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Prof. / Abd El-Azeim Al-HefnyProf. of Internal Medicine, Rheumatology & Immunology

Director of Rheumatology Unite

Ain Shams University

Chronic systemic inflammatory disease

Unknown etiology, association with HLA-DR.

Starts at any age & peaks at30-50y.

It affects ~ 1-2% of the population in USA.

Female/male ratio ~ 3/1

Primarily affects the peripheral joints in Symmetric pattern with exacerbations and remissions .

It has variable extra-articularfeatures

In most cases, RA is a chronic progressive disease that, if left untreated, can cause joint damage and disability with increased morbidity & mortality.

Presentation of an antigen (e.g. bacteria, viruses) by APC"macrophage") activation of T helper cells activation of B cells RF + IgG immune complexes in synovial fluid and blood activation of complement and release of inflammatory mediators, proinflammatory cytokines(TNF,ILK-1,ILK-6) chronic inflammation, granuloma formation and joint destruction.

Synovium in RA. Only modest synovial lining hyperplasia is present, although sublining mononuclear cell infiltration, lymphoid aggregates, and vascular proliferation are prominent

Normal synovium

Synovium in RA

Early RA Intermediate RA Late RA

1. Morning stiffness > 1 hour*

2. Arthritis of 3 or more joint areas* (right & left PIPJs, MCPJs, elbows, MTPJs, ankles, & knees)*

3. Hand arthritis (PIPJs, MCPJs, wrist)*

4. Symmetrical arthritis*

5. S.C. nodules (observed by physician)

6. Positive RF

7. Radiological findings in hand or wrist joints (periarticular osteopenia, erosions)

* = present for at least 6 weeks.

At least 4 criteria should be present to diagnose RA

Joint Effusion

Hand deformities

Chronic synovitis and tenosynovitis result in characteristic joint deformities classic for chronic rheumatoid arthritis. Patients may have swan neck deformities, Boutonniere's sign, ulnar deviation, cock-up toes, or hammer toes.

Hand deformities

Z deformity

Foot deformities

Cock-up toes, or hammer toes in RA

R. nodules, vasculitis, palmar erythema

Atlanto-axial (C1-2 subluxation)

CTS (Median nerve)

Hematologic

Anemia

Leukopenia

(Felty's syndrome)

Leukocytosis

Thrombocytosis

Myocardial

infarction/

Asymptomatic IHD

Rheumatoid lung nodules & pl eff in pt with chronic RA

lung nodules

•20% of patients have SC rheumatoid nodules, most commonly situated over bony prominences but also observed in the bursae and tendon sheaths. (firm, non-tender, freely mobile)•Nodules are occasionally seen in the lungs, the sclerae, and other tissues. •Nodules correlate with the presence of RF ("seropositivity"), as do most other extra-articular manifestations.•all patients with rheumatoid nodules are seropositive for RF.

Radiographic progression of

joint damage

(Conventional radiology)

Increased severity

Both MRI and ultrasonography are more sensitive than radiographs in detecting bony erosions & soft tissue changes in early RA

Higher sensitivity than XR for detection of bone erosions in RA

( M. Szkudlarek et al, eular June,2004)

Ultrasonography in RA

2010 ACR/EULAR

Target Population of the Classification Criteria

Two requirements:

(1) Patient with at least one joint with definite

clinical synovitis (pain, tenderness &

swelling)

(2) Synovitis is not better explained by

“another disease”

Differential diagnoses differ in patients with different presentations.

If unclear about the relevant differentials, an expert rheumatologist should be consulted.

2010 ACR/EULARClassification Criteria for RA

I- JOINT DISTRIBUTION (0-5)1 large joint 0

2-10 large joints 1

1-3 small joints (large joints not counted) 2

4-10 small joints (large joints not counted) 3

>10 joints (at least one small joint) 5

II- SEROLOGY (0-3)Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

III- SYMPTOM DURATION (0-1)<6 weeks 0

≥6 weeks 1

IV- ACUTE PHASE REACTANTS (0-1)Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

What if the score is <6?

