Rheumatoid Arthritis

Mohammed A. Omair, MBBS, SF Rheum

Consultant Rheumatologist

Background

Rheumatoid Arthritis is the most common form of inflammatory arthritis worldwide.

It affects 0.5-1% of the population. Female to male ratio is 3:1 Age of onset 16-70 years. Strong association with HLA DRB1. Concordance in identical twins is 30%. Pathogenesis= Genetic + Environmental

+ Immune disturbance

Definition

Chronic Multisystem autoimmune inflammatory disorder primarily affecting joints producing a proliferative synovitis that often progresses to destruction of the articular cartilage and ankylosis.

Presentation

Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature)

Progressive articular deterioration Extra-articular involvement Difficulty performing activities of daily

living Constitutional symptoms

Presentation

Small joints of the hands and feet are affected in a relatively symmetric distribution. In decreasing frequency,

MCP Wrists PIP Knees MTP Shoulders Ankles Cervical spine Hips Elbows TMJ

Presentation

Affected joints show inflammation with swelling, tenderness, warmth, and decreased range of motion (ROM).

Atrophy of the interosseous muscles of the hands is a typical early finding.

Joint and tendon destruction may lead to deformities such as ulnar deviation, sublaxation, boutonniere, swan neck, Z-shaped thumb and hammer toes.

Presentation

Tenosynovitis and tendon rupture can complicate the course of the disease especially the 4th and 5th digital extensor tendons at the wrist.

Early periarticular osteopenia and later on generalized osteoporosis are due to osteoclasts.

Entrapment neuropathies are due to joint derangement and swelling of adjacent tissues.

Disease Activity

Mild Disease – 20% Mild AM stiffness 30 – 60 mins. Few (< 5) swollen joints No disabilityModerate Disease – 65%

Moderate symptoms AM stiffness 30 mins – 120 mins 5-15 swollen joints Leisure/work disabilitySevere Disease – 15%

Severe symptoms AM stiffness > 120 mins 15 swollen joints Difficulty with usual care

1994 Classification CriteriaCriterion Definition

1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement

2. Arthritis of 3 or more joint areas At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints

3. Arthritis of hand joints At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint

4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides fo the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)

5. Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician

6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects

7. Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)

2010 Classification Criteria

When to Initiate DMARDs ?

The Day You Make The Diagnosis!

Rationale for Early Aggressive Therapy

Rapid onset disability 50%: some disability at 5 years

Early joint damage 95%: damage on x-ray at 3 years

Mortality with severe disease Life expectancy reduced by 15% (8

years)

Extra-articular Manifestation of RA

Cardiopulmonary:- Pleuritis and pericarditis- Interstitial lung disease- Lung nodules Cutaneous:- Rheumatoid nodules- Skin ulcers- Cutaneous vasculitis- Pyoderma gangrenosum

Extra-articular Manifestation of RA

Ocular:- Secondary Sjogren’s with keratoconjuctiva sicca- Scleritis- Episcleritis- Peripheral ulcerative keratitis

Extra-articular Manifestation of RA

Hematological:- Anemia of chronic illness- Felty’s syndrome: triad of RA,

splenomegaly and leucopenia Neurological:- Entrapment neuropathies: carpal tunnel

syndrome and tarsal tunnel syndrome- C1-C2 sublaxation Others: Amyloidosis

Arsenal of RA Treatment

1. Methotrexate 2.Hydroxychloroquine 3. Leflunomide 4. Sulfasalazine TNFI- 1. Adalimumab- 2. Etanercept- 3. Infliximab- 4. Certolizumab pegol- 5. Golimumab Non-TNFI- 1. Abatacept- 2. Rituximab- 3. Tocilizumab- 4.Tofacitinib

DMARDs

Methotrexte

MTX was developed in the 40’s as an antifolate therapy that inhibit malignant cell proliferation. Low dose intermittent therapy have demonstrated efficacy for treatment of Rheumatoid Arthritis in the med 80’s.

