Update in Rheumatoid Arthritis

Sandeep K. Agarwal M.D., Ph.D.

Chief, Immunology Allergy and Rheumatology
Department of Medicine
The Cullen Trust for Health Care Endowed Chair in Immunology
Director, Biology of Inflammation Center
 Disclosures
Sources of Funding for Research:
NIH/NIAMS
Department of Defense
Scleroderma Foundation
Ford Foundation

Consulting Agreements: None

Speakers’ Bureau/Honorarium
Agreements: PRIME CME (will give
CME talks on RA and PsA)

Financial Interests/Stock Ownership:

Hold options in Adheron
Therapeutics, purchased by Roche.
Adheron seeks to develop agents to
target cadherin-11 in rheumatoid
arthritis and fibrosis

New Yorker, July 2008

OBJECTIVES

1. Discuss updates in the pathogenesis of rheumatoid

arthritis

2. Discuss the clinical presentation and assessment of

patients with rheumatoid arthritis

3. Discuss updates in the treatment of rheumatoid arthritis

 “When an arthritis patient walks in the front door, I feel like leaving by the back door”
-Sir William Osler

Corticosteroids
Nonsteroidals

Synthetic DMARDS
Hydroxychloroquine
Sulfasalazine
Methotrexate
Leflunomide

Biologics Targeted synthetics

TNF inhibitors (etanercept, infliximab, adalimumab, golimumab, certolizumab)
IL1ra (anakinra) Tofacitinib
AntiCD20 mAb (rituximab) Baracitinib
CTLA4Ig (abatacept)
AntiIL6R (tocilizumab, sarlimumab) Upadacitinib
 Rheumatoid Arthritis : Epidemiology

• Systemic progressive inflammatory disorder

• Predominantly manifests in the synovial membrane of diarthroidal

joints but can also have extrarticular manifestations
– Classically presents as a symmetric small joint polyarthritis

• Prevalence of 0.8% in most developed countries

• Female : Male ratio of 2.5 : 1

• Peak incidence is 4th to 6th decades of life

• 2013 health care costs $10 billion

– Societal cost $45 billion
Evidence for genetics (RA)
risk
unrelated
0.5-1%
individuals

first-degree
3-5%
relatives

identical twins
15%
(triplets!)
Suggest 50-60% of risk is genetic
6
Slide courtesy of Robert Plenge MDPHD, Harvard Medical School
Rheumatoid arthritis : risk factors
GENETIC
–MHC Class II
• DR4 : HLA-DRB1*0401 and HLA-DRB1*0404
• DR1 : HLA-DRB1*0101
• Shared epitope : QKRAA or QRRAA on DRb chain

–Other genetic factors - Single nucleotide polymorphisms

• PTPN22, STAT4, Tyk2, CD40, TRAF-C1 locus, CTLA4, CD28
• PADI-4 (peptidylarginine deiminase)
• And the list continues to grow2014 – 101 confirmed RA risk loci in
individuals of European and Asian Ancestry (Nature 2013)

• But not ready for clinical application yet

ENVORINMENTAL
–Smoking – may have a role in the process of citrullination in RA

7
Pathophysiology of RA

Normal Joint RA Joint

Capsule
Early Established
Angiogenesis Neutrophils

T cells B cells
Synovial Synoviocyte Plasma Neutrophils
membrane accumulation cell
Dendritic cell Bone
Synoviocytes Cartilage erosion Pannus

Adapted from Choy EH et al. N Engl J Med. 2001;344:907-916. 8

 Normal Synovium

Synovial
lining

Synovial
Sublining

9
 Rheumatoid Arthritis Synovial Membrane

Hyperplastic
synovial
lining

Inflamed
Synovial
Sublining

10
 Rheumatoid Arthritis: Pannus

11
Lee, DM and Weinblatt, ME 2001. Lancet 358:903
 Rheumatoid Factor

• Antibodies against the Fc

portion of IgG

• Sensitivity for RA : 60-70%

• Specificity for RA : 70-80%

• Also found in
– Other autoimmune disease
– Healthy people (5%)
• 3-25% of elderly
– Bacterial endocarditis
– Hepatitis B or C
– Tuberculosis
– Syphilis
– Malignancies
Anti-Citrullinated peptide antibodies
• Citrulline is a non-standard amino acid, created by de-imination of
arginine residues
– Peptidylarginine deiminase (PADI)

• First were identified as anti-perinuclear factor (APF) or anti-filaggrin

antibodies (AFA) or anti-keratin antibodies (AKA)