Patient might fulfil the criteria…

Prospectively over time

(cumulatively)

Retrospectively if data

on all four domains have been adequately recorded in the past

“JOINT INVOLVEMENT”

- Any swollen or tender joint (excluding DIP of hand and feet, 1st MTP, 1st CMC)

“SEROLOGY”

Negative: ≤ULN (respective lab)

Low positive: >ULN but ≤3xULN

High positive: >3xULN

of “SYMPTOM DURATION”

Refers to the patient’s self-report on the maximum duration of signs and symptoms of any joint that is clinically involved at the time of assessment.

≥6/10 = definite RA

Prognosis

من هنا بدأ المعراج

After 5 years of disease, approximately 30% of patients are unable to work;

After 10 years, 50% have substantial functional disability.

Poor prognostic factors include:-

Persistent synovitis,

Increased clinical severity (more joints).

Early erosive disease (XR), poor functional status

Extra-articular findings .

Positive serum RF, CCP, acute-phase reactants (ESR,CRP)

Family history of RA,

Male sex, lower socioeconomic factors (level of education)

Advanced age.

Complications

RA is not a benign disease. With many complications

Deformities, Disability & handicap

Muscle weakness & wasting, C1-C2 subluxation (intubation)

Tenosynovitis, carpal tunnel syndrome, rupture of extensor tendons, Baker's cyst (pseudo thrombophlebitis).

Secondary amyloidosis, focal GN, possible membranous nephropathy

Osteoporosis

Rheumatoid vasculitis (2ry Vasculitis), PVD

Lymphatic obstruction , Lymphoproliferative disorder

Anemia: GI bleeding, anemia of chronic disease

Interstitial pulmonary disease, pulmonary nodules, …

Episcleritis and scleritis

2ry Sjögren's syndrome

Pericarditis, myocarditis, IHD & accelerated atherosclerosis

•The most common cause of

death (45%) in RA patients.•Chung CP, Avalos I, Raggi P, Stein CM. Atherosclerosis and inflammation:

insights from rheumatoid arthritis. Clin Rheumatol. 2007;26(8):1228-1233.

Cardiovascular

disease

•The 2nd most common cause of

death

•Sites: Lung , Skin , Joints

Infection

•Lymphoma , lung cancer and

•non-melanoma skin cancerMalignancies

Updates & Challenges In

REMISSION IS THE MISSION

RA is not a benign disease.

40% of patients with RA develop joint erosions on x-ray within the first year and 75% do so within 2 years after the onset of symptoms.

By MRI, joint damage can occur as early as 4 weeks after onset of symptoms.

In one study, 45% of patients with RA developed joint erosions within 4 months.

About 15% are classified as having serious illness, which prognostically is equivalent to 3-vessel CAD.

The targets of treatment are to :

◦ Obtain remission or (if not possible) LDA

◦ Maintain remission

◦ Prevent flares & complications (deformities, amyloidosis)

◦ Treat any complication if occurred

Early diagnosis & early referral to a

rheumatologist are essential for proper management.

When?

• Early aggressive therapy (in the window of opportunity

ie. within the first 3 month of onset) ,

Why?

• To prevent the risk of bone erosions, joint destruction

& deformity (treat to target = t2t)

• Decreases the development of CVD & other co-

morbidities

• improves patient’s survival and quality of life.

A) Synthetic DMARDs (mono or combin.):MTX , Leflunomide , SSZ, HCQ , CS

C) Biologic DMARDs1. TNF blockers2. Targeting T cells 3. Selective B cell depletion4. IL1 inhibitor5. IL-6 inhibitor

D) Combination Therapy: MTX + Biologic therapy

B) Bridge Stage TherapyNSAIDs , CS

Drug Onset Dose Side effects

MTX One

month

7.5-25 mg/week, PO (on

an empty stomach) if >20

mg (SC or IM).

(Tab. 2.5 mg) (Vial 50 mg)

Add 1 mg folic acid daily

to guard against GI&

hematol. complications

GIT (Nausea,

vomiting).

Blood S/E: rare

Contraindicated in

renal or hepatic

disease.

Monitoring: CBC, LFTs (AST or ALT) monthly .BUN & Na, K/6-12Mns.

SZZ 3-6 Mo 2-3 g PO, Enteric coated,

with meal.

Tab 500 mgMonitoring: CBC , LFTs /m for 3ms; then /3ms.

Allergic manifestation

GIT: (nausea &

vomiting).

