Rheumatoid arthritis is a progressive, systemic autoimmune disease characterized by chronic inflammation that can lead to joint destruction if left untreated. It is most common in women aged 35-60 years. Complications can affect many body systems and include rheumatoid nodules under the skin, vasculitis reducing blood supply to tissues, lung fibrosis, heart failure, and neurological issues like carpal tunnel syndrome. Aggressive management including medications targeting cytokines like TNF-alpha and IL-6 can help control the disease.

2. Rheumatoid Arthritis (RA): Definition
 Progressive, systemic, Autoimmune inflammation
 Often aggressive, devastating consequences
 Unknown etiology (auto immune, ?infection, smoking)
 Characterized by
Symmetric synovitis – Chronic Polyarthritis
Joint erosions, cartilage and bone destruction
Multisystem - extra-articular manifestations
Onset usually slow & insidious over months
In 15 to 20% may have rapid or acute
Aggressive management leads to good control

3. Rheumatoid Arthritis (RA): Epidemiology
 Prevalence of - 0.8% to 2.1% of the population
 Gender predilection ratio – Women: Men – 3:1
 Prevalence increases with age – Juvenile RA
 About 40-60% have severe disease – 3 fold  mortality
 Median life expectancy is shortened by 3 to 7 years
 Onset mostly between ages of 35 – 60 years
 Genetic – HLA-DRB1 – Class II HCA
 Exact etiology is not known

4. Risk Factors
Gender
Women are more predisposed to
RA than men1
Genetic
HLA-DRB1 and PTPN22 gene
polymorphisms3
Family history
Environment
Low level of education, exposure
to manual labour, socio-
economic status and geographic
location (living in lower latitudes)2
Behaviour
Smoking is strongly associated
with RA pathogenesis2
Caffeine?
1. Goronzy JJ & Weyand CM. Arthritis Research and Therapy. 2009.
2. Liao KP, Alfredsson L & Karlson EW. Curr Opin Rheumatol. 2009.
3. Costenbader KH, Chang S-C & De Vivo I, et al. Arthritis Research & Therapy. 2008.
? Bacterial or Viral Agent
– Parvovirus, Hepatitis, Lyme, and Rubella

5. Rheumatoid Arthritis: Pathogenesis
5
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15
B cell
T cell
Antigen-
presenting
cells
B cell or
macrophage Synoviocytes
Pannus
Articular cartilage
Chondrocytes
Macrophageother
cytokines
IFN- &
Production of collagenase and other
neutral proteases
Osteoclast
TNF
IL-1
Rheumatoid
Factors, ant
i-CCP
Immune complexes
Bone
Complement
Neutrophil
Mast cell
Current
Treatment
Targets

6. Immunology of RA

7. Imbalance in Mediators – Chronic Inflammation
7

8. The Mediators of Joint Destruction
Immune
destruction
Cytokines
TNF 
Chemokines
IL-1, IL-6
MMP
VEGF

9. IL-6 Has Numerous Articular Effects in RA1,2
Synoviocytes
Osteoclast activation
bone resorption
Endothelial cells
VEGF
Pannus formation
Joint destruction
Mediation of chronic
inflammation
IL-6Macrophage
T-cell
B-cell
Neutrophil
Antibody
production
Adapted from 1 Choy E. Rheum Dis Clin North Am. 2004;30:405–415.
2 Gabay C. Arthritis Res Ther. 2006;8(suppl 2):S3.

11. Complications of Rheumatoid
Arthritis
Rheumatoid Arthritis: Diagnosis-
Stage-Functional Classes
Current Management of Rheumatoid
Arthritis
11
Aims

12. Rheumatoid nodules
• Painless firm lumps that
appear beneath the
skin, often single or
multiple, and range in
size from millimeters to
centimeters in
diameter occur on the
underside of the
forearm and on the
elbow.

13. Rheumatoid nodules
• But they can also occur
on other pressure
points, including the
back of the head, the
base of the spine, the
Achilles tendon, and the
tendons of the hand

14. Rheumatoid nodules
• Occur in about 25% of
patients
• More common in men
than women

15. Rheumatoid nodules
• These nodules may
move easily when
touched or they may be
fixed to deeper tissues
and cause pressure on
surrounding nerves or
can rupture, causing
pain and discomfort in
surrounding tissue.