• Anti-cyclic citrullinated peptide antibodies (aCCP)

– Sensitivity for RA : 50-75%
– Specificity for RA : 90-95%

• Can be detected 1.5-9 years prior to the dx of RA (as can RF)

HLA variants and
peptide binding:
Effect of
citrullination
RA : CLINICAL
Rheumatoid Arthritis : Clinical
Features
• Symptoms • Distribution
– Pain – Symmetric
– Stiffness – Distal joints more than
• Prolonged AM stiffness > 1 hr
proximal
– Swelling
– PIP, MCP, MTP, wrist, ankle
– Weakness
> elbow, knee, shoulder, hip
– Deformity
– Fatigue
– Malaise

• Physical Examination
– Tenderness to palpation
– Synovial thickening
– Joint effusions
– Erythema
– Decreased Range of Motion
– Subluxation
Structural joint abnormality vs. Synovitis
Lab Evaluation of Systemic Rheumatic Disease

• Lytes, BUN, Cr • If history indicates:

• CBC w diff – Lyme serology
– Parvovirus serology
• Urinalysis
– Uric Acid
• ESR, CRP – HLA B27

• Rheumatoid factor
• Anti-CCP antibodies • Arthrocentesis
• ANA by immunofluorescence
– Other autoAb if positive

• Hepatitis B and C serology

• TSH
• Xrays of hands and feet
– And/or affected joints
 RA – Natural History

• Clinical Course
– 10% may remit within 3-6 months
– 60-70% variable sine wave course with overall progressive worsening
– 10-20% relentless progression

• 70% have erosive changes detectable by Xrays by 2 years (MRI earlier)

• After 20 years, 60% of patients will have significant functional disability

• Increased incidence of
– Infections
– Cardiovascular disease
– Lymphoma

• Decreased Life Expectancy

– Standardized mortality rate of 1.70
– Men live 7 years less
– Women live 3 years less
 Rheumatoid Arthritis : clinical
images
Early RA Intermediate RA Severe RA

Courtesy of J. Cush, 2002.

Rheumatoid Arthritis
 Rheumatoid Arthritis : clinical images

• “Cock up” or “claw”

toe deformity
• Plantar subluxation
of metatarsal head
• “walking on
marbles”
• Pressure Necrosis
• Callouses
 Rheumatoid Arthritis : rheumatoid nodules

• SubQ, firm, usually mobile, less commonly adherent

• Central area of necrosis rimmed by a corona of palisading fibroblasts
– surrounded by a collagenous capsule with perivascular inflammatory cells
• DDx: Rheumatic fever, granuloma annulare, gouty tophi, multicentric
reticulohistiocytosis, SLE, xanthomatosis
Marginal regions
or “bare areas”
in the hand
susceptible to
attack by
rheumatoid
pannus

NOTE: not all

“erosions are
RA”
RA : erosions
Early RA
RA : Progressive Xray Damage

2009 2014
Advanced RA
RA : Radiographic Changes
 RA Complications and Comorbidities
Cardiovascular Other Extra-Articular
Disease Cancer Infections Diseases
• Myocardial • Lymphoma • General • Sjögren's syndrome
infarction
• Lung cancer • Bacterial • Vasculitis
• Heart failure
• Skin cancers • Hematologic
• Stroke
• Interstitial lung
• Peripheral vascular disease
disease
• GI disease
• Hypertension
• Osteoporosis
• Renal amyloid
• Neuropathy
• Epi/scleritis
• Depression

Scott DL, et al. Lancet. 2010;376:1094-1108.

 RA Is an Independent Risk Factor for
Cardiovascular Events*
Incidence Rate (per 1000

70 Patients With RA (n=25,385)

60 Patients Without RA (n=252,976) •RR 1.8 for MI
person-years)

50 •RR 1.9 for stroke

40 •RR 1.3 for CV death
30 •RR 1.6 for any above
20 •18-49 yo : RR 3.3
10 •>65 yo : RR 1.6-1.9

0
18-49 50-64 65-74 75+
Age Range (y)

*Myocardial infarction, stroke

Solomon DH et al. Ann Rheum Dis. 2006;65:1608-1612.

