The document provides an overview of advancements in the treatment of rheumatoid arthritis. It discusses the disease characteristics and course, classification criteria, treatment objectives and guidelines, and various therapies including biologics. A case example is presented of a patient with joint pains and symptoms meeting classification criteria for rheumatoid arthritis.

1. Intendedforinternaluseonly.Subjecttolocalregulatoryreviewpriortoexternaluse.
Advancement in Treatment of
Rheumatoid Arthritis
DR A P NAVEEN KUMAR
CHIEF SPECIALIST ( GEN. MED. )
VISAKHA STEEL GENERAL HOSPITAL

2. POINTS TO PONDER

3. POINTS TO PONDER

4. CASE
• 51 male –joint pains – 2 months
• Polyarthritis – large and small , Symmetrical
• No rash , fever and any drug intake
• EMS – 10 joints
• ESR – 32
• Anti CCP - 48

5. Overview
• Rheumatoid Arthritis
– Disease characteristics and course
– Epidemiology and pathogenesis
– Classification criteria
– Treatment objectives & guidelines
– Therapies
– Biologics

6. Features of RA
• Multi-system autoimmune disease
– inflammatory changes in the joints
– Chronic, progressive and disabling disease
• Exact etiology unknown
– Established role for genetic factors
– Suspected role for environmental factors (smoking,
hormonal and infectious)
Alamanos Y and Drosos AA. Autoimmunity Rev 2005;4:130–136; Silman AJ and Pearson JE. Arthritis Res
2002;4(suppl 3):S265-S272.

7. The Burden of RA
• Pain and destruction of the joints
• Loss of function
• Systemic disease
• Chronic disease
• Work disability
• Economic losses
Callahan. Chapter 1. In: Klippel, eds. Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation;2001.p.1-4.

8. Overview
• Rheumatoid Arthritis
– Disease characteristics and course
– Epidemiology and pathogenesis
– Classification criteria
– Treatment objectives & guidelines
– Therapies

9. Features of RA
• Prevalence of 0.5-1.1% in Northern European and North
American areas, 0.3-0.7% in Southern European countries and
0.1-0.5% in developing countries1
• Age of onset peaks in the fifth decade1
• Two-to-three fold more common in women1
• Exact etiology unknown1,2
– Established role for genetic factors
– Suspected role for environmental factors (smoking, hormonal and
infectious agents)
• Higher mortality rates1
– Shortens life span by 3 to 10 years
1Alamanos, et al. Autoimmunity Rev 2005;4:130.
2Silman, et al. Arthritis Res 2002;4:Suppl 3:265-272.

10. An Inflamed Synovium is Central in RA:
Pathophysiology
Feldmann, et al. Ann Rev of Immun 1996;14:397-440.

11. Pathways Involved in Inflammation and
Destruction of the Rheumatoid Joint
• Five stages in disease progression:
– Intracellular signaling and
proliferation
– Adhesion
– Inflammation
– Angiogenesis
– Matrix degradation
• Five key molecules involved:
– TNF-α
– IL-1
– IL-6
– MMP
– Cathepsins
Muller-Ladner U, et al. Nat Clin Pract Rheum 2005;1:102-110.IL: Interleukins; MMP: Matrix Metalloproteinase

12. Role of TNF in the Pathogenesis of RA
Brennan FM & McInnes IB. J. Clin Invest 2008;118: 3537-45.

13. Overview
• Rheumatoid Arthritis
– Disease characteristics and course
– Epidemiology and pathogenesis
– Classification criteria
– Treatment objectives & guidelines
– Therapies

15. Clinical Course of RA
Guerne PA and Weisman MH. Am J Med 1992;16:451-460; Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911
“Kelley's Textbook of Rheumatology”, 2008; “Eular Compendium on Rheumatic Diseases”, Ed. Bijlsma JWJ, 2009
91%
78 %
64 %
65 %
50 %
43 %
38 %
17 %
Joint involvement in RA • Main presenting symptoms:
– Swelling of the joint and/or
joint margins
– Joint tenderness
– Systemic malaise
– Loss of energy
– Severe morning stiffness
Disease Characteristics

16. Joints involved in RA
• Don’t forget the cervical spine!! Instability at
cervical spine can lead to impingement of the spinal cord.
• Thoracolumbar, sacroiliac, and distal interphalangeal joints
(DIP)of the hand are NOT involved.

17. Against the diagnosis of RA

19. • Eligibility for testing with the new criteria:
– Evidence of definite clinical synovitis (swelling) in at least one
joint
– The synovitis is not better explained by another disease
• Classification criteria for RA; a score of ≥6/10 needed for
the classification of having definite RA Scoring based on:
– Number and site of involved joints (0-5)
– Serological abnormality (0-3)
– Elevated acute-phase response (0-1)
– Symptom duration (0-1)
2010 ACR Classification Criteria for RA
Aletaha D et al. Ann Rheum Dis 2010;69:1580-88.

