Update in Rheumatoid Arthritis

2012
Gwen Kane-Wanger, MD
Division of Rheumatology
Beth Israel Deaconess Medical Center

Rheumatoid Arthritis
Overview of lecture
1. Review of pathogenesis, natural history
and diagnosis of rheumatoid arthritis
2. Current DMARD therapy
3. Biologics
4. Changing treatment strategies

Rheumatoid arthritis:
epidemiology
Prevalence 1% in varied ethnic groups, 1.3 million people
in the US
Female predominance
Associated with HLA-DR4 and the DR associated DR4 B
chains (not in all populations)
Variable age of onset: peak age of onset 30-55
Harris, ED. Clinical features of rheumatoid
arthritis..In:Kelley WN, Harris ED Jr, Ruddy S,
Sledge CB (eds). Textbook of Rheumatology 6th ed.
Phila: WB Saunders 2001

ACR criteria for the classification

of rheumatoid arthritis
1987
Need at least four of seven criteria for
diagnosis:
1. Morning stiffness lasting at least 1 hr
2. Soft- tissue swelling or fluid in at least
3 joint areas simultaneously
3. At least one area swollen in a wrist,
MCP, or PIP joint
4. Symmetric arthritis
5. Rheumatoid nodules
6. Abnormal amounts of serum
rheumatoid factor
7. Erosions or bony decalcification on
radiographs of the hand and wrist
* Criteria 1 through 4 must have been
present for at least 6 weeks.

2010

Point system out of 10

1 .Confirmed presence of 1 or more
joints with synovitis
2. Absence of alternative diagnosis
3. Number and site of involved joints
4. Serology (RF and CCP)
5. Acute phase reactants
6. Symptom duration

Neogi T, Aletaha D, Sillman AJ et al. Arthritis Rheum 2010; 62:2569-2581, 2582-2591

RA Progression
Inflammation
Disability
Severity (arbitrary
(arbitrary units)
units)
Severity

Radiographs

10

15

20

25

30

Duration of Disease (years)

Adapted
Kirwan JR.
JR. JJ Rheumatol.
Rheumatol. 2001;28:881886.
2001;28:881886.
Adapted from
from Kirwan

I.6
I.6

Rheumatoid arthritis:
morbidity and mortality
1. Joint destruction
Joint erosions seen within 2 years
Many patients have erosions at presentation
2. Decline in functional status
80% decline in functional status over 5 years
3. Increased work disability
Disability is >7 fold increased in RA patients
compared to general population
earnings 50% lower for RA patients
4. Comorbid disease
increased cardiovascular disease
increased risk of infection
5. Increased mortality rate
severe disease associated with mortality rate
comparable to 3V CVD or Stage IV Hodgekins
lymphoma
Life expectancy decreased by 5-15 years
Pincus et al, Clin Exp Rheumatol 2004;22(suppl 35):s2-s11

Pathogenesis of Rheumatoid
Arthritis
A quick review

The Clinical Spectrum of RA

Images courtesy of
John Cush, MD.

ASSESSMENT OF DISEASE ACTIVITY

History/Physical exam IN RA
- joint swelling and tenderness, loss of motion, deformity

Functional status
-joint pain, morning stiffness, fatigue

Extraarticular findings
-fever, weight loss, nodules

Imaging techniques
-radiographs, ultrasound, MRI

Laboratory tests
-acute phase reactants, hemoglobin, RF, anti-cyclic citrullinated
peptide antibody (anti CCP)

Assessing disease:
early, intermediate, and long standing
Mild, moderate, and severe
DAS score: a measurement of disease activity that has
been used in clinical trials and can be helpful in daily
clinical practice

206 patients dx with RA; cohort study

1993-1996: Treatment with analgesics then DMARD (median time to treat
123 days)
1996-1998: Treatment with DMARD (median time to treat 15 days)
Conclusion: Decreased radiologic damage in early treatment group

Data from 14 randomized controlled trials of DMARD therapy

1400 patients analyzed
Patients receiving treatment within 1 year of disease responded best to
treatment.
Patient with long term disease receiving treatment has less response.

