Rheumatoid Arthritis in 2014

Uzma Jalal Haque, MD

Assistant Professor of Medicine
Division of Rheumatology
Johns Hopkins Hospital



No Relevant Financial Relationships
with Commercial Interests

I will not reference an unlabeled or unapproved use of a
drug or product in my presentation.
Uzma Jalal Haque
Topics in clinical medicine 5/08/2014
Objectives
How Rheumatoid Arthritis (RA) in different
in 2014
Diagnosis
2010 diagnostic criteria
Anti-CCP antibodies
Comorbidities and systemic consequences
Treatment paradigms and therapeutics
Future trajectory
RHEUMATOID ARTHRITIS
Chronic
Systemic
inflammatory
arthritis
Loss of physical
function
Reduced Life
Expectancy
Systemic
Involvement
Lungs, eyes,
nerves, nodules
Synovitis
Destruction of
cartilage/joints
Images courtesy of J. Cush, 2005.
The Clinical Spectrum of RA
Active with
some deformity
Early PIP swelling Late-stage
deformities
Rheumatoid Arthritis: Epidemiology and Impact
Prevalence 0.5-1%
Peak incidence between 35 and 60 years of age
Incidence 2-4x greater in women than in men
Left untreated, 20% to 30% of RA patients become
permanently unable to work within 3 years of diagnosis


Associated with premature mortality 5-15 years less
than non-RA population
Increased cardiovascular mortality in RA: RR 2-4
times age- and sex-matched controls




PATHOGENESIS
Rheumatoid Arthritis
Rheumatoid Arthritis
Feldmann M, et al. Annu Rev of Immuno.
1996; 14:397-440.
DIAGNOSIS
Rheumatoid Arthritis
A patient presents to your
clinic
42 year old female
8 week history of joint pains in hands and
feet, morning stiffness > 1 hour and fatigue
Joint exam reveals R MCP 2,3 swelling,
tenderness L PIP 2,3,4, L wrist swelling, L
knee effusion and R ankle swelling
Labs remarkable for Anti-CCP Ab 180 U, RF
neg,
ESR 52 mm/hr, CRP 1.5 mg/dl
Diagnosis of Rheumatoid Arthritis
1987 Criteria
Additive RA Criteria 2010 ( 6)
ACPA: Anti Citrullinated Peptide Antibody (e.g. anti-CCP); RF: Rheumatoid Factor
Aletaha D, et al, Arthritis Rheum 2010 Sep;62(9):2269-81.
Designed to detect
early features that
predict a high
likelihood of
developing
destructive disease

Identify those in need
of Disease Modifying
Therapy
Your Clinic Patient.
1987 Criteria

Hand Involvement
Morning stiffness
Swelling of 3 joints


No erosions
No nodules
No RF

3/7 criteria


2010 Criteria
6 small swollen joints-
score 3
2 large swollen joint
score 1
High Titer CCP score
3
Increased ESR or CRP
score 1
6 weeks score 1

Total score 8
AUTOANTIBODIES

Rheumatoid Arthritis
In Your Clinic
Patient with joint pain, morning stiffness in
the small joints of hands and feet
Single swollen joint
Send off ESR, CRP, RF and anti-CCP
Refer to rheumatology
TREATMENT
Rheumatoid Arthritis
1. TREAT EARLY
Rheumatoid Arthritis
Joint Damage Is Evident Early
in RA
Radiographically evident joint damage is
seen
In >67% of patients within the first 2 years
1
In >72% of patients within the first 5 years
2
Within months if sensitive MRI techniques are
applied
3

Radiographic damage may progress at a
more rapid rate early in disease than later
in disease
2,4
1. Pincus T, et al. J Rheumatol. 1998;41:1571-1582.
2. Wick MC, et al. Scand J Rheumatol. 2004;33:162-166.
3. Mc Queen FM et al. Ann Rheum Dis 2001;60:859-868
4. Welsing PM, et al. Arthritis Rheum. 2004;50:2082-2093.
Turning Back the RA Treatment Clock
Later
Early
NSAIDS
Steroids
Hydroxychloroquine
Sulfasalazine
Methotrexate
(lower dose)
Initial Rx
The Old RA Treatment Pyramid
Start Low and Go Slow
(Gold)
DMARDS
Disease-modifying anti-rheumatic drugs
Drugs that suppress inflammation
slow joint destruction
Improve long term disability

