update in rheumatoid arthritis gregory gardner, m.d. gilliland-henderson professor of medicine...
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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