RHEUMATOID ARTHRITIS UPDATESMohammed A. Omair

Consultant Rheumatologist

Assistant Professor

Program Director of the KSU Rheumatology Fellowship

King Khalid University Hospital

King Saud University

Disclosure

• Honoraria/speakers fees/Advisory board: Pfizer, Abbvie, Bristol Myers Squibb, Hoffman- La Roche

• Educational grant: Actelion, New Bridge, Bristol Myers Squibb, Hoffman- La Roche

• Research grants: Pfizer

Statement• Rheumatoid arthritis should be exclusively treated by a

rheumatologist.• Early referral is one of the most important factor contributing

into reaching a good long term outcome.• The presence of one clinically inflamed joint is adequate to

generate a referral to the rheumatologist.• When referring a patient with suspected rheumatoid arthritis,

you should request the following:- CBC, LFT, U&E, ESR, CRP- RF and anti-CCP- Viral hepatitis screening- Arthritis survey (hands/wrists, elbows, knees, feet/ankles)- Chest X-ray

Objectives• Background• Pathogenesis of RA revisited• Early diagnosis and the role of the new classification

criteria• Treat to target concept• Review of old and new therapies• RA and comorbidities

Background• Rheumatoid arthritis (RA) is the most common form of

chronic inflammatory arthritis.• It is characterized by synovial hyperplasia, development

of autoantibodies, inflammatory cell infiltration, bone erosion, and joint destruction, leading to irreversible disability.

• It affects 0.5-1% of the population worldwide.• Female to male ratio is 3:1• Age of onset 18-70 years.

Burden of RA• At 10 years after diagnosis 39% of patients develop

significant work related disability (Sweden).• The indirect cost of loss of work productivity reaches 10

billion dollars (US). • RA is the second most common indication for joint

replacement after osteoarthritis.

Pathogenesis of RA

Pathogenesis of RA• RA is a multifactorial disease that has genetic/epigenetic

component interacting with an environmental component leading to immune system activation.

• Genetic: HLA-DRB1 and many other non-HLA SNPs• Epigenetics• Environmental factors: smoking and Porphyromonas

gingivalis.• Auto-antibodies: rheumatoid factor and anti-cyclic

citrullinated peptide antibodies• Cellular infiltrate: mononuclear cell, T and B lymphocytes• Cytokines: TNF-α, IL-1 and, IL-6• Synovitis and pannus formation leading to invasion of

cartilage and joint destruction.

Pathogenesis of RA

RF and anti-CCP Undifferentiated arthritis Rheumatoid arthritis Arthralgia

Early Diagnosis and Classification Criteria

Early Diagnosis• Early initiation of treatment is one of the most important

predictors of having a good response to therapy and achieving long term remission.

• When RA is suspected appropriate work up and communication with the rheumatologist should be initiated.

• RA is considered a medical emergency.• The treatment of RA starts at the time of diagnosis.• There is a window of opportunity where early aggressive

therapy can induce long term drug free remission.

Example • A 25 year old woman with a painless right breast lump is

seen in your clinic.• She is asymptomatic but you feel another lump in her right

axilla.• What would you do next?• Urgent referral/admission for FNA.• Personal communication with the surgeon and oncologist

to see this patient as soon as possible and safe her life and quality of care.

Example • A 25 year old woman with a polyarthralgia involving her

MCPs and knees• You could detect 2 swollen joints.• What would you do next?

1) Write a regular referral form

2) Order labs bring the patient in 2 weeks and if positive call your rheumatology colleague

3) Call your rheumatology colleague and tell him to see her early

4) Tell the patient you need to see a rheumatologist as soon as possible (you will not be able to provide that service)

NOT ACCEPTABLE

Classification Criteria for RA

Treat To Target Concept

Treat To Target• Treat to target strategies have been used in many other

diseases:• DM• HTN• Hyperlipidemia• And now in RA• The target is remission or low disease activity (based on

outcome measure used).• Why?• Treat to target leads to achieving more remission or low

disease activity leading to

LESS RADIOGRAPHIC PROGRESSION

LESS DISABILITY

LESS CARDIOVASCULAR EVENTS

BETTER QUALITY OF LIFE

Treat To Target• Factors leading to achieving the target:• Earlier disease • Absence of bad prognostic factors• Starting with methotrexate (MTX)• MTX based combination therapy DMARDs(controversial)• Use of biologics combined with MTX• Close follow up 1-3 months till target is achieved