16. Rheumatoid nodules
• Although nodules are
mostly
benign, complications
such as
infection, ulceration, an
d gangrene can occur
following breakdown of
skin overlying the
nodules.

17. Rheumatoid nodules
• Usually no treatment is
necessary unless
nodules become
debilitating, ulcerated,
or infected. Surgical
removal may be
performed.

18. Skin complications of RA
• Skin and muscles become
atrophic (thin and
wrinkled), making it fragile
and easy to bruise .

19. Skin complications of RA
• Skin on the back of the
hands may become pale
or even translucent
• Nails may become
brittle and split length-
wise

20. Skin complications of RA
• The palms become
reddened (palmer
erythema)

21. Skin complications of RA
• A rare, serious
complication, usually with
long-standing rheumatoid
disease, is blood vessel
inflammation (Vasculitis).
Vasculitis can impair blood
supply to tissues and lead to
tissue death (necrosis). This
is most often initially visible
as tiny black areas around
the nail beds or as leg
ulcers.
• Atrophic skin

22. Skin complications of RA
• Dark purplish areas on
the skin (purpura) are
caused by bleeding into
the skin from blood
vessels damaged by
rheumatoid arthritis.

23. Skin complications of RA
• Rheumatoid Vasculitis can
cause many internal
symptoms, , hepatomegaly
(enlarged
liver), splenomegaly
(enlarged spleen), bowel
ulcers, and haematuria
(blood in urine).

24. Skin complications of RA
• Skin ulcers (usually leg
ulcers) may be extensive
and painful
• Petechiae (purplish spots)
or purpura
• Nail fold or edge breakdown
• Gangrene

25. RA - Vasculitis

26. Skin complications of RA
• Neutrophilic dermatoses
• Neutrophils are a type of
white blood cell
(leucocyte). They are
present in bacterial
infections. They are the
prominent cell seen on
skin biopsy of some
uncommon inflammatory
skin diseases known as
neutrophilic dermatoses.

27. Skin complications of RA
• Sweet disease and
pyoderma
gangrenosum are other
neutrophilic disorders
sometimes seen in
association with
rheumatoid arthritis.
• Pyoderma
gangrenosum

28. Skin complications of RA
• Interstitial granulomatous
dermatitis.
• also known as
‘rheumatoid
papules’, interstitial
granulomatous dermatitis
presents as skin coloured
or red papules often on
the trunk. It is rare.

29. Skin complications of RA
• RA can affect the glands
located near the eyes and
mouth, resulting in a
condition called secondary
Sjogren's syndrome
• Decreased tear and saliva
production can cause dry
mouth, and dry eyes.
• Sjogren's syndrome

30. GASTRO-INTESTINAL COMPLICATIONS
• Dry mouth, related to Sjogren syndrome, is the most
common symptom of gastrointestinal involvement.
• Gastritis (stomach inflammation) or stomach ulcer
caused by NSAID therapy.

31. Urinary complications of RA
• The kidneys are not usually affected directly
by rheumatoid arthritis. Kidney problems in
rheumatoid arthritis are much more likely to
be caused by medications used to treat the
condition.

32. Hematological complications of RA
• Anemia
• Low white blood cell count (leukopenia) can
occur from Felty's syndrome, a complication
of rheumatoid arthritis that is also
characterized by enlargement of the spleen.

33. Hematological complications of RA
• Immune thrombocytopenic purpura caused by
an autoimmune reaction against platelets.
• drug induced neutropenia;
thrombocytopenia, particularly autoimmune
and drug induced thrombocytopenia; and
hematological malignancy.

34. Neurological

35.  Carpel Tunnel Syndrome
 Due to compression of the medial nerve by
swelling around the wrist.
 Atlanto-Axial Subluxation
 Erosion of the odontoid process and/or transverse
ligaments in the cervical spine’s connection to the
skull.
▪ Vertebrae begin slipping over one another and compress
the spinal cord.
▪ Clumsiness is initially experienced, but without due care this can
progress to quadriplegia.
 Quadriplegia :: paralysis of all four extremities.