20. Joint involvement One large joint 0
2-10 large joints 1
1-3 small joints* 2
4-10 small joints* 3
>10 joints (at least one small joint) 5
Serology# RF- and ACPA- 0
Low RF+ or low ACPA+ 2
High RF+ or high ACPA+ 3
Acute-phase reactants# Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
Duration of symptoms <6 weeks 0
≥6 weeks 1
*With or without involvement of large joints.
# at least one test result needed for classification . ACPA: Anti-citrullinated protein/peptide antibodies; CRP: C-reactive protein; ESR:
Erythrocyte sedimentation rate
Synovitis plus score of ≥6/10 needed for the classification of definite RA
2010 ACR Classification Criteria for RA
Aletaha D et al. Ann Rheum Dis 2010;69:1580-88.

21. CLINICAL MANIFESTATIONS
• Symmetrical polyarthralgia, morning stiffness, and fatigue are
common
• Morning stiffness results from increases in extracellular fluid
in & around joint
• Later on, there may be limitation of motion due to pain or
joint destruction
• Predilection for wrists and hands; MP joints, PIP joints, and
wrists are first to become symptomatic
• Ulnar deviation, and swan-neck or boutonniere deformities
are common

22. EXTRA ARTICULAR MANIFESTATIONS:
Patients with extraarticular manifestations have –
• High-titer RF
• More severe disability
• Increased mortality rate
• Heart- pericarditis, cardiomyopathy, and valvular
incompetence
• Lungs: Rheumatoid lung (Honeycombed appearance on
CXR due to multiple nodules), Caplan syndrome
(associated with pneumoconiosis), Idiopathic
pulmonary fibrosis, interstitial fibrosis
• Eyes- scleritis (most common ocular complication of
RA), scleromalacia perforans)

23. • Nervous system- mononeuritis multiplex, compression
syndromes such as median neuropathy CTS
• Kidneys- amyloid deposition
• Hematopoietic system- Felty's syndrome (anemia,
splenomegaly, and leukopenia)
• Vasculitis: usually is a non necrotising arteritis of the
small terminal arterials, Skin lesions, leg ulcers,
necrotizing arteritis of the viscera, digital infarctions, and
fever
• Sjogren's syndrome: occurs in 15%; RA +
keratoconjunctivitis sicca, xerostomia

24. CASE
• 48 female – tingling in hands and feet
• Fever and fatigue
• Bodyaches more of arthralgia
• o/e s/o CTS and Peripheral neuritis
• Hb 8.2 ESR 98
• Anti CCP positive

25. CASE
• 38 female
• BTLN – on evaluation restrictive lung disease
• CECT chest - ILD
• Hb 7.8 ESR 110
• Anti CCP positive

26. Cervical Spine in RA
• Cervical spine involvement is common in RA
(upto 90%), more common with long standing
disease and multiple joint involvement
Most common presentations:
• Atlantoaxial subluxation: most common and
may occur in upto 40%
• Atlantoaxial impaction / Basilar invagination
• Lower cervical spine: Joints of Lushka & facet
joints are affected, subluxation may occur at
multiple levels; more common in males, with
steroid use, sero-+ RA, with RA nodules, &
severe RA
• Presentation: neck pain, neurologic involvement,
myelopathy, radiculopathy
• Investigation: Cross table lateral X-ray, MRI

27. Rheumatoid Foot
• Initially, RA involves the forefoot, then the midtarsal
joints, and finally the hindfoot; forefoot is involved
twice as often as the hindfoot
Rheumatoid forefoot
• - Hyperpronation of rheumatoid foot
• - Metatarsalgia
• - Claw toes
Midfoot:
• - Talonavicular arthritis
• - Midfoot hyperpronation
• Hind foot: calcaneovalgus

28. Features less common in RA
1. Enthesistis
2. First MTP joint involvement

29. Rheumatoid Factor (RF)
• Antibodies that recognize Fc portion of IgG
• Can be IgM , IgG , IgA
• 85% of patients with RA over the first 2 years become RF+
• A negative RF may be repeated 4-6 monthly for the first two year
of disease, since some patients may take 18-24 months to become
seropositive.
• PROGNISTIC VALUE- Patients with high titres of RF, in
general, tend to have POOR PROGNOSIS, MORE EXTRA
ARTICULAR MANIFESTATION.

