LUGANSK STATE MEDICAL UNIVERSITYDEPARTMENT OF INTERNAL MEDICINE

PROJECT WORK ON RHEUMATOID ARTHRITIS

DR. IBEANU CHARLES.S

LUGANSK 2013

OBJECTIVES:

• INTRODUCTION AND FACTS

• ETIOLOGY AND PATHOGENESIS

• CLINICAL MANIFESTATION

• DIAGNOSIS

• TREATMENT

• PROGNOSIS

INTRODUCTION

• Chronic autoimmune systemic connective tissue disease

• Multisystem affection. Primarily synovial joints causing progressing lesion, erosion and destruction of affected joint.

• Affect 1-3% of global population

• Women (3x) > Men

• Peak age 35 – 65

• Therapeutic window is 12 weeks

FACTS• There are about 63 million RA patients

• In Ukraine there are 340 RA patients per 100,000 patients

• Nearly 75% of them having erosions in the early stage of the disease

• 50% lose working ability in the first five years

ETIOLOGY & PATHOGENESIS

ETIOLOGY AND PATHOGENESIS

• Unknown but likely multifactoral

• Genetic susceptibility

• Immunological reaction involving foreign antigen at synovial joint

• Inflammatory reaction on joint and tendon sheath

• Appearance of anti-IgG antibodies(rheumatoid factor) in blood and synovium

• Possible role of infectious agents have been suggested to induce RA. Among these are mycoplasma organism, Epstein-barr and rubella virus and others

• Hormonal- sex hormone play role

PATHOGENESIS SCHEME

Immune deficiency of T-lymphocyte system which is triggered by some internal and external factors

Leads to uncontrolled synthesis of antibodies (IgG) by B-lymphocytes

Plasmatic cells & lymphocytes of synovium percepts IgG as heterogenous antigens & starts to produce rheumatoid factors against IgG

Immune complexes formation begins, this process stimulates different reactions, activation of complement system which triggers immigration of polymorphonuclear leukocytes to the synovial fluid

Macrophages (neutrophils) engulfs the immune complexes with further release of lysosomal enzymes and other mediators of inflammation

This results to lesion of microcirculatory vessels and development of inflammatory changes in synovium

Continuous inflammation stimulates synovial membrane proliferation with formation of pannus, which is rambling on joint cartilage. The outer joint lesion appear because of destruction of microcirculatory vessels of visceral organs by immune complexes

CLINICS

CLINICAL MANIFESTATION

Signs and symptoms of rheumatoid arthritis may include:

• Tender, warm, swollen joints

• Morning stiffness > 1hr easing with physical activity

• Firm bumps of tissue under the skin on the arms (rheumatoid nodules)

• Fatigue, fever and weight loss

NB: Early rheumatoid arthritis tends to affects smaller joints first — particularly the joints that attach fingers to the hands and toes to feet. As the disease progresses, symptoms often spread to the knees, ankles, elbows, hips and shoulders. In most cases, symptoms occur in the same joints on both sides of your body.

• Rheumatoid arthritis signs and symptoms may vary in severity and may even come and go. Periods of increased disease activity, called flares, alternate with periods of relative remission — when the swelling and pain fade or disappear. Over time, rheumatoid arthritis can cause joints to deform and shift out of place.

EXTRAARTICULAR INVOLVEMENT• Constitutional symptoms (most common)

• Rheumatoid nodules (30%)

• Hematological- normocytic normochromic anemia, leukocytosis/leucopenia, thrombocytosis

• Fellty’s syndrome- chronic nodular rheumatoid arthritis, splenomegaly, neutropenia

• Repiratory- pleural effusion, pneumonitis, pleuro-pulmonary nodules, ILD

• CVS- asymptomatic pericarditis, pericardial effusion, cardiomyopathy

• Rheumatoid vasculitis- mononeuritis multiplex, cutaneous ulceration, digital gangrene, visceral infarction

• CNS- peripheral neuropathy, cord-compression from atlantoaxial/midcervical spine subluxation, entrapment neuropathies

• EYE- keratoconjunctivitis sicca, episcleriitis, scleritis

DIAGNOSIS

CRITERIA FOR DIAGNOSIS

• Morning stiffness

• Arthritis of 3 or more joints

• Arthritis of hand joints

• Symmetric arthritis

• Rheumatoid nodules

• Serum rheumatoid factor

• Radiographic changes

NB: A person shall be said to have rheumatoid arthritis if he or she has satisfied 4 of 7 criteria, with criteria 1-4 present for at least 6 weeks.

2010 ACR/EULAR Classification Criteria a score of ≥6/10 is needed for classification of a patient as having definite RA A. Joint involvement SCORE 1 large joint 0 2−10 large joints 1

1−3 small joints (with or without involvement of large joints) 2

4−10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint)†† 5 B. Serology (at least 1 test result is needed for classification) Negative RF and negative ACPA 0 Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACP 3

C. Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP and normal ESR 0 Abnormal CRP or normal ESR 1

D. Duration of symptoms <6 weeks

0 ≥6 weeks

1

LABORATORY INVESTIGATIONS

• CBC-TLC, DLC, Hb, ESR & CRP

• Acute phase reactants

• Rheumatoid Factor (RF)

• Anti- CCP antibodies

RHEUMATOID FACTOR• Antibodies that recognize Fc portion (fragment crystallizable) of IgG

• Can be IgM , IgG , IgA

• 85% of patients with RA over the first 2 years become RF+

• A negative RF may be repeated 4-6 monthly for the first two year of disease, since some patients may

take 18-24 months to become seropositive.