36. Nervous complications of RA
• Entrapment of
nerves. Carpal
tunnel syndrome
or ulnar nerve
neuropathy
• including sensory
or motor
neuropathy (loss
of sensation)

38. Nervous complications of RA
• Formation of a Baker's
cyst (a cyst filled with
joint fluid and located in
the hollow space at the
back of the knee).
• Its herniation of
posterior capsule

39. RESPIRATORY COMPLICATIONS OF RA
• CAPLANS SYNDROME
• The combination of RA and exposure to coal
dust produces the condition. It develops
especially in miners working in anthracite
coal-mines and in persons exposed to silica
and asbestos.

40. RESPIRATORY COMPLICATIONS OF RA
• CXR shows
multiple, round, well
defined nodules, usually
0.5 - 2.0 cm in
diameter, which may
cavitate and resemble
tuberculosis. CT
scanning gives a better
picture of cavitation.

41. RESPIRATORY COMPLICATIONS OF RA
• well defined
nodules, usually 0.5 -
2.0 cm in
diameter, which may
cavitate and resemble
tuberculosis.

42. RESPIRATORY COMPLICATIONS OF RA
• The syndrome is named
after Dr. Anthony
Caplan, a physician on
the Cardiff
Pneumoconiosis Panel.

43. RESPIRATORY COMPLICATIONS OF RA
• Fibrosis of lung
scattered all over lung

44. The Heart & Blood Vessels

45. • Myocardial Infarction
– Commonly known as a heart attack.
• Occurs when the blood supply to part of the heart is
interrupted causing some heart cells to die.
• Disambiguation
– Stroke.
• The rapid loss of brain function(s) due to disturbance in
blood supply to the brain.
• Atherosclerosis
– The abnormal narrowing of an artery.
• The condition in which an artery wall thickens due to a
build up of fatty materials such as cholesterol.

46. • Other conditions of the heart caused by RA:
– Pericarditis
• Inflammation of the pericardium – the sac that contains
the heart and the roots of the great vessels.
– Endocarditis
• Inflammation of the inner layer of the heart.
– Left Ventricular Failure
• Commonly known as heart failure.
– Valvulitis
• Inflammation of one or more of the heart valves.

47. OCULAR COMPLICATIONS OF RA
• RA can also cause inflammation of the sclera (white
part of the eye), which may make the sclera appear
red or bluish in color.

48. OCULAR COMPLICATIONS OF RA
• Keratoconjunctivitis
sicca

49. OCULAR COMPLICATIONS OF RA
• Episcleritis

50. OCULAR COMPLICATIONS OF RA
• Scleritis

51. OCULAR COMPLICATIONS OF RA
• Stromal corneal
opacities with
peripheral
vascularisation

52. OCULAR COMPLICATIONS OF RA
• Iridocyclitis.

53. OCULAR COMPLICATIONS OF RA
• Marginal thinning of the
cornea with keratolysis

54. Lysis of bones
• Punched out lytic
changes in bones
• Lytic changes in toes

55. RA - knees
• Joint spaces in knee is
reduced due cartilage
destruction.

56. Cock-up deformity or hammer toes

57. MTP Subluxation
• Abducto hallus vulgus

58. MCP Subluxation
• Subluxation of MCP
joints.

59. Ulnar Deviation

62. Atlantoaxial Instability

63. Bow string sign
• The tendons on the back of
the hand may become very
prominent and tight, called
the bow string sign.
• Ulnar deviation
• The direction of prominent
tendons is like bow string

64. Complications of Rheumatoid
Arthritis
Rheumatoid Arthritis: Diagnosis-
Stage-Functional Classes
Current Management of Rheumatoid
Arthritis
64
Aims

65. Clinical Manifestations of RA
• Chronic and progressive inflammatory
disorder, characterised by synovitis and severe joint
destruction, if left untreated
Feldmann M, Brennan FM & Maini RN. Cell. 1996.
Recent – Onset RA
Moderately Advanced
RA*
Severely Advanced RA

66. 1987 AMERICAN COLLEGE OF
RHEUMATOLOGY CRITERIA FOR RA
• Patients must have 4 of the 7 criteria:
1. Morning stiffness lasting at least 1 hour*
2. Swelling in three or more joints*
3. Swelling in hand joints*
4. Symmetric joint swelling*
5. Erosions or decalcification on x-ray of hand
6. Rheumatoid nodules
7. Abnormal serum rheumatoid factor.
[*Must be present at least six weeks]

