Rheumatoid Arthritis

Rheumatoid arthritis : the importance of early diagnosis and treatment

Handono Kalim Div of Reumato-immunology, Internal Medicine Department, Brawijaya University, Malang

RA : a chronic and progressive joints damage

Progressive joint damage in RA Early phase

Intermediate phase

Late phase

Early arthritis rheumatoid Periarticular osteoporosis Joint swelling

Extensive erosive destruction Loss of joint space RA two years after the onset of the disease

Cumulative Percentage of Patients with Erosions

Most RA Patients Develop Bone Erosions During First 2 Years of Disease 100 90 80 70 60 50 40 30 20 10 0

Hands Feet Hands or Feet Hands and Feet

Baseline

1

2

3

4

Years of Follow-Up Patients with RA < 1 year underwent annual radiologic assessment of hands and feet. Hulsmans HM et al. Arthritis Rheum. 2000;43:1927-1940.

5

75

Grip strength Sedimentation rate

Percentage improvement*

50

25

0

-25

Ritchie articular rate Walking time Morning stiffness Pain VAS † Haemoglobin

Radiological score

Percentage deterioration* -50 -75

Contrast between improvement in measures of disease activity and deterioration in joint damage

Radiological damage is a major determinant of disability over time

Severity (arbitrary units)

Inflammation Disability Radiographs

0

5

10

15

20

Duration of disease (years) Kirwan JR. J Rheumatol. 1999;26:720-725.

25

30

RA: a systemic disease

RA: a joint and systemic disease Articular  Polyarticular, often symmetrical  Joint swelling and tenderness  Limitation of motion  Malalignment of joints  Pain, often at rest  Marked morning stiffness

Systemic  Fever, weight loss, fatigue, anemia, increased CRP  Morning stiffness almost universal

Extra-articular    

Rheumatoid nodules Vasculitis Pulmonary fibrosis Ocular disease (sicca, episcleritis)  Carditis, pericarditis

Vasculitis

Raynaud Phenomena

Sub cutaneus nodule

Xerophthalmia (Dry Eyes) Xerostomia (Dry Mouth)

Osteoporosis Pulmonary Fibrosis

Pleural effusion

Increased risk of cardiovascular disease

Functional Decline Begins Early in RA

OA

CV death

CHF

RA

Moderate loss of function*

CVA

Severe loss of function *

Very severe loss of function*

MI

1.0

1.5

2.0

Odd ratio Wolfe J Rheumatol 2003, Haara Ann Rheum Dis 2003

0

2

5

10 Years from Symptom Onset

* 50% rates of loss of function based on HAQ

scores Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.

The need of early diagnosis and treatment

New paradigm in the treatment of RA : the need of early diagnosis ACR 1987 CLASSIFICATION CRITERIA FOR RA Requires four out of the seven criteria:

1. Morning stiffness* 2. Arthritis of three or more joints* 3. Arthritis of hand joints* 4. Symmetric arthritis* 5. Rheumatoid nodules 6. Serum rheumatoid factor 7. Radiographic changes *Must have been present for at least six weeks

ACR/EULAR 2010 Rheumatoid Arthritis criteria A

Joint involvement

1 large joint

0

2-10 large joints

1

1-3 small joints

2 3 5

4-10 small joints

> 10 joints ( min. 1 small joint ) B

Serology

RF or ACPA negative RF or ACPA low positive

RF or ACPA high positive C

Acute phase reactant

Normal CRP or ESR Abnormal CRP or ESR

D

Duration of illness

< 6 weeks > 6 weeks

0 2 3 0 1 0 1

New paradigm in the treatment of RA : the need of aggressive approach

Biologic The third-line drug (DMARDs)

The second-line drug (Corticosteroid)

The first-line drug (NSAID)

Akira Hashimoto: Mansei Kansetu Ryuumachi, Hoken Dohjinsha Inc., pp. 70

Primary care physician

Rheumatologist

ACR treatment guidelines: Diagnosis and initial therapy •Establish diagnosis of rheumatoid arthritis early •Document baseline disease activity and damage •Estimate prognosis INITIATE THERAPY •Patient education •Start DMARD(s) within 3 months •Consider NSAIDs •Consider local or low-dose systemic steroids •Physical therapy/occupational therapy Periodically assess disease activity

Adequate response with decreased disease activity

Inadequate response (ongoing active disease after 3 months of maximal therapy)

ALTERNATIVE TREATMENT REGIMEN ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002; 46:328–346.

Indicators of Poor Prognosis in RA - Reduced functional status - Early radiographic changes - Multiple involved joints - Older age at onset - High titers of rheumatoid factor - Prolonged elevation of ESR - Lower educational level - Genetics (shared epitope)

Commonly Used Conventional DMARD DMARD

Typical dosage regiments

Common Side Effects

Methotrexate (MTX)

7.5-15 mg / 25 mg weekly, orally or s.c.

Nausea, mouth ulcers, neutropenia, thrombocytopenia, hepatoxicity, lung fibrosis teratogenicity

Hydroxychloroqui ne

200-400 mg daily, orally

Nausea, corneal deposits, retinopathy, skin rashes

Sulphasalazine

Nausea, rash, neutropenia, 500 mg daily orally, increasing weekly up to 2-3 thrombocytopenia, hepatotoxicity, light sensititivity g daily

Leflunomide

100 mg daily for 3 days (optional), then 10-20 mg daily

Diarrhoea, alopecia,rash, hypertension, hepatotoxicity, neutropenia, thrombocytopenia, teratogenicity

Cyclosporine A

2.5 mg/kg/day orally for 6 weeks, then 4 mg/kg/day

Renal impairment, hypertension, abnormal liver biochemistry, nausea

ACR treatment guidelines: Recommended strategy following failure of initial therapy Change/add DMARDS Suboptimal MTX response

MTX naive MTX

Other Combination monotherapy therapy

Combination therapy

Other monotherapy

Monoterapi Monotherapy

Biologics

Combination therapy

Multiple DMARD failure Symptomatic and/or structural joint damage Surgery ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002; 46:328–346.

Monotherapy with Tocilizumab ( ACTEMRA )

Effects of IL-6 on the biologic functions of various cells Monocyte/ macrophag T cells activation

Endothel

IL-6

Neutrophile

Megakariocytes maturation

Mesenchyimal cells, fibroblast/ synoviocytes

Hepatocytes Acute-phase proteins, e.g. hepcidin, CRP

B cells Osteoclast activation, bone resorption

Thrombocytosis

Auto-antibodies (RF)

Hyper--globulinaemia

Choy E. Rheum Dis Clin N Am 2004;30:405415. Rose-John S, et al. Expert Opin Ther Targets 2007;11:613–624.

Tocilizumab mechanism of action Tocilizumab block signalling pathway and gen activation by the binding to IL-6r.1 A

B

, IL-6 ACTEMRA

ACTEMRA

mIL-6R

sIL-6R

Tocilizumab bind to IL-6 cell surface (A) and soluble receptors (B) , block activation of IL-6r.1

Tocilizumab monotherapy significantly inhibits radiographic progression at Week 52 compared with DMARDs (SAMURAI) Inclusion criteria: DMARD-IR, active RA ≥6 mo but