RA

1. RHEUMATOID ARTHRITIS AND
MANAGEMENT

2. RHEUMATOID ARTHRITIS

3. RHEUMATOID ARTHRITIS
 Rheumatoid arthritis (RA) is a complex condition that is well
characterised by chronic inflammation in the synovial membrane of
affected joints, often with systemic manifestations.
 It affects approximately 1 % of the adult population.
 It is characterized by chronic inflammation in the synovial membrane
of affected joints that ultimately leads to loss of daily function due to
chronic pain and fatigue.
 The majority of patients also have deterioration of cartilage and bone
in the affected joints, which may eventually lead to permanent
disability.
 Rheumatoid arthritis is associated with increased morbidity and
mortality.

5. INDIAN SCENARIO
 RA is widely prevalent throughout the world. The overall
worldwide prevalence is 0.8-1% and steadily increases to 5% in
women over the age of 70.
 RA is two to three times more common in women compared to
men.
 In India the prevalence has been estimated to be 0.5%- 0.75%.

6. ONSET
 Although Rheumatoid arthritis may present at any age, patients
most commonly are first affected in the third to sixth decades.
 Female: male 3:1
 Initial pattern of joint involvement could be:-
1) Polyarticular : most common
2) Oligoarticular
3) Monoarticular
 Morning joint stiffness > 1 hour and easing with physical activity is
characteristic.
 Small joints of hand and feet are typically involved

7. RELATIVE INCIDENCE OF JOINT
INVOLVEMENT IN RA
 MCP and PIP joints of hands & MTP of feet 90%
 Knees, ankles & wrists- 80%
 Shoulders- 60%
 Elbows- 50%
 TM, Acromio - clavicular & SC joints- 30%

11. LABORATORY INVESTIGATION
 CBC ( TLC, DLC, Hb )
 Acute phase reactants ( ESR, CRP )
 Rheumatoid Factor (RF).
 Anti- CCP antibodies (most specific )

12. 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 positive.
 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

13. SERUM ANTI-CCP
ANTIBODIES
 The presence of serum anti-CCP antibodies has about the
same sensitivity as serum RF for the diagnosis of RA.
However, its specificity approaches 95%.
 A positive test for anti-CCP antibodies in the setting of an
early inflammatory arthritis is useful for distinguishing RA from
other forms of arthritis.
 There is some incremental value in testing for the presence
of both RF and anti-CCP, as some patients with RA are
positive for RF but negative for anti-CCP and visa versa.
 The presence of RF or anti-CCP antibodies also has
prognostic significance, with anti-CCP antibodies showing the
most value for predicting worse outcomes.

14. OTHER LAB ABNORMALITIES
 Elevated APRs( ESR, CRP )
 Thrombocytosis
 Leukocytosis
 ANA - 30-40%
 Inflammatory synovial fluid
 Hypoalbuminemia

15. OTHER LAB ABNORMALITIES
 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

16. DIAGNOSTIC CRITERIA

17. DIFFERNETIATING FEATURES WITH
OSTEOARTHRITIS

18. GOALS OF MANAGEMENT
 Focused on relieving pain
 Preventing damage/disability
 Patient education about the disease
 Physical Therapy for stretching and range of
motion exercises
 Occupational Therapy for splints and adaptive devices
 Treatment should be started early and
should be individualised .
 EARLY AGGRESSIVE TREATEMNT

19. TREATMENT OPTIONS
 The treatment of RA optimally involves
a combination of non-pharmacological
intervention (patient education, rest
and exercise, and joint protection), a
pharmacological intervention (such
as medications nonsteroidal anti-
inflammatory drugs [NSAIDs], disease-
modifying antirheumatic drugs
[DMARDs], tumor necrosis factor [TNF]-
alpha inhibitors, immunosuppressant,
and steroids) and occasionally surgery.
Treatment options in RA
1. Antiinflammatory drugs:
Non-steroidal anti-
inflammatory drugs
(NSAIDs) and
corticosteroids
2. Analgesics
3.Conventional disease
modifying antirheumatoid
drugs (DMARDs)
4. Biologicals DMARDs

20. NSAIDS
 Non-Steroidal anti-inflammatory drugs
(NSAIDS) 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.

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

22. 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 .