67. American Rheumatology Association
Remission Criteria for RA (Eberhardt a Fex 1998)
• 4 or more of the following criteria must be fulfilled for at least
2 consecutive months:
1. Duration of morning stiffness not exceeding 15 min
2. No fatigue
3. No joint pain (by history)
4. No joint tenderness or pain on motion
5. No soft tissue swelling in joints or tendonsheaths
6. ESR<30mm after 1 hour for a female or <20mm after 1 hour for a male

69. Blood Parameters in RA
 Acute Phase Reactants (APR )
 C-Reactive Protein (CRP) - > 4 mg% -
 It is the single most useful marker
 ESR is raised > 30 mm – other confounders
 Ceruloplasmin
 Haptoglobin (Hp)
 Leukocytosis, Nutrophilia
 Normocytic normochromic anemia
 Thrombocytosis
69

70. Synovial Fluid in RA
 No need in general for joint aspiration
 Required to exclude other causes of arthritis
 Inflammatory arthritis picture
 Turbid fluid with reduced viscosity
 Increased protein content
 Decreased glucose content
 WBC count from 2,000 to 50,000/l
 PMNLs predominate
 Total compliment, C3 and C4 are markedly 
70

71. Rheumatoid Factor (RA Factor)
 Developed by Eric Waller in 1937 – Rose Waller Test
 Agglutinating Abs - Latex particle agglutination assay
 Isotype specific enzyme immunoassays – New technique
 Antibodies to Fc portion of our own IgG - These Abs are IgM
 Positive in 5% of normal persons and in only 70-80% of RA
 Low specificity (false +ves) & low sensitivity (false –ves.)
 It is not a screening or Dx. tool – More a prognostic tool
 It is negative in 30% cases of RA – Sero negative RA
 RF are commonly seen other disease – see next slide
71

72. Positive Rheumatoid Factor is seen in:
Disease Frequency
Advanced Rheumatoid Arthritis 100%
Rheumatoid Arthritis (over all) 70%
Sjögren's syndrome 90%
Systemic Lupus Erythematosis (SLE) 30%
Sub acute bacterial endocarditis (SABE) 40%
Tuberculosis 15%
Old Age 20%
Normal healthy individuals 5%
72

73. Anti-CCP Antibody Test in RA (ACPA)
 Antibodies to Cyclic Citrullinated Peptides (anti-CCP)
 Similar sensitivity for RA (70%)
 Specificity for RA (>95%) better than RA Factor
 In early polyarthritis anti-CCP are useful for Dx.
 Anti-CCP are associated with more severe disease
 They spell a poor prognosis and rapid progression
 They may be positive in asymptomatic patients years
before the onset of symptoms
73

74. Serology in Rheumatoid Arthritis
74
Test
RA Factor is IgM Antibody to the Fc portion of the IgG
Anti CCP: Antibodies to Cyclic Citrullinated Peptides

75. Differential Diagnosis of RA
 Connective tissue diseases - Scleroderma and SLE
 Fibromyalgia, Palindromic Rheumatism
 Infectious endocarditis, Acute Rheumatic Fever
 Poly articular gout
 Polymyalgia Rheumatica
 Sarcoidosis, Hemochromatosis
 Sero negative spondylo arthropathies
 Reactive arthritis - evaluate for psoriasis, Reiter’s, IBD
 Still’s disease, Thyroid disease, Viral arthritis
75

76. Rheumatoid Arthritis v/s Osteoarthritis
76
Feature Rheumatoid Arthritis Osteoarthritis
Pathology Autoimmune Degenerative
Age Any age – usually 35+ Increases with age
Joints involved Small joints MCP, PIP Large joints, TIP
Spine (Axial) C1-C2 - Subluxation Lumbosacral
Extra articular Many systemic effects Few systemic effects
Course Rapidly progressive Slowly progressive
Disability Highly disabling Mild to moderate

77. The Joints Involved in RA
77

79. Commonly affected joints
MCP 90-95%
PIP 65-90%
Temporomandibular 20-30%
MTP 50-90%
Ankle 50-80%
Knee 60-80%
Hip 40-50%
Shoulder 50-60%
Cervical spine 40-50%
Elbow 40-50%
Wrist 80-90%

80. Pathology
 RA is generalized disorder of connective tissue
affecting
 Articular structure &
 Extra articular structures

81. Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
Undifferentiated
Polyarthritis
Early RA – Mild
Disease
Severe RA with
Deformities
The Natural Course of RA

82. Progressive changes in joints
 Stage I:
 Inflammation of the synovial membrane spreads to articular
cartilage & other soft tissues.
 Limitation of joint movt with pain & muscle spasm

83. Stage II:
 Granulation tissue formation within synovial membrane
& spread to periarticular tissue.
 Cartilage disintegration & joint filled with granulation
 Thickening of joint capsule, tendon (with sheaths) &
impaired joint movt permanently.