HCQ 3-6 Mo 6.5mg/kg in 2doses

200-400 mg/d PO

Retinal examination

every 6 month - 1 year

Retinopathy is v. rare

and is reversible.

Nausea, rash

Skin hyperpigment.

Drug

Onset

of

action

Dose Side effects

Leflunomide One

month

100 mg loading 3 days?

Then 20 mg/d.

Most experts no longer

use a loading dose

because of increased side

effects esp. if combined

with MTX.

Falling of hair.

Diarrhea, nausea

Increase liver enzyme

but s. albumin and PT

are normal.Monitoring: CBC . LFTs and BP/m for the first 6 months and then 2ms.

Corticostero

ids.

Hours Not >7.5-10 mg/d.

+ calcium & vit. D.

HTN, DM

Osteoporosis.

DEXA/yr +/- Bisphos.

(Avara,

Apetoid,

Arthfree,

Vamid)

The most widely used combinations

include:

MTX, SSZ, and HCQ with or without

prednisolone

MTX plus leflunomide

- Leflunomide-MTX

-SSZ- HCQ 3-6 Months

DMARDs (1-6 Mo)

start Onset of action

`

one month

- CS Hours

DMARDs has no analgesic effect

Symptoms modifying and not disease modifying drugs

(SMARDS) (i.e.) do not stop the progress of the

disease, so used during the bridge stage because

DMARDs has no analgesic effect.

NSAIDs

D M A R D sSTART

Onset of

action

A key mechanism is the interference with the synthesis of pro-inflammatory prostaglandins by inhibition of COX enzyme; isoform COX-2.

Traditional NSAIDs, however, also inhibit the COX-1 isoform, which may affect platelets and GI mucosa leading to gastrointestinal mucosal injury.

COX-2 selective NSAIDs have a better GI safety, but may induce CV complications with prolonged use??

Alternatively, reduction in gastrointestinal toxicity can be obtained by co-administration of traditional NSAIDs + PPI.

Taken in the morning (8-10 am) low dose < 10mg/d

gives a rapid relief of symptoms because:

it inhibits cytokines: (Anti-IL1, 2, Anti-TNFa) Anti-

COX, NSAIDs action, so they have actions equivalent

to DMARDs, NSAIDs & Anticytokines.

As well as inhibits lymphocyte proliferation and

antigen presentation.

GC were used only during the bridge stage but now,

are used in the combination therapy because it has a

(DMARD) effect

decrease side effects when used with Ca & Vit. D and

in a dose <10 mg/d (7.5mg) + Bisphosphonates

Adverse effects: Osteoporosis, hypertension, hyperglycemia, fluid

retention and premature atherosclerosis.

Calcium and vitamin D supplements should be added if use of glucocorticoids is planned for more than 3 months

Ask for DEXA during follow up + Bisphosphonates.

Intra-articular GC are not associated with significant systemic adverse effects, and are used to control inflammation in mono- or oligoarthritis.

Biological therapy

I) TNF blockers as1. Etanercept= Enbrel 50 mg SC /week

2. Infliximab = Remicade 5 mg/kg IV infusion at weeks 0 , 2 , 6 , then every 8 weeks

3. Adalimumab = Humira 40 mg/2weeks SC

4. Golimumab = Simponi 50mg SC injections/month

Biological therapy

II) Non-TNF blockers1. IL-I receptor blocker [Anakinra=Kineret]

100mgSC/day

2. Ant-B cell therapy (Rituximab=Mabthera) 1000mgIVI/6 months

3. Anti T-cell therapy (Abatacept=Orencia) 500 – 1000mg IVI /m

4. IL-6 antagonist [Toscilizumab=Actemra] 8mg/kg/month IVI & can be used without MTX.

Biological therapy

54

Increased risk of bacterial infection

Screening for latent TB ( chest X ray &tuberculin)

CHF grades III & IV (Anti –TNF is contraindicated)

Optic neuritis and demylenating diseases (Anti –TNF is contraindicated).

Significant coronary artery disease

Skin malignancy

COPD

Viral infection HCV or HBV (viral replication)

Avoid Vaccination with live vaccine (German measles or oral polio or rabies )

Temporarily suspended in patients underlying surgery > one week before & after surgery.

