Ayu Paramaiswari

AYU PARAMAISWARI RHEUMATOLOGY DIVISION DEPARTMENT OF INTERNAL MEDICINE SARDJITO GENERAL HOSPITAL/ GAJAH MADA SCHOOL OF MEDICINE

DEFINITION RA  Inflammatory symmetric polyarthritis if

untreated can lead to erosions, joint space loss, destruction of joint  Rare: self limited, more often: chronic, disabling, and sometimes ~ systemic manifestation

Definisi

Rheumatoid Arthritis

UMU M

membuat kegiatan sehari-hari sulit, keterbatasan gerak, keterbatasan untuk bekerja dan aktivitas sosial.

Penyakit inflamasi sistemik kronik yang mempengaruhi banyak organ, terutama menyerang membran sinovial sendi

Epidemiology  Women:Men 3:1  Peak onset age 30-55  Incidence 30/100,000

 Prevalence  1% Caucasians  0.1% rural Africans

Patofisiologi  Berbagai sitokin dan proses sinyal selular terlibat dalam patogenesis

artritis reumatoid1 Sendi Sehat

Sendi Rheumatoid

Femur

 T cells  B cells

Capsule Cartilage Synovial membrane

Synoviocytes

Plasma cell

 IL-6  TNF-α  IL-1

Synovial villi

Tibia

1. Choy E and Panayi G. N Eng J Med 2001;344:907-916

Angiogenesis

Eroded bone

Pannus Neutrophils

Rheumatoid Arthritis Pathology

Rheumatoid Arthritis Pannus

Clinical Presentation  Typically: insidious onset of symmetric joint pain,    

swelling, morning stiffness Commonly: small joints of hands (wrist, MCP, PIP, MTP) Less common: large joint: shoulder, knee, elbow, hip Generalized malaise, fatigue Disease course: waxing & waning pattern of synovitis coupled with progressive structural damage, deformities, disability.

Rheumatoid Arthritis Physical

Physical Examination  Active synovitis:  Warmth, swelling, pain, palpable efusion  Synovial proliferation (soft & rubbery tissue margin)  Range of Motion restricted:  Wrist: radial-ulnar subluxation, carpal subluxationradial deviation, CTS  Hands: ulnar deviation, z shape thumb, swan neck, boutonniere deformities  Extra-articular:  Skin: rheumatoid nodules & vasculitis, ocular, pulmonary, neurologic, cardiac, GI, hepar, hematology

Rheumatoid Arthritis Physical

Rheumatoid Arthritis Deformities

Ulnar Deviation

Swan neck deformities

Boutenaire deformities

Rheumatoid Arthritis Deformities

Bayonet Deformities MTP Subluxation

Rheumatoid Arthritis Extraarticular Involvement

Rheumatoid Nodules

Rheumatoid Arthritis Extraarticular Involvement

Rheumatoid Vasculitis

Rheumatoid Arthritis Extraarticular Involvement Pulmonary •Pleurasy

Differential Diagnosis  Other common cause of symmetric inflammatory

polyarthritis (SLE, psoriatic arthritis, viral arthritis)  Other common cause of less symmetric mono or oligi articular arthritis (gout, septic arthritis, SPA).  Non inflammatory polyathralgia.  Palindromic rheumatism (recurrent onset of acute, self limited arthritis)

Diagnotic test: Rheumatoid Factor Antibodies to Fc portion of IgG 75-80% of Patients have during course of disease Useful for prognosis

Cyclic Citrullinated Peptide Antibodies (anti CCP)

Schellekens, A&R, Vol 43, pp. 155-163

Rheumatoid Arthritis X-Ray

Rheumatoid Arthritis X-Ray

CT/MRI scans Used for better visualization of soft tissue MRI is particularly sensitive for the early and subtle features of RA Can detect changes of Rheumatoid Arthritis prior to an X-Ray

(Radiopaedia, 2010; Dat et al., 2010)

Rheumatoid Arthritis Classification 1987 Criteria

Arnett, A&R, Vol 31, pp. 315-324

ACR Criteria 2010 score of ≥ 6 is needed for classification of patient as having definite RA

Joint involvement 1 large joint 2-10 large joints 1-3 small joints 4-10 small joints > 10 joints

0 1 2 3 5

Negative RF and negative ACPA Low + RF or low + ACPA High + RF or high + ACPA (ACPA=anti-citrullinated protein antibody)