84. Stage III:
 Granulation tissue converted into fibrous tissue with
adhesion formation between tendon, joint capsule &
articular surface.
 Articular surface cover partly by cartilage & partly by
fibrous tissue.

85. Stage IV:
 Permanent joint damage and deformity  disability

86. Rheumatoid Arthritis – ACR Functional Classes
Classification Specifications of activity levels
Class I
Complete ability to perform daily activities
self-care, vocational and avocational
Class II
Ability to perform usual self-care and vocational
activities; limited avocational activities
Class III
Ability to perform usual self-care activities;
limited vocational or avocational activities
Class IV
Limited ability to perform usual self-care or
vocational or avocational activities

87. DAS28 (Disease Activity Scoring) for RA - EULAR
 Calculated using a formula that includes
 Counts for tender and swollen joints – (28 joints)
 General health by the patient (on a scale of 0 to 100)
 A measurement of ESR or CRP
 Score > 5.1 – High disease activity,
 Score 5.1 to 3.2 – Moderate disease activity
 Score < 3.2 – Low disease activity
 Score < 2.6 – Being in Remission
 Response to Rx. –  of ≥ 1.2 – Good and < 0.6 – Poor
European League Against Rheumatism (EULAR)

88. 88

89. FORMULA:DAS28(4) = 0.56*sqrt(t28) + 0.28*sqrt(sw28) + 0.70*Ln(ESR) + 0.014*GH
DAS 28 - Disease Activity Score Calculator for
Rheumatoid Arthritis

90. Extra articular changes
 Nodule formation:
 In the pressure area & may be
subcutaneous or intracutaneous.
 They may present in organs such as
lung & heart.
 Vascular changes:
 It constitute inflammation of all size
arteries.
 The lumen of small vessels can
become obliteration.

91. Rheumatoid Arthritis: Typical Involvement
 Wrist joints and MCP joints - very commonly involved
 Index and middle Metacarpophalangeal joints
 Proximal interphalangeal joints (PIP)
 Metacarpophalangeal joints (MCP)
 Metatarsophalangeal joints (MTP)
 Elbows, Shoulders
 Knees, Ankles, Hips. Lumbosacral area is not involved
 Spine: only Atlanto-axial joint (C1– C2), subluxation
 Terminal interphalangeal (TIPS) joints are not involved
91

95. Rheumatoid Arthritis: Predictors of Prognosis
 Presence of > 20 inflamed joints
 Markedly elevated ESR
 Radiographic evidence of bone erosions
 Presence of rheumatoid nodules
 High titers of RA Factor and anti CCP
 Higher class of functional disability
 Persistent inflammation; comorbidities
 Advanced age of onset
 Low socio-economic status, low education level
 HLA-DR*0401 or DR*0404
95
40%-85% of RA pts unable to work in
8-10 years

96. Complications of Rheumatoid
Arthritis
Rheumatoid Arthritis: Diagnosis-
Stage-Functional Classes
Current Management of Rheumatoid
Arthritis
96
Aims

97. Goals of Therapy
1. Relief of pain
2. Reduction of inflammation
3. Protection of articular structures
4. Maintenance of functional activity
5. Control of systemic involvement
6. Slow the progression of disease
7. Increase the over all quality of life

98. Non Pharmacological Management
 Rest
 Exercise
 Flexibility/stretching
 Muscle conditioning
 Cardiovascular/aerobic
 Diet
 Weight management
 Physical and occupational therapy

99. Therapeutic Window of Opportunity
 Erosive changes occur early in disease
 Even a brief delay of therapy can have a significant
impact on disease parameters years later
 Early DMARD treatment to arrest progression
 MTX is the sheet anchor – Combination of DMARDs
 Bridge the gap initially with NSAID and GC
 Biologics only for refractory case – with caution; cost
 Surgical treatment options in selected patients
O’Dell JR. Arthritis Rheum. 2002;46:283-285.
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.