30. Causes of positive test for RF
• Rheumatoid arthritis
• Sjogrens syndrome
• Vasculitis such as polyarteritis nodosa
• Sarcoidosis
• Systemic lupus erythematosus
• Cryoglobulinemia
• Chronic liver disease
• Infections- tuberculosis , bacterial endocarditis, infectious
mononucleosis, leprosy, syphilis, leishmaniasis.
• Malignancies
• Old age(5% women aged above 60)

31. Anti-CCP
• IgG against synovial membrane peptides
damaged via inflammation
• Sensitivity (65%) & Specificity (95%)
• Both diagnostic & prognostic value
• Predictive of Erosive Disease
– Disease severity
– Radiologic progression
– Poor functional outcomes

32. Anti CCP
• Highly specific (90 to 95%)– RA
• Low sensitivity( 60- 70%)
• RF +ve, ACCP +ve  RA
• RF neg, ACCP +ve RA ( = 40% of RF negative RA)
• RF +ve, ACCP neg  RA possible, but exclude other diseases
• RF –ve, ACCP neg  Still RA possible(10- 15%)
• When present, CCP is very reassuring that you have RA

33. Acute Phase Reactants
Positive acute phase reactants () Negative acute phase reactants ()
Mild elevations
– Ceruloplasmin
– Complement C3 & C4
Moderate elevations
– Haptoglobulin
– Fibrinogen (ESR)
– 1 – acid glycoprotein
– 1 – proteinase inhibitor
Marked elevations
– C-reactive protein (CRP)
– Serum amyloid A protein
– Albumin
– Transferrin

34. Relationship Between Inflammation, Radiographic
Progression and DisabilitySeverity(ArbitraryUnits)
0
Duration of Disease (years)
5 10 15 20 25 30
Inflammation
Disability
Radiographs
“In early RA irreversible damage is seen in 60% of patients
within the first 2 years of diagnosis.” Kirwan J. Rheum 1999;26:720.
Saleem et al. Clin Exp Rheum 2006;24:S33.

35. Radiographic Features
• Peri-articular osteopenia
• Uniform symmetric joint space
narrowing
• Marginal subchondral erosions
• Joint Subluxations
• Joint destruction
• Collapse
• Ultrasound detects early soft tissue lesions.
• MRI has greatest sensitivity to detect
synovitis and marrow changes.

36. ACR Response Criteria
≥ 20% / 50% / 70% Improvement in:
• Number of swollen joints (SJC)
• Number of tender joints (TJC)
• Improvement of at least three of the following:
• Patient Global Assessment
• Physician Global Assessment
• Patient Pain Scale
• Health Assessment Questionnaire (HAQ)
• ESR or CRP
Felson DT et al. Arthritis Rheum. 1993; 41: 1564-1570

37. • Disease Activity Score of 28 joints (DAS28). It is widely used as an
indicator of RA disease activity and response to treatment The
joints included in DAS28 are PIP ,MCP joints
,wrists, elbows , shoulders and knees
• When looking at these joints, both the number of joints with
tenderness upon touching (TEN28) and swelling (SW28) are
counted.
• In addition, the ESR is measured.
Score less than 3.2 means pt is inactive
3.2-5.1 means moderately active patient
more than 5.1 means pt is active
Monitoring progression

39. Overview
• Rheumatoid Arthritis
– Disease characteristics and course
– Epidemiology and pathogenesis
– Classification criteria
– Treatment objectives & guidelines
– Therapies

41. Rheumatoid Arthritis Treatment Goals
• Classical objectives:1
– Reduce disease activity
– Decrease disability
– Delay/prevent structural damage
• Current goals:2,3
– Suppression of inflammation and control of
comorbidities and complications2
– Achieve persistent, total disease suppression resulting in
remission. Remission will halt damage, prevent disability,
improve quality of life (QoL) and lower mortality rates3
1van der Heijde D. Ann Rheum Dis 2001;60:iii47-iii50; 2Colmegna I et al. Clin Pharm & Therapeutics 2012;91:607-620;
3Mease PJ. J Rheumatol 2010;37:1570-1578.

42. Medical Management of RA
Symptom control: NSAIDs, corticosteroids
Disease-modifying therapy: DMARDs
Tumor necrosis factor (TNF)-inhibitors
Other biologics/mechanisms of action
Orals: Tofacitinib (approved by FDA November 2012;
Rejected by EMA in April and July 2013)
----- Not considered first line therapies, only symptom control therapies;
NSAID: Non-steroidal Anti-inflammatory Drug

43. Non-Steroidal anti-inflammatories (NSAIDS)
/ Coxibs for symptom control
1) Reduce pain and swelling by inhibiting COX
2) Do not alter course of the disease.
3) Chronic use should be minimised.
4) Most common side effect related to GI tract.

44. Corticosteroids in RA
• Corticosteroids , both systemic and intra-articular are
important adjuncts in management of RA.
• Indications for systemic steroids are:-
1. For treatment of rheumatoid flares.
2. For extra-articular RA like rheumatoid vasculitis and
interstitial lung disease.
3. As bridge therapy for 6-8 weeks before the action of
DMARDs begin.
4. Maintainence dose of 10mg or less of predinisolone daily in
patients with active RA.
5. Sometimes in pregnancy when other DMARDs cannot be
used.

45. Disease Modifying Anti-rheumatic Agents
• Drugs that actually alter the disease course .
• Should be used as soon as diagnosis is made.
• Appearance of benefit delayed for weeks to
months.
• NSAIDS must be continued with them until true
remission is achieved .
• Induction of true remission is unusual .