2. TREAT-TO-TARGET
Rheumatoid Arthritis
What is the treatment target?
To achieve
Low disease activity
OR
Remission

To suppress
inflammation, control
disease, prevent joint
damage, disability


How is the target defined?
Several validated measures of disease
activity
Commonly used in clinical practice
Well defined cut-off points
CDAI Clinical disease activity index
SDAI simple disease activity index
DAS disease activity score



TICORA = Tight Control for Rheumatoid Arthritis
TSS = total Sharp score.
Grigor C, et al. Lancet. 2004;364:263-269.
Therapy Decisions Based on Measurement Are
Superior to Gestalt: TICORA Study
Single-blind, 18-month, controlled trial, including 110 patients with RA <5 years, randomized to either
intensive management of protocol-based escalation of DMARDs or routine care
I
n
c
r
e
a
s
e

i
n

M
e
d
i
a
n

T
S
S


f
r
o
m

B
a
s
e
l
i
n
e

Intensive Group (n = 55)
64
18
16
71
65
91
0
20
40
60
80
100
ACR20 ACR70 EULAR Remission
P
a
t
i
e
n
t
s

(
%
)

Routine Group (n = 55)
0
8.5
4.5
1
2
3
4
5
6
7
8
9
3. Adjust Therapy if Target not
met
After starting a DMARD, if patient does not
meet the target :
low disease activity state or remission
Adjust / Escalate treatment
till target is achieved


RA TREATMENT IN CLINIC
Rheumatoid Arthritis Therapy
Leave the Pyramids in Egypt!
Traditional DMARDs
Methotrexate
Sulfasalazine
Leflunomide

What are NOT DMARDS:
NSAIDS, Prednisone*
hydroxychloroquine*
*adjunctive but not as
monotherapy
Combined with DMARDs
Biologic therapies
TNF antagonists
Adalimumab
Etanercept
Infliximab
Certolizumab pegol*
Golimumab*
IL-1 antagonist
Anakinra
Costimulation modulation
Abatacept
B cell depletion
Rituximab
IL-6 antagonist
Tocilizumab
JAK inhibitor
Tofacitinib

*Investigational agents
ABATACEPT
Synoviocytes
Pathogenesis & Targets of Approved RA
Therapy
M
B cell
Immune complexes
Complement fixation
Attract inflammatory
cell infiltrates
IL-2
IFN
TNF
IL-17
RANKL
Pannus
Articular
cartilage
TNF, IL-1, IL-6,
Metalloproteinases
IL-4
IL-6
IL-10
IL-6, TNF,
IFN, IL-10, Lymphotoxin
Adapted from 1. Smolen JS et
al. Nat Rev Drug Discov. 2003.
2. Choy EH et al N Engl J Med.
2001, 3. Silverman GJ et al
Arthritis Res Ther 2003
Plasma
cell
Antigen-presenting
cells (APC)

Osteoclast
Chondrocytes
Production of metalloproteinases and other effector molecules
Migration of polymorphonuclear cells
Erosion of bone and cartilage
RF and anti-CCP antibodies
T cell
APC
RITUXIMAB
TNF INHIBITORS
IL-1 INHIBITOR
In our ClinicEach Visit
History
joint pain, minutes of
morning stiffness,
medication toxicity
Co-morbidity
Examination
assess joints for
tenderness and swelling
Joint score
Patient Forms
Patient global assessment
Pain assessment
Assessment of disability
Physician global assessment

Small
Joints
Large
Joints
Small
Joints
Small
Joints
Large
Joints
Large
Joints
In Our Clinic .each visit
Assess disease activity
calculating a score usually CDAI
[TJC28 + SJC28 + (Patient GA VAS 10) + (Physician
GA VAS 10)]
High > 22
Moderate > 10 - < 22
Low < 10
Remission < 2.8
----- > Adjust DMARD if indicated
------------ > Assess DMARD toxicity
----------------- > Assess co-morbidity