• PROGNISTIC VALUE- Patients with high titres of RF, in general, tend to have POOR

PROGNOSIS, MORE EXTRA ARTICULAR MANIFESTATION.

• Causes: Rheumatoid arthritis, Sjogrens syndrome, Vasculitis such as polyarteritis nodosa, Sarcoidosis, Systemic lupus erythematosus, Cryoglobulinemia, Chronic liver disease, Infections- tuberculosis , bacterial endocarditis, infectious mononucleosis, leprosy, syphilis, leishmaniasis, Malignancies, Old age(5% women aged above 60)

ACUTE PHASE REACTANTS

Positve ACR Negative ACR

MILD ELEVATIONS:- Ceruloplasmin- Complement C3 & C4

MODERATE ELEVATIONS:- Heptoglobulin- Fibrinogen (ESR)- Alpha-1. acid glycoprotein- Alpha-1- proteinase inhibitor

MARKED ELEVATIONS:- C- reactive protein (CRP)- Serum amyloid A protein

- Albumin- Transferrin

ANTI- CCP• IgG against synovial membrane peptides damaged via inflammation

• Sensitivity (65%) & Specificity (95%)

• Both diagnostic & prognostic value

• Predictive of Erosive Disease

• Disease severity

• Radiologic progression

• Poor functional outcomes

• OTHER LAB ABNORMALITIES

• Elevated APRs( ESR, CRP )

• Thrombocytosis

• Leukocytosis

• ANA

• 30-40%

• Inflammatory synovial fluid

• Hypoalbuminemia

RADIOLOGICAL & HISTOLOGICAL FEATURES

RADIOLOGICAL FEATURES

• Peri-articular osteopenia

• Uniform symmetric joint space narrowing

• Marginal subchondral erosions

• Joint Subluxations

• Joint destruction

• Collapse

• Ultrasound detects early soft tissue lesions.

• MRI has greatest sensitivity to detect synovitis and marrow changes.

STAGES

• I. Periarticular osteoporosis

• II. Osteoporosis + narrowing of joint space (there can be the solitary erosion)

• III. Same as stage (II) + pleural erosion

• IV. Same as stage (III) + osteal ankylosis

HISTOLOGY

MANAGEMENT

GENERAL CONCEPTS

• Treat early to avoid damage, disability

• Sequential monotherapy is outdated

• If inadequate response to first DMARD, add a second DMARD (“step up”)

• Occasionally, combination therapy as intial therapy is indicated

CURRENT TREATMENTS FOR RA

• Non-biologic DMARDs

-Methotrexate

-Sulfasalazine

-Leflunomide

• New jak kinase inhibitor

-Tofacitinib

• Biologic DMARDs

-Cytokine inhibitors

> Anti-TNF

> Anti-IL-1

> Anti-IL-6

-Cellular depletion/inhibitor

> B cell depleting

> T cell costimulatory inhibitor

RA: INTIAL DMARD TREATMENT

• Hydroxychloroquine

- Only occasionally; for mild disease

• Methotrexate

- Starting dose: 15 mg/wk

- Pre-treatment eval: Hep B/C, baseline H % F xrays, ESR/CRP (plus CBC, CMP)

- Post- treatment lab monitoring: q 3-4 mos with MD visits

• Exceptions:

- Liver disease: SSZ or TNF inhibitor

- Pre-pregnancy: TNF inhibitor

INADEQUATE RESPONSE TO MTX

• By +/- 4 months (at 20-25 mg/wk)

• ADD DMARDs

- If mild activity remaining, HCQ

- If moderate activity remaining:

> SSZ +/- HCQ (“triplr therapy”) OR

> Leflunomide (Arava) OR

> Biologic: TNF inhibitor

BIOLOGIC DMARDS: CYTOKINE INHIBITORS• Anti- TNF

- Etanercept, adalimumab, infliximab, certolizumab, golimumab

- Efficacy similar; possibly more infectious risk with infliximab

- Infliximab should be used with MTX; others can be used as monotherapy

• Anti-IL-6 receptor – Tocilizumab

- Effective as monotherapy or with MTX

- Elevates lipids more than other biologics; relatively contraindicated in patients with diverticulosis/itis

• Anti-IL-1

- Anakinra, rilonocept, canakinumab

- Much less effective than other DMARDs except for Still’s disease

BIOLOGIC DMARDS: CELL BASED INHIBITORS

• B cell depleting agent: Rituximab

- Very effective but (very) small risk of progressive multifocal leukoencephalopathy

• T cell co-stimulatory inhibitor: Abatacept

- Slower onset of action but safer from infectious viewpoint

NEW DMARD: TOFACITINIB# Janus kinase (JAK-3) inhibitor

- Key kinase in signaling of cytokine receptor

> IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

# Oral drug (Xeljanz); dose 5 mg bid; quick onset of action

# Can be used as monotherapy or in combination with other non-biologic DMARDs

# Potential side effects: cytopenias, lipid elevations, infections, malignancy

THERAPEUTIC CHALLENGE IN RA

• So many effective therapies

• Need for a rational approach based on

• - Comparative effectiveness of agents

• - Pathway differences (e.g , IL-1, TNF, IL-6)

• Biomarkers to pre-identify those who are likely to respond to one agent but no another

PROGNOSIS

The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 20%–30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.

RA is known to reduce the lifespan of patients by anywhere from 3-12 years. A new line of research does, however, show that the use of new biologic drug therapies extend the lifespan of patients with RA and reduce the risk and progression of atherosclerosis.

"Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA—such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints—have been shown to associate with higher mortality“

Positive responses to treatment may indicate a better prognosis. Research shows that RA sufferers suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index.