D) Combination Therapy

MTX + Biologic therapy

Combination between MTX and biologic therapy provides greater benefit in improving signs & symptoms

Preventing radiographic deterioration and improving physical function in comparison to monotherapy

No combination of biologic therapy because of higher rate of adverse effects & lack of any additive effect .

Don’t shift to another biologic except after at least 3 month.

Surgical treatment◦ Synovectomy (partial or total)

◦ Correction of deformities

◦ Arthroplasty

◦ Arthrodesis

Rehabilitation

How to select dugs for every patient??????

Assessment Of Disease Activity

CategoriesVariablesMeasure

Remission <2.6

LDA <3.2, MDA ≤5.1,

HDA >5.1

SJC28, TJC28,

APR(ESR or CRP),

PGA

DAS28

Remission ≤3.3,

LDA ≤11, MDA ≤26,

HDA >26

SJC28, TJC28,

APR(ESR or CRP),

PGA, MGA

SDAI

(Simplified Disease

Activity Index)

Remission ≤2.8

LDA ≤10, MDA ≤22,

HDA >22

SJC28, TJC28,

PGA, MGA

CDAI

(Clinical Disease Activity

Index)

van Gestel AM, et al. J Rheumatol. 1999;26:705-711.

Smolen JS, et al. Rheumatology (Oxford). 2003;42:244-257.

Wolfe F, et al. J Rheumatol. 2001;28:1712-1717.

28 Swollen JC

28 Tender JC

1. Objective arthritis: ◦ Swelling, effusion◦ Limitation of movement◦ Tenderness◦ Pain on motion◦ Joint warmth

2. Continuous arthritis > 6 W, in a child < 16yrs; of unknown etiology.

3. Exclusion of other chronic arthritis (≈100)4. No specific test to establish the diagnosis

IT IS A DIAGNOSIS OF EXCLUSION.

Classified according to onset within the first 6 months.

Classification of JIA

1-

2-

3-

4-

5-

6-

7-

Woo P (2006) Systemic juvenile idiopathic arthritis:Nat Clin Pract Rheumatol 2: 28–34 doi:10.1038/ncprheum0084

Arthritis with, or preceded by, daily fevers of at least 2 weeks' duration, quotidian fever for at least 3 days, and the presence of at least 1 of:

(i) evanescent, non-fixed, erythematous rash;

(ii) generalized LNopathy;

(iii) hepatosplenomegaly.

(iv) Serositis .

Pale pink, blanching, transient (minutes-hrs), nonpruritic small rash Found on the trunk & extremities Worsen with fever.

Systemic-onset JIA

Typical pale-pink, macular rash

Woo P (2006) Systemic juvenile idiopathic arthritis: diagnosis, management, and outcomeNat Clin Pract Rheumatol 2: 28–34 doi:10.1038/ncprheum0084

Typical quotidian fever of systemic juvenile idiopathic arthritis, which is resistant

to high-dose oral prednisone (>1mg/kg)

Daily recurrent fevers of at least 2 weeks' duration, for at least 3 days/w (rises > 39C & returns to < 37 between fever spikes).

UVEITISERAsJIApoJIAoJIA

Topical steroid

Sulfasalazine (Male+periph.j)

NSAIDs/steroid (fever, serositis)

MTXNSAIDs

MTXAnti-TNFIL-1 , IVIG, Sulfa/lefluoIAsteroid

InfliximabIL-6 antagonist Anti-TNFAs poJIA

TTT of ps-JIA:It can be presented as oligo-, poly-, or ERA; so it should be treated as the parallel JIA subset.

Indeed, there are strong indications that patients should

be treated aggressively as early as possible with MTX

(10mg/m2/w + folic acid) & if not controlled the use of

biologics should be considered for best outcome.

NSAIDs (eg, ibuprofen, 800 mg 3-4 times daily) or naproxen (500 mg twice daily)

Corticosteroids, prednisone dose is 0.5 -1mg/kg /day.

Pulse methylprednisolone IVI (0.5-1g/d for 3d) for life-threatening disease

Hydroxychloroquine, & methotrexate and biologic agents (anti-TNF, IL-1a, & rituximab) in refractory cases.

2013 EULAR recommendations

for the management of RA

2013 EULAR recommendations

for the management of RA

2013 EULAR recommendations

for the management of RA