46. DMARDs
Commonly used Less commonly used
Methotrexate Chloroquine
Hydroxychloroquine Gold(parenteral &oral)
Sulphasalazine CyclosporineA
Leflunomide D-penicillamine/bucillamine
Minocycline/Doxycycline
Levamisole
Azathioprine,cyclophosphamide,
chlorambucil

47. Clinical information about DMARDs
NAME DOSE SIDE EFFECTS MONITORING ONSET OF
ACTION
1) Hydroxycloro
quine
200mg twice
daily x 3 months,
then once daily
Skin
pigmentation ,
retinopahy
,nausea,
psychosis,
myopathy
Fundoscopy&
perimetry yearly
2-4 months
2) Methotrexate 7.5-25 mg once a
week orally,s/c or
i/m
GI upset,
hepatotoxicity,
Bone marrow
suppression,
pulmonary
fibrosis
Blood counts,LFT
6-8 weekly,Chest
x-ray annually,
urea/creatinine 3
monthly;
Liver biopsy
1-2 months

48. Clinical information about DMARDs contnd..
NAME DOSE SIDE EFFECTS MONITORING ONSET OF
ACTION
3)Sulphasala- 2gm daily p.o Rash,
myelosuppressio
n, may reduce
sperm count
Blood counts ,LFT
6-8 weekly
1-2 months
4)Leflunomide Loading 100 mg
daily x 3 days,
then 10-20 mg
daily p.o
Nausea,diarrhoe
a,alopecia,
hepatotoxicity
LFT 6-8 weekly 1-2 months
zine

49. Recommendations for optimal followup laboratory monitoring intervals for
complete blood count, liver transaminase levels, and serum creatinine levels for
patients with rheumatoid arthritis receiving disease-modifying antirheumatic
drugs*
Monitoring interval
based on duration of therapy
Therapeutic agents <3 months 3–6 months >6 months
Hydroxychloroquine None after baseline None None
Leflunomide 2–4 weeks 8–12 weeks 12 weeks
Methotrexate 2–4 weeks 8–12 weeks 12 weeks
Sulfasalazine 2–4 weeks 8–12 weeks 12 weeks

50. When to start DMARDs?
• DMARDs are indicated in all patients with RA who
continue to have active disease even after 3
months of NSAIDS use.
• The period of 3 months is arbitary & has been
chosen since a small percentage of patients may go
in spontaneous remission.
• The vast majority , however , need DMARDs and
many rheumatologists start DMARDs from Day 1.

51. How to select DMARDs?
• There are no strict guidelines about which
DMARDs to start first in an individual.
• Methotrexate has rapid onset of action than other
DMARD.
• Taking in account patient tolerance, cost
considerations and ease of once weekly oral
administration METHOTREXATE is the DMARD of
choice, most widely prescribed in the world.

52. Should DMARDs be used singly or in
combination?
• Since single DMARD therapy (in conjunction with
NSAIDS) is often only modestly effective ,
combination therapy has an inherent appeal.
• DMARD combination is specially effective if they
include methotrexate as an anchor drug.
• Combination of methotrexate with leflunamide are
synergestic since there mode of action is different.

53. EULAR Recommendations for the Management
of Rheumatoid Arthritis with Synthetic and
Biological Disease-Modifying Anti-Rheumatic
Drugs: 2013 Update
Smolen et al. Ann Rheum Dis published
online October 25, 2013
(doi: 10.1136/annrheumdis-2013-204573)

54. 2013 EULAR Recommendations: Phase I
Newly diagnosed RA patients
Smolen J et al. Ann Rheum Dis 2013, epub 25OCT13 (doi: 10.1136/annrheumdis-2013-204573).
**The treatment target is clinical remission according the ACR-EULAR definition or, if
remission is unlikely to be achievable, at least low disease activity (LDA)

55. 2013 EULAR Recommendations: Phase II
Smolen J et al. Ann Rheum Dis 2013, epub 25OCT13 (doi: 10.1136/annrheumdis-2013-204573).
Methotrexate inadequate responders
**The treatment target is clinical remission according the ACR-EULAR definition or,
if remission is unlikely to be achievable, at least low disease activity (LDA)

56. 2013 EULAR Recommendations: Phase III
Smolen J et al. Ann Rheum Dis 2013, epub 25OCT13 (doi: 10.1136/annrheumdis-2013-204573).
Patients failing first TNF inhibitor
**The treatment target is clinical remission according the ACR-EULAR definition or, if
remission is unlikely to be achievable, at least low disease activity (LDA)

57. Drug category Descriptions
• Triple DMARD therapy MTX,SSZ,HCQ.
• DMARD combination therapy Double or triple
traditional/conventional DMARD therapy.
• Low-dose glucocorticoid <10 mg/day of prednisone (or equivalent)
• High-dose glucocorticoid >10 mg/day of prednisone (or equivalent) and
up to 60 mg/day with a rapid taper
• Short-term glucocorticoid 3 month treatment.