0 2

Normal CRP and normal ESR Abnormal CRP or abnormal ESR

0 1

<6 weeks >6 weeks

0 1

Serology

Acute-phase reactans Duration of symptoms

3

DAS 28 Scoring Arnett # Last Name

Rheumatoid Arthritis Implementation DAS scoring & aggressive approach in a community rheumatology practice

DAS

Date First Name

Comment

Pain Count

Birth Date

DAS28 < 2.6 Remission DAS28 2.6 to < 3.2 Low Disease Activity

Sw elling Count

DAS28 3.2 to 5.1 Moderate disease Activity

VAS Patient

DAS28 >5.1 High Disease Activity

WSR

Patient Assessment of Disease Activity

Not Active at all

I________________________________________________________________I

Extremely Active

Physician Assessment Pain

Swelling

Measurement of Disease Activity: DAS28 as Example DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH  Includes:  Tender joint count  Swollen joint count  ESR (or CRP in different version)  GH: Patient global disease activity assessment  Categorized as low, moderate, or high

Benefits of early detection and DMARD therapy  Decreased RA severity, disability and mortality with

DMARDs  Less need for joint replacement surgery  May decrease risk of cardiovascular disease and mortality

DMARDs (Disease-Modifying AntiRheumatic Drugs) Traditional  Hydroxychloroquine

(Plaquenil)  Sulfasalazine  Methotrexate  Leflunomide (Arava)  Less commonly used:  Minocycline

 Azathioprine  Gold, PO or IM  Cyclosporine

Biologics         

Etanercept (Enbrel) Infliximab (Remicade) Adalimumab (Humira) Golimumab (Simponi) Certolizumab Pegol (Cimzia) Anakinra (Kineret) Rituximab (Rituxan) Abatacept (Orencia) Tocilizumab (Actemra)

Role of MTX in RA  Methotrexate considered mainstay of RA therapy  Recommended first-line therapy in DMARD-naïve

patients  All TNF inhibitors studied with/without MTX work better with MTX  New biologics studied in combination with MTX— incomplete response required for enrollment in most trials

Katchamart et al. Ann Rheum Dis 2009;68:1105-12. Feely MG, O’Dell JR. Curr Opin Rheumatol 2010;22:316

DMARD (Disease Modifying Anti Rheumatic Drugs) DMARD

Sediaan

Monitor

Toxicity

Methotrexate

IM atau oral, mingguan

Tes fungsi hati Complete blood count (CBC) Creatinine

Mual/muntah, hepatoxicity, supresi sumsum tulang, fibrosis paru, teratogenicity

Hydroxychloroquine

Oral, sekali sehari

Fundoscopic tahunan dan penilaian lapangan pandang

Kerusakan macula retina

Sulfasalazine

Oral, dua kali sehari

CBC

Supresi sumsum tulang, sensiitf thdp cahaya

Preparat emas

IM, bulanan (maintenance); oral, harian

Urinary protein CBC

Proteinuria, supresi sumsum tulang

Leflunomide

Oral, harian

Tes fungsi hati CBC

Diare, kebotakan, kulit kemerahan, sakit kepala, toxic thdp hati, teratogenicity

D-penicillamine

Oral, once harian

CBC Creatinine Urinary protein

Toxic thdp ginjal dan haematological, lupus, alergi, kelemahan otot.

Bekerja sangat lambat hasil >12 minggu

EULAR 2013

EULAR 2013

EULAR 2013

Biologics in RA  All recommended with methotrexate  Biologic agents target:  Tumor necrosis factor-a (TNF-a)  Co-stimulation between B and T cells  B cell surface proteins  Interleukin-6 (IL-6)  More likely to come soon….

TNF Inhibitors Generic (Brand)

Class

Route Dose

Frequency

Etanercept (Enbrel)

Soluble TNFR

SQ

50 mg

Q week

Infliximab (Remicade)

Chimeric mAb

IV

3-10 mg/kg

At 0, 2, 6 weeks, then q 8 weeks

SQ

40 mg

Q 2 weeks

Human mAb SQ

50mg

Q month

400 mg

At wks 0, 2, 4, then 200 mg q 2 wk or 400 q 4 wk

Adalimumab Humanized (Humira) mAb Golimumab (Simponi)

Certolizumab PEGylated pegol fragment of (Cimzia) humanized mAb

SQ

Poor Prognostic Factors in RA  Presence of RF and/or CCP antibodies  Radiographic erosions  Functional limitation

 Extraarticular disease

TEAR Trial: RCT in early RA Immediate MTX+HCQ+SSZ (Triple Therapy)

Immediate MTX+ etanercept

Step up from MTX to triple therapy

Step up from MTX to MTX+etanercept

If DAS > 3.2 at 6 months DAS28 at 2 years

2.9

3.0

2.8

3.1

ACR20 at 6 months (%)

64.0

63.6

47.7

45.2

ACR50 at 6 months (%)

38.6

35.5

21.5

22.1

ACR70 at 6 months (%)

11.4

13.1

4.7

3.2

Moreland LW et al. ACR Annual Meeting, October 2009, Abstract #1895.