Rheumatoid Arthritis : Clinical Course

Total Symptoms

Structural
Symptom Index

Symptoms

Symptoms from
Inflammation

Time (years)
RA : TREATMENT
ACR Recommendations: Early Aggressive
Treatment of Rheumatoid Arthritis
“Successful treatment to limit joint damage and functional loss requires early diagnosis
and timely initiation of disease modifying agents. The goal of treatment is to arrest the
disease and achieve remission.”
American College of Rheumatology (ACR)
Ad Hoc Committee on Clinical Guidelines

Disease
onset

Early Established End Stage

Critical window 50% to 70% of patients have
of opportunity radiographic damage within the first 2
years of disease onset

ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46(2):328-346.

Van der Heijde DM, et al. Br J Rheumatol. 1995:34(suppl 2):74-78.
Quinn MA, et al. Rheum Dis Clin N Am. 2005;31:575-589.
 Core Principles in RA Management

Early recognition Early use of Treat-to-target

and diagnosis DMARDs (T2T)

Target of Frequent
Individualized
remission or low monitoring of
treatment
disease activity disease activity

DMARDs = Disease-Modifying Antirheumatic Drugs.

Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1–25; Smolen JS, et al. Ann Rheum Dis. 2014;73(3):492–509; Smolen JS, et al. Ann
Rheum Dis. 2010;69(4):631–637; Smolen JS, et al. Ann Rheum Dis. 2016;75(1):3–15.
35
Rheumatoid Arthritis : Treatment landscape

36
Rheumatoid Arthritis : Available Therapeutics
DMARDS
– Antimalarials, (hydroxycholorquine
– Sulfasalazine
– Methotrexate
– Leflunomide (Arava)
• Biologics
– TNFa inhibitors
• Subcutaneous  Etanercept (Enbrel) , Adalimumab (Humira),
Golimumab (Simponi), Certolizumab pegol (Cimzia)
• Intravenous Infliximab (Remicaide), Golimumab (Simponi aria)
– IL1 blockade
• Anakinra, IL1 receptor antagonist (Kineret)
– Tcell costimulation inhibitor
• Abatacept (SQ, IV) (Orencia)
– Bcell depeltion
• Rituximab (Rituxan)
– IL-6 receptor blockage
• Tocilizumab (Actemra), Sarilumab (Kevzara)
• JAK Inhibitors : Tofacitinib (Xeljanz), baracitinib (Olumiant), upadacitinib
(Rinvoq)
• NSAIDS
• Corticosteroids
RA: Methotrexate
• Aminopterin (folic acid antagonist) beneficial in 7 of 8 “rheumatoid
arthritis” patients (Am J of Med Sci. 1951)

• Uncontrolled trials of low dose intermittent methotrexate in RA

(RF Wilkens et al. J Rheum. 1980)
(K Steinsson et al. J Rheum. 1982)

• RCT of low dose methotrexate in RA (ME Weinblatt et al. NEJM. 1985)

– 35 patients, double blind cross over study, placebo controlled, 24 weeks
– 12 weeks : MTX group with fewer swollen and tender joints, improved
grip strength, less morning stiffness
– 24/33 patients who received mtx (73%) had at least a 30% improvement
in the joint-tenderness/pain index
– 20/33 patients who received mtx (61%) had at least a 30% improvement
in the joint-swelling index
Methotrexate in RA
• Should not be used in patients with hepatic or renal dysfunction

• Patients should abstain from alcohol and use appropriate birth

control

• Laboratories to obtain prior to starting:

– BUN/Cr
– Liver function tests
– CBC
– Hepatitis C and B panel

• Given one day per week,

– start with 7.5 mg one day per week
– average dose ~17.5 mg one day per week
– folic acid 1-2 mg daily

• Laboratories to obtain for monitoring of toxicity

– Bun/Cr, ALT, AST, Albumin, CBC every 6-8 weeks
Methotrexate : RA and Mortality
• Subjects : RA patients seen at the Wichita Arthritis Center between 1981 and 1999
who had not been previously treated with methotrexate

• Cohort study comparing all cause mortality (primary outcome) in patients who
received methotrexate (n=588) vs those who have not (n=660)

• MTX group had more severe RA

• 191/1240 RA patients died

– 72 in mtx group, 119 in control group

HK Choi et al. Lancet. 2002

 Traditional DMARDs for RA
Agent Usual Dosage Adverse Effects Monitoring
Methotrexate 10–25 mg weekly Hepatotoxicity, CBC and CMP every 8
(oral or myelotoxicity, weeks
subcutaneous) pneumonitis

