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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
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