Randomized controlled trial of 155 patients with

early active RA (pre anti TNF era)
2 treatment arms
2 year trial with extension to 5 years
Assess clinical and radiographic outcome
11 year data: suggestion that there is improved
mortality rate in patients on combination therapy

Early

Window of Opportunity for Treating RA

Established

End Stage

window of
opportunity
van der Heijde DM, et al. J Rheumatol. 1995;22:17921796.
ODell JR. Arthritis Rheum. 2002;46:283285. Editorial.
Landewe RBM, et al. Arthritis Rheum. 2002;46:347356.

Treatment of
Rheumatoid arthritis 2012
Non pharmacologic treatment
Medications

Non pharmacologic treatment

Education and counseling

Rest
Exercise, physical and occupational therapy
Bone protection
Immunizations
Modifying cardiovascular risk factors:
Cardiovascular risk assessment should be
performed yearly; risk modification
according to accepted guidelines

Peters MJL, et al Ann Rheum Dis. 2010; 69:325-331.

Pharmacologic therapy

DMARDs

Drug

Response
Rate;
Onset
of
Action

Magnitude
of
Efficacy

Major Toxicities

Dosage

2.5-5.0 mg/kg/day

Cyclosporine

30%; 2-3 mo

++

Renal (irreversible), hypertension,

hypertrichosis,
immunosuppression

Gold

30%; 3-6 mo

++

Skin rash, hematologic, renal

5.0 mg/wk I.M. x 6

mo

Hydroxychloroquine

30%-50%; 2-6 mo

++

Retinopathy, myopathy,
hyperpigmentation

200 mg b.i.d.

Leflunomide

50%; 2-3 mo

++

Liver, teratogen, gastrointestinal,

skin rash

20 mg/day

+++

Liver (fibrosis, elevated

enzymes), hematologic,
oral ulcers

7.5-20 mg/wk

++

Dyspepsia, hemolysis in glucose6-phosphate

dehydrogenase deficiency

1 g b.i.d. or t.i.d.

Methotrexate

Sulfasalazine

> 70%; 6-8 wk

> 30%; 2-3 mo

Biologic Response
Modifiers

Biologics: anti TNF agents

Biologic

Description

dosing

Approval
date

Half life

etanercept

TNF receptor
Fc fusion
molecule
human

50mg sc q w
or 25 mg biw

1998

4 days

infliximab

Chimeric
murine/human
monoclonal
antibody

3-10mg/kg
IVq 4-8 weeks

1999

8-10 days

adalimumab

Humanized
monoclonal
antibody

40 mg sc q 2
weeks

2002

10-20 days

Efficacy of Anti-TNF Therapy

Summary of Clinical Trials
Randomized controlled studies including 6000
patients
Most in comparison to methotrexate
Effect on early RA and established RA (moderate
to severe disease)
Outcome measures: ACR core set of disease
activity variables (20,50,70): physician and patient
assessment, functional status and lab data to
evaluate efficacy of therapy.

Response to anti-TNF:
Early RA
ACR 70:
-methotrexate monotherapy 19-28%
-TNF inhibitors with methotrexate 33-48%
-Significant reduction in progression of
erosions radiographically
-Significant improvement of functional scores
compared to MTX monotherapy
COMET, ERA,ASPIRE, Premier trials

Response to anti-TNF:
Established RA
ACR 70:
Methotrexate monotherapy <5%
TNF inhibitors with methotrexate 10-27%
Decrease in radiographic erosive changes
Functional scores improved compared to
MTX monotherapy (not as robust as in early
RA)
Tempo, Attract, Armada trials

Long term data

1. >10 year experience with
etanercept demonstrates persistent
response to treatment
2. 7 years of adalimumab therapy:
ACR response rates were
maintained throughout
3. No increased rate of serious
toxicity over time

Safety considerations with anti-TNF

treatment

Administration reactions

Most common side effect, 20-37%.

