Simplified knowledge about the diagnosis & medical treatment of RA for undergraduates & GPs.

1. 1

2. Prof. / Abd El-Azeim Al-Hefny
Prof. of Internal Medicine, Rheumatology & Immunology
Director of Rheumatology Unite
Ain Shams University

3.  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

4.  Primarily affects the peripheral
joints in Symmetric pattern with
exacerbations and remissions .
 It has variable extra-articular
features

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

6. 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.

7. 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

10. Early RA Intermediate RA Late RA

12. 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

15. Joint Effusion

16. 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.

18. Hand deformities
Z deformity

19. Foot deformities
Cock-up toes, or hammer toes in RA

20. 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

21. Rheumatoid lung nodules & pl eff in pt with
chronic RA
lung
nodules

22. •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.

23. Radiographic progression of
joint damage
(Conventional radiology)
Increased severity

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

28. Higher sensitivity than XR for detection of bone erosions in RA
( M. Szkudlarek et al, eular June,2004)
Ultrasonography in RA

29. 2010 ACR/EULAR

30. 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.

31. 2010 ACR/EULAR
Classification 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

32. Prognosis
‫المعراج‬ ‫بدأ‬ ‫هنا‬ ‫من‬

33.  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.

34. Complications

35.  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

36. •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 cancer
Malignancies

37. Updates & Challenges In
REMISSION IS THE MISSION

38.  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.

39.  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.

40. 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.

42. A) Synthetic DMARDs (mono or combin.):
MTX , Leflunomide , SSZ, HCQ , CS
C) Biologic DMARDs
1. TNF blockers
2. Targeting T cells
3. Selective B cell depletion
4. IL1 inhibitor
5. IL-6 inhibitor
D) Combination Therapy: MTX + Biologic
therapy
B) Bridge Stage Therapy
NSAIDs , CS

43. 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 mg
Monitoring: 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.

44. 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)

45. The most widely used combinations
include:
 MTX, SSZ, and HCQ with or without
prednisolone
 MTX plus leflunomide

46. - Leflunomide
-MTX
-SSZ
- HCQ 3-6 Months
DMARDs (1-6 Mo)
start Onset of
action
`
one month
- CS  Hours
DMARDs has no analgesic effect

47. 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 s
START
Onset
of
action

48.  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.

49.  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

50. 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.

51. Biological therapy

52. I) TNF blockers as
1. 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

53. II) Non-TNF blockers
1. IL-I receptor blocker [Anakinra=Kineret]
100mgSC/day
2. Ant-B cell therapy (Rituximab=Mabthera) 1000mg
IVI/6 months
3. Anti T-cell therapy (Abatacept=Orencia) 500 – 1000
mg IVI /m
4. IL-6 antagonist [Toscilizumab=Actemra] 8mg/kg/
month IVI & can be used without MTX.
Biological therapy

54. 54

55.  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)

56.  Avoid Vaccination with live vaccine (German
measles or oral polio or rabies )
 Temporarily suspended in patients underlying
surgery > one week before & after surgery.

57. 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.

58.  Surgical treatment
◦ Synovectomy (partial or total)
◦ Correction of deformities
◦ Arthroplasty
◦ Arthrodesis
 Rehabilitation
How to select dugs for every patient??????

59. Assessment Of
Disease Activity

60. 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.

61. 28 Swollen JC
28 Tender JC

63. 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.

64. Classified according to
onset within the first 6
months.
Classification of JIA
1-
2-
3-
4-
5-
6-
7-

65. 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

66. Woo P (2006) Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome
Nat 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).

67. UVEITISERAsJIApoJIAoJIA
Topical
steroid
Sulfasalazine
(Male+periph.j)
NSAIDs/steroid
(fever, serositis)
MTXNSAIDs
MTXAnti-TNFIL-1 , IVIG,Sulfa/lefluoIA
steroid
InfliximabIL-6 antagonistAnti-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.

68.  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.

70. 2013 EULAR recommendations
for the management of RA

71. 2013 EULAR recommendations
for the management of RA

72. 2013 EULAR recommendations
for the management of RA