Limitations of traditional DMARDs  Lack of efficacy in some patients  May not slow radiographic progression  Toxicity (less common reason for discontinuation)

SWEFOT Trial  Early RA  Start MTX first up to 20mg/wk  If DAS high after 3-4 months, randomized to add

either SSZ+HCQ vs. infliximab  Open label

 Primary outcome: 1 year EULAR good response  Achieved in 25% on SSZ+HCQ vs. 39% on infliximab

(p=0.016)

van Vollenhoven RF et al. Lancet 2009;374:459

Rheumatoid Arthritis Approach to Therapy Triple Drug Therapy Triple Drug: 77% get 50 % improvement

Methotrexate: 33% Plaquenil/Sulfasalazine: 40%

O’Dell, NEJM vol. 334, pp 1287-1291

Major Paradigm Shift in RA  Treat early and aim for low disease activity  Many more options leading to:  New goal of treatment  REMISSION

Cytokine Signaling Pathways Involved in Inflammatory Arthritis

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

TNF inhibitors  Generally accepted as first-line biologics  Add to methotrexate when disease activity remains

moderate to high after adequate trial  Five different agents available

TNF Antagonists: Contraindications  Current active infection  Chronic or recurrent infections  History of TB or positive PPD (untreated)    

Congestive heart failure Recent malignancy Systemic lupus erythematosus Multiple sclerosis, optic neuritis

Cumulative incidence of tuberculosis (TB) following first exposure to anti-tumour necrosis factor (anti-TNF) therapy (most recent drug model, with person-years censored at death, last returned follow-up form, or date of switching to second anti-TNF).

Dixon W G et al. Ann Rheum Dis 2010;69:522-528

©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

How long do I have to take this?  Goal: treat to remission  Next goal: drug-free remission  Can early aggressive treatment induce drug-free or

biologic-free remission?  Treat early in disease  Obtain remission  Withdraw agents

ALHAMDULILLAH…

RRR Trial  Remission Induction by Remicade in RA  Low disease activity (DAS < 3.2) for 24 weeks on infliximab  114 patients had infliximab discontinued  102 re-evaluated at year 1  56 patients (55%) continued to have low DAS  In those who failed, retreatment with infliximab occurred

Tanaka Y et al. Annals Rheum Dis 2010;online first as 10.1136/ard.2009.121491

How to approach failure of TNFi  TNF inhibitors are not universally efficacious  Options after TNF inhibitor failure:  Within-class switching

 TNF to non-TNF class biologic switch  Rituximab  Abatacept  Tocilizumab

 Future direction: biomarkers to direct choice

Buch MH. Curr Opin Rheumatol 2010;22:321

Cautions with DMARDs  Most combinations are acceptable  Do not combine 2 biologic agents  Risk of infection  Use caution combining methotrexate and leflunomide  Risk of liver toxicity

Vaccines and Biologics  Avoid live vaccines in patients on all biologics  FluMist (seasonal or H1N1 nasal)  Zoster  MMR  Other vaccines are recommended  Seasonal and H1N1 influenza  Pneumovax

Rheumatoid Arthritis History  Onset: Weeks to Months  Can be Palindromic onset  Can have pauciarticular onset  Constitutional features  Morning stiffness lasting for hours  Functional Questions

Rheumatoid Arthritis Deformities

Atlantoaxial Instability MRI

Rheumatoid Arthritis How do we proceed?  Aggressive approach, <5 yr disease, monthy followup  DAS calculated monthly

 Aggressively escalating therapy  Goal: DAS remission or low disease activity  Results: ACR 50 = 84% vs 40% standard tx.  Decrease erosions  Total Costs less Grigor, Lancet, Vol. 364, pp. 263-269

PATHOPHYSIOLOGY  T-cell activation triggered by unknown Ag  B lymphocyte act as APC in synovium  Ab &

proinflammatory cytokines  Characterized by synovial inflammation (hyperplasia & increased vascularity (pannus)) enlarge membrane invade cartilage & bone more profound destruction, subchondral bone erosion, periarticular ligament laxity  Cytokines stimulate osteoclast activityn erosion & periarticular osteoporosis