Rarely lead to discontinuation of drug.
Decrease with time.
Reactions include erythema, pruritis,
swelling, recall reactions.
Infliximab associated with infusion
reaction: premedicate with steroids,
antihistamines or tylenol.

Infection

Up to 1/3 in clinical trials report minor infection,

same rate as placebo.
RA patients are more susceptible to serious
infections; most individual trials did not show
significant difference in compared to
methotrexate.
Possibly, patients with comorbid disease are more
susceptible to infection while on anti TNF therapy.
Post marketing studies/observational studies
suggest increased risk of serious infection
compared to DMARDs, occurs early in treatment;
may be higher risk of upper respiratory infections,
soft tissue and skin infections
Patients on anti TNF medications should not
receive live vaccines.

Opportunistic infection
Cases of bacterial, fungal, parasitic, viral all
reported
Mycobacterial infection most widely
described in association with therapy
TB: reactivation of TB, occurs early in
therapy, and is commonly disseminated
PPD testing is mandatory

Cardiovascular disease
RA patients have increased risk; higher risk in
patients with more severe disease.
Anti TNF agents has been associated with
worsening CHF (patients without RA)
? Anti TNF protection against cardiac disease
Recent prospective study of >12,000 patients
with RA found no evidence of association
between anti-TNF treatment and mortality in
patients with rheumatoid arthritis
Nicola, PJ et al. Arthritis Rheum 2005;52:412-420
Jacobsson J , et al J Rheum 2005; 32: 1213-18
Peters MJL, et al Ann Rheum Dis. 2010;69:325-331
Lunt M, Watson KD, Dixon WG, Symmons DP, Hyrich KL. Arthritis
Rheum. Nov 2010;62(11):3145-53.

Malignancy
No increased rate of solid tumor to date
(when compared to NCI database rates).
Lymphoma: increased rate in RA
patients, risk increases with severity of
disease
Lymphoma rates observed in patients
treated with TNF antagonists are higher
than in the general population, but
appear to approximate those seen in RA
patients in general

Demyelination

SLE-like illness

Optic neuritis, MS,

transverse myelitis
Improvement with
discontinuation
Very few cases reported
overall; relationship not
known
Avoid use in patients
with history of
demyelinating disease

ANA found in RA
patients (20-40%)
Does not indicate disease
Rare cases of SLE;
usually arthritis, rash,
serositis, anti DNA
antibodies
Resolves with
discontinuation of
therapy

Evaluating Therapeutic Strategies

2012

TICORA: Intensive vs Routine Control

of Disease Activity in RA

Objective:
18-month study to determine whether closely monitored
step-up therapy with nonbiologic DMARDs would result in significantly better
outcomes than routine care
Study Population:
110 patients aged 1875 years with RA of < 5 years duration and active disease
(DAS > 2.4)
Outcomes:% of patients achieving a DAS score of < 2.4
% of patients achieving remission (DAS score < 1.6)
Intensive Care Group:
Monthly review of disease activity and measurement of DAS
Structured escalation of therapy if DAS > 2.4 after 3 months of a new DMARD.
Routine Care Group:
Review every 3 months (with no measure of disease activity)
Management at the discretion of attending rheumatologist (ie, DMARD
therapy; intra-articular, intramuscular, and/or oral corticosteroids)
TICORA = Tight Control for Rheumatoid Arthritis.
Grigor C, et al. Lancet. 2004;364:263269.

TICORA: Disease Activity Scores

Intensive vs Routine Therapy
Intensive Therapy
Routine Therapy

Intensive Routine
Therapy Therapy
DAS < 2.4
82%
44%
DAS < 1.6
65%
16%

P Value
< 0.0001
< 0.0001

Mean DAS Score

5
4
3
Primary end point

Remission

P < 0.0001 for intensive therapy vs

routine therapy after month 3

0
0

Month
TICORA = Tight Control for Rheumatoid Arthritis.
Grigor C, et al. Lancet. 2004;364:263269.