58. VACCINES IN RA
• Pneumococcal
• Influenza
• Hepatitis B
• Human papilloma
• Herpes Zoster

59. ADJUVANT DRUGS
• Statin
• Antihypertensives
• Aspirin
• OHA
• Antibiotics
• Calcium and Biphosphonates

60. Pregnancy, lactation and RA
• Stop methotrexate 3 months before pregnancy
• Leflunomide better avoided in child bearing age
group
• Sulfasalazine, HCQ, prednisolone <15 mg/d safe in
pregnancy
• Biologicals - controversial

61. Limitations of conventional DMARDs
1) The onset of action takes several months.
2) The remission induced in many cases is partial.
3) There may be substantial toxicity which requires
careful monitoring.
4) DMARDs have a tendency to lose effectiveness with
time.
 These drawbacks have made researchers look for
alternative treatment strategies for RA- The Biologic
Response Modifiers.

63. How long should Tt. be continued?
• Once remission is achieved , maintenance dose for long period is
recommended.
• Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is
discontinued in most instances.
• DMARDs are discontinued by patients because of toxicity or
secondary failure(common after 1-2 yrs) and such patients might
have to shift over different DMARDs over 5-10 yrs.
• Disease flare may require escalation of DMARD dose with short
course of steroids.

64. Overview
• Rheumatoid Arthritis
– Disease characteristics and course
– Epidemiology and pathogenesis
– Classification criteria
– Treatment objectives & guidelines
– Therapies
– Biologics

65. Important points
•Biologics are effective
•Biologics may be your only medication or part of a
combination approach
•Biologics may increase your risk for infection
•Biologics are usually given by Injection or IV
•Biologics have safety issues
•Biologics require a strict follow-up schedule
• Biologics are expensive

66. Choy EH et al. Nat Rev Rheumatol 2013;9:154-163.
Golimumab
Infliximab
Adalimumab
Certolizumab
Etanercept
Tocilizumab
Abatacept
Rituximab
Tofacitinib
Rheumatoid Arthritis Available Therapies

67. Therapeutic Window of Opportunity
• Erosive changes occur early in disease
• Even a brief delay can have significant impact
on disease parameters on later life
• Early DMARD therapy can reset rate of
progression for years to come

68. Treatment: Earlier The Better

69. Evolving RA Treatment Paradigm
• Current approach • Evolving paradigm
Initial treatment
Traditional DMARDs
Early aggressive
treatment
Biologics
Combination therapy

70. TNF Blockers: Antibodies and Fusion
Proteins
CDR=Complementarity-determining region
PEG=Polyethylene glycol
Human recombinant
receptor/Fc fusion
protein
Humanized
Fab’ fragment
Human
recombinant
antibody
Humanized
monoclonal
antibody
Chimeric
monoclonal
antibody
CDR
TNFR2 (p75)
Fc
Mouse
Human
Fab
Infliximab
Rituximab
Tocilizumab Adalimumab
Golimumab
EtanerceptCertolizumab
pegol
VL VH
CH1Ck
Adapted from Keystone E and Ware C. J Rheum 2010;85:27-39.
Adapted from Feldmann M. Nature 2002; 2(May):364-71.

71. Monoclonal Antibodies and Immunogenicity
High immunogenicity Low immunogenicity
golimumab4
adalimumab2
ustekinumab6
tocilizumab5infliximab2
rituximab2
Fully human
-umab
Humanized
-zumab
Chimeric
-ximab
Murine
-omab
In principle, for a given agent, IV administration is associated with lower immunogenicity
than SC administration3
Adapted from 1Breedveld FC. Lancet 2000; 355:735-40. 2Johnston SL. J Clin Pathol 2007; 60:8-17. 3Clark M. Immunol Today 2000;21:397-
401. 4Keystone E and Ware C. J Rheum 2010;85:27-39. 5RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC);
dated July, 2013. 6Benson JM, et al. mAbs 2011; 3(6):535-45.

72. Characteristics of Biologics
Golimumab Infliximab Etanercept Adalimumab Abatacept
Target TNF TNF TNF TNF T cell
Activation
Half life 12-15 days 8-10 days 3-5 days 10-20 days 13-16 days
Construct Human Chimeric Human Human Human
Dosing Once
monthly
Every 4-8
weeks
Once
biweekly-
weekly
Once biweekly-
weekly
Once
monthly
Route SC IV SC SC IV

73. Treatment Summary
• Early appropriately aggressive intervention in
inflammatory arthritis: Critical to best possible
outcome
• Combination of biologic plus MTX is
frequently more effective than either alone