Sulfasalazine 1,000–1,500 mg twice Hepatotoxicity, CBC and CMP every 3-4

daily (oral) myelotoxicity months

Leflunomide 10–20 mg daily (oral) Hepatotoxicity, CBC and CMP every 8

myelotoxicity weeks

Hydroxychloroquine 400–600 mg daily CNS, Annual ophthalmology

Maintenance dosing neuromuscular, exam
200 mg to 400 mg ocular,
daily (oral) dermatologic, and
GI reactions
Glucocorticoids Varies Osteoporosis, Bone density if
elevation of blood prolonged steroids
sugar, infection,
weight gain, etc
etc

Sweiss N, Hushaw LL. J Infus Nurs. 2008;32(15):S4-S17.

van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531–541.
 Molecular Structures of TNF-α Inhibitors*
Human recombinant
receptor/Fc fusion Humanized Fab’
protein fragment
Human
Chimeric recombinant
monoclonal antibodies Receptor VL VH
antibody
CL

CH1
Constant 2
CDR Fc
Constant 3

PEG PEG
Infliximab Adalimumab Golimumab Etanercept
IgG1 IgG1 IgG1 IgG1 Certolizumab
Mouse
Human
CDR=Complementarity–determining region *Structural differences not indicative of
PEG=Polyethylene glycol differences in efficacy or safety.

Adapted from Tracey D et al. Pharmacol Ther. 2008;117:244-279

 RA Treatment : TNF inhibitors

Study Treatment ACR20 (%) ACR50 ACR70 (%)

(%)
Moreland et al. Placebo 11 5 1
NEJM 1997
Etanercept 59 40 15

Weinblatt et al. Methotrexate 27 3 0

NEJM 1999
Etanercept + methotrexate 70 39 15

Maini et al. Methotrexate 20 5 0

Lancet 1999
Infliximab + methotrexate 50 27 8

Weinblatt et al. Methotrexate 15 8 5

Arth Rheum 2003 Adalimumab + methotrexate 67 55 27
 TNFα Inhibition: Certolizumab Pegol
RAPID 1

• Phase 3, 52-week RCT, Placebo Certolizumab 200 mg Certolizumab 400 mg

N=982 60 55*
53*

Patients Responding (%)

• Background MTX 50 *P<0.001
40 *
• Loading dose to improve 40 38*
early response
30
• Patients randomized to: *
21 *23
20
– Certolizumab 400 mg 13
doses every 2 weeks, 8
10
4
followed by doses of
200 mg 0
ACR20 ACR50 ACR70
– Certolizumab 400 mg
every 2 weeks
– Placebo

Keystone EC et al. Ann Rheum Dis. 2008;67:186.

 RAPID 1 and 2: Certolizumab Pegol Effects
on Radiographic Outcomes in RA
RAPID 1 RAPID 2
(52 weeks) (24 weeks)
Placebo + MTX (n=127)
Placebo + MTX (n=199)
CZP 200 mg + MTX (n=246)
CZP 200 mg + MTX (n=393)
3.5 CZP 200 mg + MTX (n=246)
1.5
in Modified Total Sharp Score

1.2
Mean Change from Baseline

3 2.8
1
2.5

2 0.5
0.2
†
1.5
1.1 0
1
-0.5 -0.4*
0.5 0.4*
0.1 *
0 -1
LOCF Linear Extrapolation Total ITT Population-Linear Extrapolation

*P<0.001; †P≤0.01 vs placebo.

Keystone E et al. Arthritis Rheum. 2008;58:3319-3329. Smolen JS et al. Arthritis Rheum. 2008.
 RA : Combination Therapy

PREMIER Trial TEMPO Trial

MTX vs Adalimumab vs Both MTX vs etanercept vs both

FC Breedveld et al . Arth Rheum 2006

D ven der Heijde et al. Arth Rheum. 2006
 TNF inhibitors : adverse events

• Infections • Injection site reactions

– TB and Reactivation of TB • Infusion reactions
• Screen by taking a history for • Malignancy
TB exposures
• Annual skin test or
• Leukopenia, pancytopenia,
Quantiferon gold +/- CXR aplastic anemia
• Treat with INH/B6 for 6-9 • Worsening of NHYA Class
months III/IV heart failure
– Opportunistic infections • +ANA, +dsDNA, SLE like
– Listeria, histoplasmosis, illness
coccidiomycosis • Demyelinating illness
– Cellulitis, viral syndromes • Psoriatic skin lesions
– Hepatitis
• Increased viral burden in
HepB
• OK in HepC
Biologic Trials in RA

