional class and mortality reatment 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 ieinitial therapy with subsequent withdrawlvs add (discussed below)


Non biologic dmards for ra
Non-Biologic DMARDs for RA functional class and mortality

  • Methotrexate

    • 7.5-25 mg/week po or sc

    • ETOH restriction, avoid pregnancy, folic acid

  • Leflunomide

    • 10-20 mg poqd

    • Avoid pregnancy, liver toxicity

  • Sulfasalazine

    • 500 mg 2 po bid

    • Sulfa allergies, agranulocytosis, azospermia

  • Hydroxychloroquine

    • 200-400 mg poqd (6.5mg/kg)

    • Rash, retinal toxicity


Biologic therapies 2011
Biologic Therapies 2011 functional class and mortality

  • 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
Monitoring DMARDS functional class and mortality

  • 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

Intensive treatment functional class and mortality group (n = 55)

6

Routine case group (n = 55)

5

4

3

Disease Activity Score

2

1

0

0

3

6

9

12

15

18

Months

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

Mean DAS Scores Over Time

Total Sharp Score Progression

Routine Rx 8.5

Intensive Rx 4.5

P < 0.0001, intensive vs routine after month 3.


Comet emery lancet 2009 372 375 382
COMET functional class and mortality Emery. 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


Update in rheumatoid arthritis

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


Update in rheumatoid arthritis

better than Mtx alone p<0.05 vs. etanercept

‡p<0.05 vs. etanercept

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

3.3

1.1†

Mean Change From Baseline

-0.6†

Baseline

1 Year

2 Years

Inhibition

*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).

Klareskog L, et al. Lancet. 2004;363:675-681.


Healing of erosions
Healing of Erosions better than Mtx alone

1998

42 y/o woman with 10 yrHx

of RA. On etanercept since

Note filling of erosions

On 3rd an to a lesser extent

4th MTP heads

2005


Update in rheumatoid arthritis
Can we stop therapy in RA? better than Mtx alone 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


Ra mortality and current therapy michaud k wolfe f arthritis rheum 2005 52 suppl s145
RA Mortality and Current Therapy better than Mtx alone Michaud K, Wolfe F. Arthritis Rheum 2005;52(suppl)S145

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


Dl scott on early aggressive therapy scott dl british medical bulletin 2007 81 82 1 97 114
DL Scott on Early Aggressive Therapy better than Mtx alone Scott 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 arthritis3

Rheumatoid Arthritis better than Mtx alone

Perioperative Management


Perioperative concerns in ra
Perioperative concerns in RA better than Mtx alone

  • 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 joints

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


Perioperative concerns
Perioperative Concerns better than Mtx alone

  • Cervical spine disease:

    • Three types:

      • C1-C2 subluxation

      • Atlantoaxialimpaction

      • 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
NSAIDs better than Mtx alone

  • 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
Methotrexate better than Mtx alone

  • Continue for most surgeries

    • Grennan demonstrated fewer infections and flares in group of RA patients who continued Mtxperioperatively

  • 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
Other Non-Biologic DMARDs better than Mtx alone

  • 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
TNF Agents better than Mtx alone

  • 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
Summary better than Mtx alone

  • 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