23. DMARDS
Most commonly used
 Methotrexate
 Leflunomide
 Sulfasalazine
 Hydroxychloroquine
Less commonly used
 Chloroquine
 Gold
 Cyclosporine A
 D-penicillamine
 Azathioprine
 Cyclophosphamide

26. 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.

27. SELECTION OF 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

29. DMARDs - ALONE OR IN
COMBINATION?
 Since single DMARD therapy (in conjunction with NSAIDS) is
often only modestly effective , combination therapy has an
inherent approach .
 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.

30. LIMITATIONS OF
CONVENTIONAL DMARDS
 The onset of action takes several months.
 The remission induced in many cases is partial.
 There may be substantial toxicity which requires
careful monitoring.
 DMARDs have a tendency to lose effectiveness
with time-(slip out).
 These drawbacks have made researchers look for
alternative treatment strategies for RA- The Biologic
Response Modifiers.

31. BIOLOGICAL AGENTS
 Biological agents are produced in a living system like a
microorganism, plant or an animal cell by harnessing rDNA.
 The end product is a protein directed against a specific gene or
another protein which is highly specific for its function and target
antigen.
 The introduction of biological such as erythropoietin, insulin,
growth hormones and anti-cytokine therapies brought a new
era in modern medicine and transformed the treatment of many
chronic diseases.
 The first biologic approved was humulin in 1982 by USFDA.

32. DEFINITIONS
 BIOLOGICAL PRODUCT: Medical products are made from a variety of
natural sources using biotechnology methods and other cutting edge
technologies and are intended to prevent or treat diseases and medical
conditions.
 BIOSIMILAR(EMA): A biosimilar is biological medicinal product that
contains a version of the active substance of an already authorized original
biological medicinal product. It demonstrates similarity to the reference
product in terms of quality characteristics, biological activity, safety and
efficacy.
 BIOSIMILAR(INDIA): A biological product/drug produced by genetic
engineering techniques and claimed to be similar in terms of safety,
efficacy, and quality to a reference biological.

33. HOW ARE BIOLOGICAL DRUGS
MANUFACTURED?

34. WORLDWIDE SCENARIO
 Biologics are one of the top selling drugs worldwide but the major
drawback of this drug has been its exorbitant cost, which makes it
unaffordable and inaccessible to many patients, especially in
developing countries where a large number of people are poor and
the concept of health insurance is at its nascent stage.
 But the silver lining is that once the innovator company loses their
intellectual property right and patent protection after a stipulated
period, it opens the window of opportunities for companies evince
an interest in manufacturing similar products, which cost less, and
at that time, it is known as biosimilar or similar biologic

35. GENERICS BIOSIMILARS
They have active ingredients whose
chemical and therapeutic characteristics
are identical to the reference products
in terms of dosage, strength, route of
administration, quality, safety, efficacy
and intended use.
The same standards of generic drugs
cannot be applied to biosimilars as there
are many differences
Regulatory agencies generally approve
applications of generic drug
manufacturers requiring only
demonstration of bioequivelance to
reference products in terms of
pharmacokinetics parameters and
bioavailability.
Biosimilar cannot be made an exact
replica of reference biological due to:
1- Complex structure.
2- Complex manufacturing process and
heterogenecity.
3- Characterisation.
4-Effect of external conditions

36. BIOSIMILARS VS BIOLOGICS
DEVELOPMENTAL PATHWAY

37. HOW BIOSIMILARS DIFFER
FROM ORIGINAL OR INNOVATOR
BIOLOGICS

38. DIFFERENCE BETWEEN
BIOLOGIC AND BIOSIMILAR

39. DIFFERENCE BETWEEN
BIOLOGIC AND BIOSIMILAR

40. ADVANTAGES
Biologics have benefitted the patients with rheumatologic
diseases, inflammatory bowel disease, malignant
conditions, dermatological conditions, and other
connective tissue disorders by halting the disease
progression, alleviating the symptoms, and improving the
quality of life.

41. SAFETY AND
IMMUNOGENICITY
 Immunogenecity is an important safety concern for biosimilars.
 Immune reactions may lead to inactivation of drugs and thus
limiting its efficacy and affecting its safety leading to adverse
effects.
 Factors affecting immunogenicity include:
1- Product-Related factors
2- Route of administration
3- Patient Factors
4- Eprex episode.