100. Early RA: The Window of
Opportunity to Intervene

101. Therapeutic Window of Opportunity
 Erosive changes occur early in disease
 Even a brief delay of therapy can have a significant
impact on disease parameters years later
 Early DMARD treatment to arrest progression
 MTX is the sheet anchor – Combination of DMARDs
 Bridge the gap initially with NSAID and GC
 Biologics only for refractory case – with caution; cost
 Surgical treatment options in selected patients
O’Dell JR. Arthritis Rheum. 2002;46:283-285.
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Surgical Treatment will be mandated in
25%

102. MANAGEMENT OF R.A.
 Medications are divided into three main classes
 1.NSAIDs
 2.corticosteroids
 3.DMARDs
 4.BIOLOGICS
 5.Surgery

103. Medical Management – Drug Classes
Classes NSAIDs – Cox-1 & Cox-2 inhibitors
Glucocorticoids – Prednisolone, MP
IAS – Intra articular steroids
DMARDs – MTX, SSZ, HCQ, CQ
Immunosuppressive Rx.– AZT, Leflunomide, CS
Cytotoxic agents – Cyclophosphamide
Biologics – TNF-antibodies, IL-1 R antagonist
Old drugs – Gold salts, D-Penicillamine

104. NSAIDS in RA
NSAIDs
COX 1 COX2
 Selective COX 2 Inhibitors
 Improved GI tolerability
 Reduced effects on RBF
 No effect on platelets
 Called as COXIBs
 May have adverse effect
on heart
 Celecoxib
 Etoricoxib
 Meloxicam
Constituent pathway
Renal and GI
homeostasis
Inducible
pathway
Inflammation

105. NSAID Class of Drugs
Non Selective
 Ibuprofen
 Ketoprofen
 Diclofenac
 Aceclofenac
 Piroxicam
 Lornaxicam
 Naproxen
 Indomethacin
NSAIDs used as analgesics
 Ketorolac
 Aspirin (NSAID)
Selective COX-2
 Celecoxib, Etoricoxib
 Meloxicam
Analgesics
 Tramadol
 Paracetamol

106. Pros and Cons of NSAID Therapy
PROS
 Effective control of
inflammation and pain
 Effective reduction in
swelling
 Improves mobility,
flexibility, range of motion
 Improve quality of life
 Relatively low-cost
CONS
 Does not affect disease
progression
 GI toxicity common
 Renal complications
(eg. Irreversible renal
insufficiency, papillary
necrosis)
 Hepatic dysfunction
 CNS toxicity

107. Pros and Cons of Corticosteroid Therapy
PROS
 Anti-inflammatory and
immunosuppressive effects
 Can be used to bridge
gap between initiation
of DMARD therapy and
onset of action
 Intra-articular steroid (IAS)
injections can be used for
individual joint flares
CONS
 Does not conclusively
affect disease progression
 Tapering and
discontinuation of use
often unsuccessful
 Low doses result in skin
thinning, ecchymoses, and
Cushingoid appearance
 Significant cause of steroid-
induced osteopenia

108. RA Pharmacologic Therapy:
DMARDs
• Methotrexate
• Leflunomide (Arava)
• Sulfasalazine
• Azathioprine
• Mycophenolate Mofetil
• “Corticosteroids”
• “Hydroxychloroquine”
• “Minocycline”

109. Methotrexate (MTX)
 MTX is given 10 to 30 mg orally, IM, or SC per week
 It is DHF reductase inhibitor – Supplemental folic acid
 The clinical improvement takes one to two months
 Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT
 Rare: low WBC & platelets; pneumonitis; sepsis; liver disease;
EBV related lymphoma;
 CBC, creatinine, and LFTs monthly for six months, then every one
to two months; repeat AST or ALT in two to four weeks if initially
elevated, and adjust dose as needed;
 Rapid onset (six to 10 weeks); tends to produce more sustained
results over time than other DMARDs and lowers all-cause
mortality;
 Can be used when cause of polyarthritis uncertain;
 Often combined with other DMARDs like Leflunomide, SSZ, HCQ
109