74. TNFα inhibitors
• Etanercept (Enbrel) :
• MOA: It is recombinant fusion protein consisting of two
soluble TNF p75 receptor moieties linked to Fc portion of
human IgG1, it binds TNFα molecule
• It decreases rate of formation of new erosion
• DOSE: 25 mg twice weekly given s.c.
• SIDE EFFECTS : “Injection site reactions, Increased risk of
infections (Tuberculosis (TB) and fungal infections)

75. Adalimumab
• MOA: It is fully human IgG1 anti TNF monoclonal
antibody complexes with soluble TNFα and prevents its
interaction with cell surface receptors causing down
regulation of macrophages and T-cell function
• DOSE: 40 mg given every 2 weekly given s.c.
• Common side effect : Redness, itching, pain, or swelling
at the injection site, Respiratory infection
• Combination with MTX to improve response

76. Infliximab
• MOA: It is chimeral IgG1 monoclonal antibody that binds
with TNFα
• DOSE:3 mg/kg IV infusion, Weeks 0, 2 and 6; then every
8 weeks Combine with Methotrexate
• SIDE EFFECT: URTI, nausea, headache, sinusitis,
activation of latent , severe allergic reaction with swelling
of the lips, difficulty breathing and low blood pressure

78. • Anakinra (Kineret)- It is recombinant human IL-1
receptor antagonist.
• Used in cases who have failed on others drugs.
• Side effects: local reaction on s/c inj. & chest
infection
S.NO AGENT CLASS DOSE FREQUENCY
1 Anakinra IL-1 receptor
antagonist
100 mg SC Daily
IL-1 RECEPTOR ANTAGONIST

79. IL-6 RECEPTOR ANTAGONIST :
TOCILIZUMAB (Actmera)
• Tocilizumab is a Humanized anti IL-6 monoclonal
Ab that specifically inhibits the action of 1L-6
• It is reserved for Resistant RA
• Side effects : Infusion related reaction (flushing,
headache, fever, nausea, fatigue)
S.NO AGENT CLASS DOSE FREQUENCY
1 Tocilizumab IL-6 receptor
antagonist
IV: 4 mg/kg; may
increase to 8 mg/kg
Every 4 weeks
SC: 162 mg < 100 kg: every other week;
increase to every week
based on clinical response ≥
100 kg: every week

80. • It is recombinant fusion protein.
• MOA: inhibits activation of T cell
• Used when there is inadequate response to DMARDS
A/e : Risk of infections
• Hypersensitivity reaction
S.NO AGENT CLASS DOSE FREQUENCY
1 Abatacept T-Cell
co-stimulation
inhibitor
IV: < 60 kg: 500 mg 60–
100 kg: 750 mg
> 100 kg: 1000 mg
Weeks 0, 2, 4, then monthly
SC: 125 mg Weekly May be initiated with
or without single IV loading
dose If using loading dose,
use weight-based dose above
and start SC injection within
24 hours of the initial IV
infusion
T-Cell co-stimulation inhibitor :
Abatacept (Orencia)

81. RITUXIMAB (RITUXAN OR MABTHERA)
B CELL DEPLETION THERAPY
• Targeting B-lymphocytes in these patients has opened a new therapeutic window
• Chimeric monoclonal Ab, targets CD20 B cells
• Used in resistant RA .
• Combination therapy with Methotrexate
• Dose: 2 IV infusions 2 wks apart
• Side effects: Mild infusion reactions (flushing, headache, fever, nausea,
fatigue)
S.NO AGENT CLASS DOSE FREQUENCY
1 Rituximab Anti-CD 20 1000 mg IV plus 2 IV infusions 2 wks apart
Combine with Methotrexate

82. Janus Kinase enzyme inhibitor/ SYK inhibitor
S.NO AGENT CLASS DOSE FREQUENCY
1 Tofacitinib Janus Kinase
enzyme inhibitor
5 mg PO Days 1 and 15 may retreat every
24 weeks (no sooner than every
16 weeks) Combine with
Methotrexate
• Tofacitinib (Xeljanz) JAK inhibitor
• USE: Similar to biologics in effectiveness and side effects
• Mechanism:
 Oral disease modifying medication
 Targets inflammation signaling pathway
• Oral agents (Biosimiliar):
 Tofacitinib (Pfizer)
 Baricitinib (Eli lilly)
• SYK inhibitor (spleen tyrosine kinase (Syk) inhibitors): Fostamatinib

83. Adverse Effects of Biologics
 Infusion related reactions : Dyspnoea , chest pain , headache, high blood
pressure, dizziness, rash, flushing, hypotension or a “tickle in the throat.”
 Serious Infections
– Tuberculosis and sepsis
 Malignancy : Lymphoma ?, Solid Tumors ?
OTHERS:
 Optic neuritis, Increase LFT
 Severe allergic reaction
 Numbness and Tingling
• Pregnancy: stop before 3 months
• No live vaccines should be given