12

15

18

BeSt Trial: treatment strategies

for early RA
Randomized clinical trial of 508 patients
comparing four treatment strategies with
evaluation and treatment changes according to
strict guidelines.
Goal: to attain DAS score<2.4 (low disease
activity); assessed every 3 months
Treatments:

Group 1 single DMARD; sequential monotherapy

Group 2 step up to combination therapy
Group 3 initial MTX, sulfasalazine, prednisone
Group 4 initial MTX/ infliximab

Goekoop- Ruiterman YP et al Ann intern Med 2007; 146: 406-415

American College f Rheumatology metting Atlanta 2010 abstract #334.

BeSt Trial: Results

At 1 year:
Patients on initial combination therapy had better response
in faster time.
At 2 years:
The same proportion of patients in all groups attained low
level of disease activity
At 3 years:
Patients who responded had less progression of xray
changes compared to non responders
Rate of radiologic progression was slower in combination
groups. 51% in group with infliximab discontinued
treatment and maintained remission for average 2.5 years.
At 7 years:
16-17% of patients in all groups achieved remission
Radiological damage progression rates were similar in all
groups. (no difference in total damage after 7 years)
Patients treated initally with infliximab maintained
improved function compared to other groups and a greater
percentage remained on initial therapy.

Anti TNF therapy v.

methotrexate
Swefot trial
Tear trial

open label randomized

trial 487 pts
30% reached target on
methotrexate alone
Pts responded best
clinically and
radiographically to
infliximab treatment
compared to DMARD
combination therapy.
Van Vollerhoven RF, Ernestam S, Geborek P et al Lancet 2009, 374:459-466.
American College of Rheumatology (ACR) 2009 Annual Meeting; October 17-21,
2009; Philadelphia. Presentation LB6.
Moreland, L and ODell, J et al. American College of Rheumatology (ACR) 2009:
Abstract 1895. Presented October 20, 2009, Presented at ACR 2010 abxtract 1368..

Randomized blinded
controlled trial of 755
received immediate
triple/antiTNF or step up
therapy
there was no difference in
clinical measurements
between groups
Preliminary radiographic
results: etanerecpt treated
patients have less xray
proogression

Newer Therapies for RA

Approved:
Abatacept: Selective blocker of costimulatory molecule
required for T cell activation.
Rituximab: Chimeric mouse-human monoclonal
antibody target CD20 antigen on B cells.
Golimumab: monthly injection, similar to Infliximab
Certolizumab pegol: PEGylated anti-TNF agent
Tocilizumab: monoclonal antibody targeting IL-6
receptor

Treatment of RA

1980

ACR Treatment Algorithm

R
h
e
u
m
a
t
o
l
o
g
i
s
t

P
C
P

Establish diagnosis of RA
early
Initiate therapy (3 months)
Periodically assess disease
activity
Inadequate response

Adequate
response

Change/Add DMARDs
MTX naive
MTX

Other Combination
mono

Adapted from: American College of Rheumatology

Subcommittee on
Rheumatoid Arthritis Guidelines. Arthritis Rheum.
2002;46:328346.

Suboptimal MTX response

Combination Other Biologics
mono MonoCombination
Multiple DMARD
failure
Symptomatic and/or structural
joint damage
surgery

Clinical signs that aid in detection of

early RA and reasons for referral
> 3 swollen joints
-RLQWV\PSWRPVZHHNV
Diagnosis is possible in 6-12 weeks, but not firm
Symmetric arthritis
RF positive or anti-CCP positive
Hand-joint involvement
Elevated ESR or C-reactive protein
Emery P, Breedveld FC, Dougados M,et al Ann Rheum Dis. 2002;61:290-7.

Conclusion
Early and aggressive treatment of RA
slows progression.
Treatment goals in 2012: decrease risk of
joint damage as well as symptomatic
relief.
Future research: Better identification of
patients at high risk of developing erosive
disease (biomarkers, MRI/ultrasound,
genetic markers) in order to individualize
therapy