110. Methotrexate Adverse Events
• GI - Mucositis, diarrhea, abdominal pain
• Hematologic - Cytopenias, macrocytosis
• Hepatic- Transaminitis, fibrosis, and cirrhosis
• Pulmonary - Hypersensitivity
pneumonitis, pulmonary fibrosis
• Infections
• Neoplasia - reversible lymphoproliferative
disorder, lymphoma, and leukemia
• Accelerated nodulosis and vascultitis
• Reproductive – abortifacient and teratogen
– Must use birth control and d/c drug 2-6 months before
planned pregnancy

111. Changing Paradigm of Treatment
•Early
Aggressive Rx.
•Biological
•Combination
treatment
Evolvingparadigm
111
Current Treatment
Traditional DMARDs

113. New Treatment Paradigm for RA
113
Orthopedic surgery
Higher dose steroids
for flares or extraarticular disease
Occupational therapy
Physical therapy
Patient
education
Intraarticular steroids
Simple
analgesic
Weaver AL, 2008.

114. Biological Agents in RA
 TNFα antagonists
 Adalimumab (Humira)
 Etanercept (Enbrel)
 Infliximab (Remicade)
 Interleukin-1 antagonist
 Anakinra (Kineret)
 Suppressors of T-Cell activation
 Abatacept (Orencia)
 Anti B-Cell monoclonal antibody
Rituximab (Rituxan)
 IL-6 receptor
Tocilizumab
114

115. Biologic DMARDs Included in the Comparative
Effectiveness Review
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
Biologic Disease-Modifying anti-rheumatic Drugs
Name Trade Name Target of Activity
Adalimumab Humira® TNF-α
Certolizumab pegol Cimzia® TNF-α
Etanercept Enbrel® TNF-α
Golimumab Simponi® TNF-α
Infliximab Remicade® TNF-α
Abatacept Orencia® CD28
Anakinra Kineret® IL-1
Rituximab Rituxan® CD20
Tocilizumab Actemra®
RoActemra®
IL-6 receptor
Abbreviations: IL = interleukin; TNF-α = tumor necrosis factor-alpha

116. Agent Usual dose/route Side effects Contraindications
Infliximab
(Anti-TNF)
3 mg/kg i.v infusion at wks
0,2 and 6 followed by
maintainence dosing every
8 wks
Has to be combined with
MTX.
Infusion reactions,
increased risk of
infection, reactivation of
TB ,etc
Active infections,uncontrolled
DM,surgery(with hold for 2 wks
post op)
Etanercept
(Anti-TNF)
Active infections,uncontrolled
DM,surgery(with hold for 2 wks
post op)
Adalimumab
(Anti-TNF)
40 mg s/c every 2
wks(fornightly)
May be given with MTX or
as monotherapy
Same as that of
infliximab
Active infections
.
25 mg s/c twice a wk
May be given with MTX
or as monotherapy.
Injection site
reaction,URTI ,
reactivation of
TB,development of
ANA,exacerbation
of demyelenating
disease.

117. Abatacept
(CTLA-4-IgG1 Fusion
protien)
Co-stimulation
inhibitor
10 mg/ kg body wt.
At 0, 2 , 4 wks & then
4wkly
Infections, infusion
reactions
Active infection
TB
Concomittant with other anti-
TNF-α
Rituximab
(Anti CD20)
1000 mg iv at
0, 2, 24 wks
Infusion reactions
Infections
Same as above
Tocilizumab
( Anti IL-6)
4-8 mg/kg
8 mg/kg iv monthly
Infections, infusion
reactions,dyslipidemia
Active infections
Agent Usual
dose/route
Side effects
.
Anakinra 100 mg s/c once
daily
May be given with
MTX or as
monotherapy.
Injection site
pain,infections,
neutropenia
Active infections
Contraindications
(Anti-IL-1)

118. Biologics: Relative Contraindications
118
 Active Hepatitis B Infection
 Multiple sclerosis, optic neuritis
 Active serious infections
 Chronic or recurrent infections
 Current neoplasia
 History of TB or evidence of Koch’s
 Congestive heart failure (Class III or IV)

119. Safety Considerations of Biologicals
119
 Serious Infections
 Opportunistic infections
(TB)
 Malignancies/lymphoma
 Demyelination
 Hematologic
abnormalities
 Administration reactions
 Congestive heart failure
 Hepatic
 Autoantibodies and drug
induced lupus
 Vaccination