RA TREATMENT IN CLINIC
YOUR NEW PATIENT
Treatment Broad Strategies
Initiate therapy with ONE non-biologic
DMARD (monotherapy)
e.g., Methotrexate or Leflunomide
If target not met in 3 months, ADD another
DMARD (combination therapy)
dual therapy
MTX + hydroxychloroquine (HCQ)
MTX + Sulfasalazine (SSZ)
Triple therapy
MTX + SSZ + HCQ
Leflunomide + SSZ + HCQ

Treatment- Broad Strategies
MTX monotherapy achieves
LDA/remission in 30% of patients with RA
Combination therapy more effective than
monotherapy
Role of Steroids in RA
initially to control disease as DMARDs take time to be
effective
treat flares
Avoid long term use


Treatment Broad Strategies
If traditional DMARD combination does not
achieve target or not tolerated
Add a biologic to a non-biologic DMARD
Anti-TNF therapy typically first biologic
used
After that, no particular order
recommended
Driven by physician experience and
insurance approval and toxicity profile



Assess disease activity in 3 months
Treatment Algorithm for Rheumatoid Arthritis
Start a DMARD
Assess disease activity in 3 months
Assess target (LDA or remission)
Increase dose
Add DMARD
Switch DMARD
Continue
treatment
Reassess in
3 months
Reassess in 3
to 6 months
Yes No
At 5 yrs, 48%
remission DAS <
1.6
14% in DFR
In Clinic Treatment Broad concepts
MTX is standard initial /anchoring therapy
efficacy as monotherapy
long term safety profile/well tolerated
dose 15-25 mg/week
add folic acid 1 mg daily to reduce side effects
low incidence of side effects
Adverse events:
GI intolerance Headache fatigue - Alopecia Oral
ulcers
LFTs Anemia cytopenia - teratogenicity

* May respond to switch to SQ administration

#
May respond to increased folate or folinic acid (Leukovorin) 5 mg 12-24 hr after MTX




Safety Concerns with TNF
Antagonists
Injection/Infusion reactions
Infectious complications (low threshold for Abx)
Serious bacterial infections (hold agent until infection resolves)
Tuberculosis ( reactivation of latent TB, often systemic)

Opportunistic (coccidiomycosis, histoplasmosis)
Other potential safety concerns
Avoid all live vaccines
Nonmelanoma skin cancerincreased in several national registries
Congestive heart failure
Lymphoma (?) latest data shows no increase in risk above expected
for RA
Lupus-like syndrome
Demyelinating disease
Cytopenia
Olsen and Stein. N Engl J Med. 2004;350:2167.
Screening and Evaluation for TB
with TNF antagonists
Ideally perform PPD before steroids and other
immunomodulatory therapy
History suggestive of high TB risk exposure critical
5 mm induration is considered positive in RA
Quantiferon/TB-SPOT useful in detecting latent exposure
PPD should be repeated every 1-2 years, or if travel to
endemic areas, exposure, or high risk
Patients with +PPD and negative CXR can have
reactivation
Risk reduced with INH initiation with/before TNF
antagonist
Greenberg JD, Reddy SM, Schloss SG, Kurucz OS, Bartlett SJ, Abramson SB, Bingham CO. J Rheumatol.
2008:35:770-5. ; Saag K, et al, Arthritis Rheum (Arthritis Care and Research) 2008; 59:76284.
Safety Concerns with Abatacept
Infection risk increased
Higher in patients with COPD
Though very few cases of TB have been seen, screening
is recommended
No clear increase in malignancies except lung cancer in
smokers
Immunizations should be completed before starting
therapy
Infusion reactions are uncommon
Safety Concerns with Rituximab
Infusion related reactions
Increased serious infections
Reactivation of latent viral infection (eg VZV, HepB, ?JC)
Reports of progressive multifocal
leukoencephalopathy (PML) in 2 patients with lupus
and 3 patients with RA
Complete all immunizations before initiating
therapy
Avoid live virus vaccination
Prolonged B-Cell Depletion
Tocilizumab
Anti- IL 6 therapy
AEs:
Increased serious infections including herpes zoster
Dose dependent, reversible Neutropenia
Reversible transaminitis
>3x ULN in 3.4% TCZ versus 1.5% control in one
pivotal study, 1.9% TCZ versus 0.7% control in
another
Lipids (LDL and HDL)
GI perforation
TB screening recommended
Shingles vaccine before initiation