TherapiesConventional DMARDs

Methotrexate

Leflunomide

Sulfasalazine

Hydroxychloroquine

TNFI Biologics

Infliximab

Adalimumab

Etanercept

Golimumab

Certolizumab

Non-TNFI Biologics

Rituximab

Abatacept

Tocilizumab

Corticosteroids

Oral

Intra-articular

T2T

JAK2 inhibitors

Tofacitinib

Conventional DMARDs and Corticosteroids

Corticosteroids• Still considered as an induction therapy• Rapid onset of action• Usually used in the first 6 months of therapy and then

discontinued• Oral course of 30mg tapered over 6 weeks to 6 months.• Intramuscular injection is an alternative route• Gastroprophylaxis and bone protection strategy should be

considered.

Methotrexate• The anchor drug• Should be initiated in any patient with moderate to severe RA with

no contraindications.• Decreases risk of CVD events.• Mechanism of action in oncology is:

1. Competitive inhibition of dihydrofolate reductase.

2. Inhibition the de novo synthesis of purines and pyrimidines which leads to inhibition of cell proliferation.

• Mechanism of action in rheumatology is:

1. Inhibition of neutrophil adhesion to endothelial cell and superoxide production.

2. T cell deactivation

3. Increasing intracellular adenosine and potentiate the stimulation of receptors α2 That is way we give folic acid with MTX

Methotrexate• Screening:- CBC, LFT, U&E- Viral hepatitis- Chest X-ray• Adverse events:- Mucositis- Hair loss- Bone marrow suppression- Hepatitis- Pneumonitis

Hydroxychloroquine• Can be used as monotherapy in mild disease or in

combination in moderate to severe. • Increase pH within intracellular vacuoles and alter

processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and post-translation modification of proteins in the Golgi apparatus which leads to decreased reactivity against autoantigens while leaving responses to exogenous antigens relatively intact.

• Decrease antigen processing and presentation by both macrophages and lymphoid dendritic cells.

Hydroxychloroquine• Extra-articular positive effects includes:- DM- HTN- Hyperlipidemia- CVD events- Mortality and thrombotic events (in lupus literature)

Hydroxychloroquine• No pre-screening test is warranted• Needs yearly ophthalmology evaluation• Can be continued during; pregnancy, breastfeeding and

severe infection.

Sulfasalazine• The anti-inflammatory mechanism of sulfasalazine is not

well understood. • It has recently been shown that sulfasalazine inhibits de

novo purine biosynthesis.• It was also shown to increase adenosine hence

decreasing inflammation.

Sulfasalazine• Screening:- CBC, LFT, U&E- Viral hepatitis- Chest X-ray• Adverse events:- Azospermia- Hypersensitivity - Bone marrow suppression- Hepatitis- Pneumonitis

Leflunomide• Leflunomide is an immunomodulatory drug that may exert

its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP).

• Leflunomide prevents the expansion of activated and autoimmune lymphocytes.

Leflunomide• Screening:- CBC, LFT, U&E- Viral hepatitis- Chest X-ray• Adverse events:- Hair loss- Bone marrow suppression- Hepatitis- Pneumonitis

Biologics

TNF-α

Macrophages

Synovial Lining Cell

ActivatedT cell

B cell

Role of TNF-α in RA

Increases proliferation and cytokine production

Increases proliferation and differentiation

Expression of ICAM-1, VCAM-1, ELAM-1, IL-8

Endothelial Cells

Enhances proliferation, increases IL-2 receptor

Induces synthesis of IL-1, GM-CSF, collagenase prostaglandins

From Harris Jr. ED: Rheumatoid Arthritis

General Concepts about all TNFI• First class of drugs approved.• Better results with MTX• Requires screening of latent

tuberculosis

• Is associated with infection especially herpes zoster• Can precipitate failure in patients with decompensated

cardiac failure • Can cause brain demyelination

Different structure One Family• Infliximab is a chimeric IgG1 mAb that is formed of human constant

regions and murine variable regions.

• Adalimumab is a human mAb against TNF-α. It is produced by recombinant DNA technology using a mammalian cell expression system.

• Certolizumab pegol is a recombinant Fab’ antibody fragment against TNF-α which is conjugated to polyethylene glycol 

• Golimumab is a human IgG1қ mAb derived from immunizing genetically engineered mice with human TNF-α.