Classic MOA is competitive inhibition of dihydrofolate reductase.

This drug inhibits the de novo synthesis of purines and pyrimidines inhibit cell proliferation.

Methotrexte

Inhibit neutrophil adhesion to endothelial cell and superoxide production.

T cell deactivation.

Increase intracellular adenosine and potentiate the stimulation of receptors A2.

Hydroxychloroquine

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 posttranslation modification of proteins in the Golgi apparatus.

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.

Antimalarial compounds may directly influence the ability of monocytes to release cytokines IL_1 and TNp3 after mitogen stimulation.

Sulfasalzine

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.

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 by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms involving p53.

Biologics

TNF

Macrophages

Synovial Lining Cell

ActivatedT cell

B cell

TNF: A Pivotal Cytokine 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, Stromelysin, collagenase prostaglandinsFrom Harris Jr. ED: Rheumatoid Arthritis

Infliximab

Infliximab is a chimeric IgG1 mAb that is formed of human constant regions and murine variable regions. It is only available in the intravenous (IV) form.

Adalimumab

Adalimumab is a human recombinant IgG1 mAb that has no murine component.

Etanercept

Etanercept is a Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody.

Golimumab

Golimumab is a human IgG1 anti-TNF-α antibody that was generated and affinity matured in an in-vivo system.

Certolizumab

Certolizumab pegol is a humanized Fab fragment fused to a 40-kd polyethylene glycol (PEG) moiety.

Rationale for Targeted B-cell Therapy

CD20

B(R.I.P.)

TNF IL-1 IL-15

C’

AgAg

T

Rituximab

Ag

FollicularSignals

Antigen Presentation

Inflammation

?

Antibodies

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 filed in the treatment of various types of lymphoma.

CD4CD4

Nu

cleu

sN

ucl

eusMHC

II TCR

CTLA-4CTLA-4

Antigen Presenting CellAntigen Presenting Cell T CellT Cell

B7B7 CD28CD28CTLA-4 IgCTLA-4 Ig

CTLA4-IgCTLA4-Ig

Abatacept is a selective co-stimulation modulator that inhibits T-cell activation by binding to CD80/86, and modulating its interaction with CD28 [28] a co-stimulatory signal necessary for the full activation of T cells.

Activated T cells are implicated in the pathogenesis of RA via amplification of the inflammatory cascade that leads to joint inflammation and destruction in RA.

Abatacept

Pivotal role of IL-6: Biological activities

Monocytes/macrophages

T-cell activation

Endothelial cells Mesenchymal cells,fibroblasts/

synoviocytes

Hepatocytes

Acute-phase responseHepcidin, CRP

↓ CYP450Maturation ofmegakaryocytes

Thrombocytosis

Osteoclast activationBone resorption

B-cells

Hyper---globulinemiaAuto-antibodies (e.g. rheumatoid factor)

Adapted from: 1. Firestein GS, Nature 2003; 423:356-361. 2. Smolen JS, et al. Nat Rev Drug Disc 2003; 2:473-488.

IL-6

Systemic Effects of IL-6 in RA

IL-6

Acute phaseresponse1

Alterations in iron homeostasis2

Liver

Acute phase proteins (e.g. CRP)

Hepcidin production

Osteoporosis1

Alterations inlipid metabolism3

Thrombocytosis1

1Choy E. Rheum Dis Clin North Am. 2004;30:405–415.2McGrath H, Rigby PG. Rheumatology. 2004; 43:1323-1325.3Al-Khalili et al. Molecular Endocrinology. 2006;20:3364–3375.

P-DS-ND-007

Tocilizumab

Previously called MRA, tocilizumab is a humanized mAb directed against IL-6 receptor in its soluble and membrane form.

Rationale for Intracellular targeted Therapy

Tofacitinib

JAK2 inhibitors It expresses its effect on intracellular

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

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