Safety Concerns with Tofacitinib
Inhibition of JAK pathway involved in
cytokine signalling
AEs
Increased risk of serious infections, including
disseminated herpes zoster
Elevated LFTs
Cytopenias
GI perforation
Cancer - lymphomas
Primary Care Rheumatologist
Partnership
Primary Care Rheumatologist

Initial evaluation
Timely Refer
Monitor for toxicities
Manage co-morbidites
Collaboration
RA in 2014

Early recognition and aggressive treatment
Treat-to-target approach
Growing armamentarium of biologics
Recognition and modification of co-morbid
risks
Future goals include prevention and long
term remission induction in RA


Safety Concerns with
Biologicals
Infectious complications
Serious bacterial infections
Tuberculosis

Opportunistic (coccidiomycosis, histoplasmosis)
Other potential safety concerns
Anti-TNF
Lupus-like syndrome
Demyelinating disease
Congestive heart failure
Olsen and Stein. N Engl J Med. 2004;350:2167.
Safety Concerns with
Biologicals
Other potential safety concerns
Anti-TNF
Lupus-like syndrome
Demyelinating disease
Congestive heart failure
Orencia
COPD exacerbation
Rituximab
PML
DAS = Disease Activity Score 28-defined remission; SDAI = Simplified Disease Activity Index; CDAI = Clinical
Disease Activity Index; RAPID = Routine Assessment Patient Index Data.

Saag KG, et al. Arthritis Rheum. 2008;59(6):762-784.
*Though commonly DAS28-ESR cut are used with DAS28-CRP, some have advocated different cut points. Castrejon I,
et al. J Rheumatol 2010; 37:1429-43. Others have suggested modifying the equation for DAS28-CRP.
Clinical Measures of RA Disease Activity
>12 6 and 12 <6 0-30 RAPID
>22 >10 and 22 10 0-76.0 CDAI
>26 >11 and 26 11 0.1-86.0 SDAI
>5.1 >3.2 and 5.1 3.2 0-9.4 DAS28ESR
High Moderate Low Score Range Instrument
Thresholds of Disease Activity
2.8
3.3
2.6
Remission
>4.9 >3.8 and 4.9 3.8 0-9 DAS28 CRP* 2.3
3
Treatment Algorithm for
biologics
No particular order recommended
Driven by physician experience and
insurance approval and toxicity profile
Head to head trial data emerging
Expert consensus is that all biologicals are
equally effective

In Your Clinic
Patients with RA
--- same risk as diabetic for CVD
Monitoring and management of
cardiovascular risk factors
High index of suspicion for CVD
Cardiovascular Disease in RA
Increased cardiovascular events/mortality in
RA: RR 2-4 times age- and sex-matched
controls
Not explained by traditional risk factors
(smoking, lipids, hypertension, DM);
adjusted RR still 3.2
High index of suspicion necessary, as
atypical, silent chest pain and sudden death
are more common
Del Rincon ID, et al. Arthritis Rheum. 2001;44:2737; Solomon DH, et al. Circulation. 2003;107:1303; Turesson C, et al. Ann Rheum Dis.
2004;63:952-955; Jacobsson JT, et al. Arthritis Rheum. 1993;36:1045; Del Rincon ID, et al. Arthritis Rheum. 2001;44:2737; Maradit-Kremers H,
et al. Arthritis Rheum. 2005;52;402-411; Turesson, et al. Ann Rheum Dis. 2007 Jan;66(1):70-5. Crowson, C, et al. Arthritis Rheum.
2005;52;3039.