• Etanercept is a dimeric human tumor necrosis factor receptor (TNFR) p75-Fc fusion protein made of 2 extra-cellular domains (p75) TNFR linked by the constant Fc portion of human immunoglobulin 1 (IgG1). Does not affect the transmembrane form of TNF-α

IV

IV SC

SC

SC

SC

Not indicated in IBD

IgG1 Fc

Monoclonal Antibody

RecombinantReceptor/

Fc Fusion Protein

Fab′

PEG

PEGylated Fab′ Anti-TNF

• Etanercept

• Infliximab• Adalimumab• Golimumab

• Certolizumab pegol

p75 Soluble TNF Receptor

Fab

Structure of the TNF-Blocking Agents

Rituximab• Rituximab is a chimeric monoclonal antibody which binds

the CD20 cell surface marker found on B lymphocytes and depletes these cells.

• Rituximab was first used in the oncology field and then widely used by numerous sub-specialties.

• Better results when combined with MTX• It is not a must to screen for TB but we do it anyway.• It works better in seropositive RA patients.• It is a reasonable option in patients with concomitant

malignancy and in patients with ILD.• Specific adverse events: hypersensitivity reaction and

progressive multifocal leucoencephalopathy. IV

Rationale for Targeted B-cell Therapy

CD20

B

TNF IL-1 IL-15

C’

AgAg

T

Rituximab

Ag

FollicularSignals

Antigen Presentation

Inflammation

?

Antibodies

Abatacept• Abatacept is a selective co-stimulation modulator that

inhibits T-cell activation by binding to CD80/86, and modulating its interaction with CD28 a co-stimulatory signal necessary for the full activation of T cells.

• Adverse events and screening are similar to TNFIs.• Better results when combined with MTX

IV SC

AbataceptAbatacept

Extracellular

Cell membrane

Intracellular

CTLA-4 Abatacept IgG1

Binds high affinity Fc receptorDoes not induce ADCC Not complement-fixing

Abatacept (CTLA4-lg) is a recombinant human fusion protein comprising an extracellular domain of human CTLA-4 and a fragment ofthe modified Fc domain of human IgG1

AbataceptAbatacept

APCAPC

CD80/86CD80/86

MHCMHC

AbataceptAbatacept

CD28CD28

TCRTCR

T cellT cell

Abatacept inhibits full activation of T cells1

Abatacept inhibits full activation of T cells1

Systemic Effects of IL-6

IL-6

Acute phaseresponse

Alterations in iron homeostasis

Acute phase proteins (e.g. CRP)

Hepcidin production

OsteoporosisAlterations in

lipid metabolism

Thrombocytosis

P-DS-ND-007

Elevated cholesterolHarmful?

Tocilizumab• Tocilizumab is a humanized mAb directed against IL-6

receptor in its soluble and transmembrane form. • Has a very potent effect on anemia and acute phase

reactants.• Similar screening and adverse events to TNFI• Can increase lipid profile• Better results when combined with MTX but has the best

results as monotherapy

IV SC

gp130

Classical membrane signalling

mIL-6R

IL-6

Trans-signalling

sIL-6R

gp130

IL-6

Tocilizumab

Tocilizumab

gp130 gp130

Classical membrane signalling Trans-signalling

IL-6 IL-6

mIL-6R sIL-6R

Tofacitinib• JAK2 inhibitor• It expresses its effect on intracellular transducers and

activators of transcription (STATs) which generates gene expression and protein production leading to maintaining of inflammation

• Its efficacy is similar to biologics• Similar safety signals

ORAL

Intracellular signaling

Production of more cytokines and maintaining of inflammation

Comorbidities in RA

Osteoporosis• Osteoporosis is an important comorbidity that can be due

to osteoclast activation from different cytokines.• Could be steroid induced• Could be related to immobility • RA patients are more liable to develop an osteoporotic

fracture compared to age matched population even in the absence of corticosteroids.

• Prevention and regular screening are really important• FRAX tool is an important aid to guide and escalate

therapy.

Cardiovascular Events• RA patients have a decreased survival of 8 years

compared to normal population• Causes: genetic, smoking, chronic inflammation, and

sedentary life• Accelerated atherosclerosis due chronic inflammation can

be reduced with adequate therapy.• Regular screening and treatment of comorbidities is a

very important part of our daily practice.

• Cardiovascular symptoms should be taken seriously in a patient with RA

Conclusion• RA is a multifactorial disease with a chronic course• Despite all of the advancement it is still an important

cause of disability and mortality• Early recognition and treat to target strategy can lead to a

substantial improved outcome• Prevention and management of comorbidities can never

be overemphasized

Thank You For Your Attention