84. Antibody Formation Across All Indications
REMICADE® (infliximab) EU Summary of Product Characteristics (SmPC); dated August, 2013. HUMIRA® (adalimumab) EU Summary of Product
Characteristics (SmPC); dated April, 2013. CIMZIA® (certolizumab) EU Summary of Product Characteristics (SmPC); dated Nov, 2013.
SIMPONI® (golimumab) EU Summary of Product Characteristics (SmPC); dated August, 2013. ENBREL® (etanercept) EU Summary of Product
Characteristics (SmPC); dated April, 2013. MabThera® (rituximab) EU Summary of Product Characteristics (SmPC); dated April, 2013.
Stelara® (ustekinumab) EU Summary of Product Characteristics (SmPC); dated March, 2013. ORENCIA® (abatacept) EU Summary of Product
Characteristics (SmPC); dated July, 2013. RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC); dated July, 2013.
Range of antibody formation in all clinical trials with or without co-medication
(immunosuppressor) as indicated in the most recent European SmPCs (PIs)
0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%
Infliximab
Adalimumab
Certolizumab
Golimumab
Etanercept
Rituximab
Ustekinumab
Tocilizumab
Abatacept Only infliximab has been
studied with an episodic
treatment strategy.
Since immunogenicity analyses
are product-specific,
comparison of antibody rates
with those from other products
is not appropriate.
(HUMIRA® (Adalimumab) EU Summary of
Product Characteristics (SmPC); April 2013.)
Percentage of Antibody Formation (%)

85. Monoclonal Antibodies and Immunogenicity
High immunogenicity Low immunogenicity
golimumab4
adalimumab2
ustekinumab6
tocilizumab5infliximab2
rituximab2
Fully human
-umab
Humanized
-zumab
Chimeric
-ximab
Murine
-omab
In principle, for a given agent, IV administration is associated with lower immunogenicity
than SC administration3
Adapted from 1Breedveld FC. Lancet 2000; 355:735-40. 2Johnston SL. J Clin Pathol 2007; 60:8-17. 3Clark M. Immunol Today 2000;21:397-
401. 4Keystone E and Ware C. J Rheum 2010;85:27-39. 5RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC);
dated July, 2013. 6Benson JM, et al. mAbs 2011; 3(6):535-45.
Although there is clear evidence that chimeric antibodies are less
immunogenic than murine monoclonal antibodies, little evidence exists
to support claims for further improvement as a result of more elaborate
humanization protocols3

86. Evolution of Antibody Technology
1975 1980 1985 1990 1995 2000 2005 2010
ears
1986
Mouse monoclonal antibodies Ibritumomab
Tositumomab
1994
Chimeric recombinant antibodies
Infliximab
2002
Phage display synthetic antibodies
Transgenic human antibodies
2009
Adalimumab
Golimumab
Adapted from Lonberg N. Nat Biotechnol 2005;23:1117–25.
SIMPONI® (golimumab) EU Summary of Product Characteristics (SmPC); dated August, 2013.

87. Concentration and Injection Volume
• Highly concentrated subcutaneous formulation:
– Golimumab 100 mg/mL
– Adalimumab 50 mg/mL
– Etanercept 50 mg/mL
• Low injection volume:
– Golimumab (Monthly) 50 mg/0.5 mL
– Adalimumab (EOW) 40 mg/0.8 mL
– Etanercept (Weekly) 50 mg/1.0 mL
Note: SIMPONI does not contain citric acid
HUMIRA (adalimumab) Prescribing Information (PI); Abbott Laboratories., dated April, 2013.
ENBREL® (etanercept) Prescribing Information (PI); Amgen Inc., dated April, 2013.
SIMPONI® (golimumab) Prescribing Information (PI); dated August, 2013.
Kay J, and Rahman, M. Core Evidence Arthritis Rheum 2009;4:159-170.
Unlike HUMIRA,
SIMPONI requires no
(painful) citrate as a
stabilizer to prevent
aggregation.
EOW=every other week

88. Dosing Schedule of Various Drugs Including
Golimumab Over One Year
For each product: respective EU SPC
Etanercept
50 mg
Total injections/year
=52
Adalimumab
40 mg
Total
injections/year=26
Certolizumab
pegol 200 mg
Total injections/year
=26*
Golimumab
50 mg
Total injections/year
=12
HUMIRA (adalimumab) Summary of Product Characteristics (SmPC), August, 2013.
ENBREL® (etanercept) Summary of Product Characteristics (SmPC), April, 2013.
CIMZIA® (certolizumab pegol) Summary of Product Characteristics (SmPC), November, 2013.
SIMPONI® (golimumab) Summary of Product Characteristics (SmPC), August 2013.
* EU and US labeling allows
consideration of 400 mg q4 dosing
after initial response has been
confirmed.