• For the interest of time-

• Clinical trials support the effectiveness of all FDA approved biologics

with regards to treatment synovitis and symptoms of RA as well as
preventing radiographic progression of RA

– TNFa inhibitors
• Subcutaneous  Etanercept (Enbrel) , Adalimumab (Humira), Golimumab
(Simponi), Certolizumab pegol (Cimzia)
• Intravenous Infliximab (Remicaide), Golimumab (Simponi aria)
– Tcell costimulation inhibitor
• Abatacept (SQ, IV) (Orencia)
– Bcell depeltion
• Rituximab (Rituxan)
– IL-6 receptor blockage
• Tocilizumab (Actemra), Sarilumab (Kevzara)
RA Biologics, special considerations
• All increase the risk of infections
• All should be screened for TB prior starting and annually thereafter

• TNF inhibitors (Etanercept, Infliximab, Adalimumab, Golimumab, Certolizumab pegol)

– Malignancy
– Congestive heart failure
– Hepatitis B
– Demyelination

• Abatacept
– Chronic obstructive pulmonary disease (COPD)

• Tocilizumab, sarilumab
– Liver toxicity
– LDL elevation
– Neutropenia, thrombocytopenia
– Gastrointestinal perforations

• Rituximab
– PML
– Hepatitis B
Cytokine Receptors and JAKs
 Efficacy and Safety of Tofacitinib (JAK 1/3) + MTX
in TNFi-IR Patients

Burmester GR, et al. Lancet. 2013;381(9865):451-460; Wollenhaupt J, et al. ACR/ARHP 2017. San Diego, CA. Abstract 522; Kremer J, et al. EULAR 2019. Madrid, Spain. Abstract OP0028. 51
 Efficacy and Safety of Baricitinib (JAK 1/2)
in bDMARD-IR Patients

Genovese MC, et al. N Engl J Med. 2016;374(13):1243-1252; Fautrel B, et al. ACR/ARHP 2017. San Diego, CA. Abstract 508; Genovese MC, et 52
al. Rheumatology (Oxford). 2018;57(5):900-908; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract THU0078.
 Efficacy and Safety of Upadacitinib (JAK 1)
in bDMARD-IR Patients

*P < .001 relative to PBO.

UPA = Upadacitinib; QD = once daily; bDMARD= biologic DMARD; VTE = Venous Thromboembolic Events; MACE = Major Adverse Cardiovascular Events; PRO = Patient-Reported
Outcomes
Genovese MC, et al. Lancet. 2018 Jun 23;391(10139):2513-2524; Kremer J, et al. EULAR 2019. Madrid, Spain. Abstract FRI0155; Cohen SB, et al. EULAR 2019. Madrid, Spain. Abstract
THU0167; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract THU0172. 53
 JAK Inhibitors : Adverse events

• Increase risk of infections

• Herpes zoster/Shingles reactivation
• Elevations in LDL
• Reductions in neutrophil counts
• Elevated LFTs
• Increased risk of thrombosis (venous, arterial)
• Malignancy?

Fleischmann et al. NEJM. 2012; 367:495-507

Screening Prior to Biologics and JAK
inhibitors
• Assess infection risk

• PPD or quantiferon gold for TB exposure

• Hepatitis B and C serologies

• CBC for cytopenias, lipid panel and CMP for baseline

• Screen for comorbities

– Class III or IV CHF – avoid TNFi
– COPD - avoid abatacept
– Liver disease – avoid antiIL6r and JAKinhibitors
Vaccinations in adults with rheumatoid
arthritis
• No lives vaccines in patients on biologics

• All patients who are treated should get pneumococcal vaccine,

annual inactivated influenza vaccine (IM) and HBV vaccines
– Influenza – use inactivated IM form, not nasal spray
– Ideally family members should get influenza vaccine (not nasal spray)
– Pneumococcus vaccine - PCV13 followed 8 weeks later by PPSV23
– Preferably prior to immune suppression but would not delay immune
suppression

• Herpes zoster should be done in patients over 50

– Prefer recombinant (non-live) glycoprotein E vaccine (recombinant
zoster vaccine, RZV, Shingrix)
Conclusions

• Rheumatoid arthritis is a common autoimmune form of arthritis

• RA patients can have premature coronary artery disease,

osteoporosis and lung disease

• Early treatment with disease modifying anti-rheumatic drugs and/or

biologics is effective is treating symptoms of RA and preventing
damage to joints

• Treatment options continue to grow!

• Patients require monitoring for disease activity and adverse effects