89. Patient Experience and Satisfaction
with GLM
A study on patient satisfaction with GLM,
ETN, and ADA in RA, AS, and PsA patients

90. Patient Injection Experience and Satisfaction
with GLM, ADA, and ETN
Most Recent Injection Experience
Bolge S, et al. ACR 2012 [abstract] 1925, poster presentation.
Discomfort Pain
49
32
18
38
43
59
10
23 23
3 2 0
0
20
40
60
80
100
GLM ADA ETN
PercentageofPatients(%)
None Mild Moderate Severe
*
*
*
*
#
*p<0.05 vs. GLM; #p<0.10 vs. GLM
49 44
28
39
32
57
7
23
15
4 1 0
0
20
40
60
80
100
GLM ADA ETN
PercentageofPatients(%)
None Mild Moderate Severe
*
*
#

91. Patient Injection Experience and Satisfaction
with GLM, ADA, and ETN (Cont’d)
Most Recent Injection Experience
Bolge S, et al. ACR 2012 [abstract] 1925, poster presentation.
Stinging Burning
Conclusions: GLM patients reported comparable satisfaction with effectiveness, and less discomfort,
pain, burning and stinging compared to ETN and ADA patients
41
16 12
49
53 59
4
28 26
6 3 3
0
20
40
60
80
100
GLM ADA ETN
PercentageofPatients(%)
None Mild Moderate Severe
*p<0.05 vs. GLM; #p<0.10 vs. GLM
* *
*
*
58
41 40
30
36 34
9
20 24
3 3 2
0
20
40
60
80
100
GLM ADA ETN
PercentageofPatients(%)
None Mild Moderate Severe
*#
# *

92. Conclusions – Monoclonal Antibody Technologies
• Monoclonal antibodies, including human mAbs, are not born
equal
• The characteristics of an antibody are linked to the
technology used for its development and to the antibody
itself
• These characteristics, including half- life, affinity ,stability,
solubility and immunogenicity, combine to determine
possible routes of administration and dosing regimens of an
antibody
Antibodies with similar half-lives can have different
dosing schedules

93. Conclusions – Golimumab
• Through careful selection and testing, Janssen was able to
identify and develop an antibody with characteristics favorable
to clinical use:
– Affinity
– Stability
– Solubility
– Immunogenicity
• Resulting in an agent with:
– A monthly dosing schedule
– Low injection volumes
– Less pain for the patient
– Expected anti-TNF efficacy and safety, both over the short and
long-term

94. • Treatment should start early and aggressively to
prevent functional limitations and structural damage
• Methotrexate is the first line drug, but in high risk
patients early combination of Methotrexate with
prednisone or a tumour necrosis factor inhibitor
improves outcomes
• The goal of treatment today is remission, which has
been defined in several ways, including the DAS28
score, SDAI, CDAI, and a provisional ACR/EULAR
definition
Summary

95. • There are currently five TNF inhibitors on the market,
which vary in mode and frequency of administration. The
drugs are generally similar in efficacy and side effect
profiles
• A safety concern with the biologic drugs is the potential
for serious infections, so monitoring is needed
Summary

96. Thank you
THANK YOU

97. JUVENILE RHEUMATOID ARTHRITIS
ACR dignostic criteria
• Age < 16
• Arthritis of 1 or more joints
• Symptoms of at least 6 weeks
• An onset type after 6 months of observation –
pauciarticular, polyarticular or sysytemic
• Exclusion of other forms of arthritis

98. Types:
• Pauciarticular – less than 5 joints involved;
with ANA + iridocyclitis or HLA B 27 +
spondylitis
• Polyarticular –5 or more joints affected; RA
factor + or -
• Systemic (Still’s disease)
• < 20% have progressive destructive disease;
mostly systemic

99. Pauciarticular:
A. With ANA + iridocyclitis
• F>M
• Onset age < 5yr
• Fewer joint involved
• 30-35% have chronic iridocyclitis; complications- posterior synechia,
band shaped keratopathy, cataract, glaucoma, blindness
B. With HLA B 27 + spondylitis
• M>F
• Onset age- >8 years
• Arthritis involve lower limbs
• Radiographic sacroiliitis
• Iridocyclitis, reiter’s seen

100. Polyarticular:
A. Rh factor -ve
• F>>M
• Symmetrical polyarthritis of small joints of hand, feet, elbow, ankle,
knee
• Low grade extraarticular manifestation
• Inv of temporomandibular joint & cervical spine common
• 10-15% develop severe destructive arthritis
B. Rh factor +ve
• F>M
• Onset: late in childhood
• Childhood equivalent of adult RA
• Symmetric small joint arthritis with rheumatoid nodules, Felty’s
synd, fibrosing pneumonitis
• >50% develop destructive arthritis

101. Systemic (Still’s disease)
• M>=F
• Intermittent quotidian fever (>1030 F) with chill &
evanescent rash
• During fever- myalgia, arthralgia, transient arthritis,
pleuritis, pericarditis, adenitis, abdominal pain
• Hepatosplenomegaly
• Multiple symmetric joint involvement
• Recur in > 50% cases
• No iridocyclitis
• Inv: leucocytosis, anaemia