42. BIOSIMILARS APPROVED IN INDIA

43. BIOLOGICS IN
RHEUMATOLOGY

44. ROLE IN RA
 Biologics are typically reserved for people whose
arthritis has not responded adequately to traditional
disease-modifying anti rheumatic drugs (DMARDs)
 Biologics are usually given by Injection or IV
 Biologics require a strict follow-up schedule
 All biologics increase risk of infection.
 Patients should be screened for tuberculosis and other
infections before starting a biologic.

45. HOW DO BIOLOGICS TREAT
RHEUMATOID ARTHRITIS
 They inhibit specific components of the immune system that
play pivotal roles in inflammation.
 Biologics are used to treat moderate to severe rheumatoid
arthritis that has not responded adequately to other
treatments.
 Slow down the progression of rheumatoid arthritis when 1st
line drugs have failed.
 Aggressive treatment is known to help prevent long-term
disability from RA.

46. Anti-TNF agents
 Biologics, and specifically the anti-TNF biologics, can have a
very rapid onset of action: same day.
 Radiographic efficacy of the anti-TNF agents exceeded
expectations.
 Anti-TNF agents, and biologics in general, are surprisingly
well tolerated and relatively safe.
 Biologics have a well-defined and specific mechanism Of
action

48. ROLE OF B CELL IN
PATHOGENESIS OF RA
 B cells may function as antigen presenting cells and provide
important co-stimulatory signals required for CD4+ T cell clonal
expansion and effector functions.
 B cells in RA synovial membrane may also secrete pro-inflammatory
cytokines such as TNFα and chemokines.
 Rheumatoid synovial membrane contains an abundance of B cells
that produce the rheumatoid factor (RF) antibody.

49. ROLE OF B CELL IN
PATHOGENESIS OF RA
 RF may also be a self-perpetuating stimulus for B cells, potentially
leading to activation and antigen presentation to Th cells, which may
be mechanistically responsible for further RF production. Thus, RF
immune complex mediated complement activation, in conjunction
with binding of the Fcg receptor, collectively contribute to the
propagation of the inflammatory cascade.
 T cell activation is considered to be a key component of the
pathogenesis of RA. Recent evidence indicates that this activation is
critically dependent on the presence of B cells.

50. ROLE OF RITUXIMAB IN RA
 It is uncertain which of these mechanisms is most important in the
depletion of B cells in patients with RA, although some data suggest
that Fc receptor mediated antibody-dependent cytotoxicity and
antibody-dependent phagocytosis are the principal mechanisms.
 Intravenous rituximab in RA patients results in almost complete
depletion of peripheral B cells and variable depletion of B cells in
synovium and other sites such as lymphoid tissue and bone marrow.
 Rheumatoid factor levels are reduced by a greater proportion than are
serum immunoglobulin (Ig) levels by rituximab treatment.
 The advantage of rituximab therapy is that there is no increased risk for
TB.

51. DOSAGE AND ADMINISTRATION
 Rituximab has been approved by the US Food and Drug
Administration and the European Medicines Agency in Europe
for the treatment of RA in patients with an incomplete response
or intolerance to tumor necrosis inhibitors (TNFi).
 Administer Rituximab as two 1000-mg intravenous infusions
separated by 2 weeks.

52. DOSAGE AND ADMINISTRATION
 INFUSION RATE ON DAY 1
Time mg/hour ml/hour
1st 30 minutes 50 mg/hour 25 ml/hour
2nd 30 minutes 100 mg/hour 50 ml/hour
Thereafter the rate can be increased by 50mg/hour
(25mls/hour) every 30 minutes to a maximum rate of
400mg/hour (200mls/hour) providing no adverse reactions
occur

53. DOSAGE AND ADMINISTRATION
 INFUSION RATE ON DAY 15
Time Mgs/hour Mls/hour
1st 30 minutes 100 mg/hour 50 mls/hour
2nd 30 minutes 200 mg/hour 100 mls/hour
Thereafter the rate can be increased by 100mg/hour (50
mls/hour) every 30 minutes to a maximum rate of
400mg/hour (200mls/hour) providing no adverse reactions
occur

56. BIOSIMILAR AGENTS USED IN
RHEUMATOLOGY IN INDIA

58. ADVERSE EFFECTS
 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

60. TOXICITY

62. SURGICAL APPROACHES
 Synovectomy is ordinarily not recommended for
patients with rheumatoid arthritis, primarily because
relief is only transient.
 However, an exception is synovectomy of the wrist,
which is recommended if intense synovitis is persistent despite
medical treatment over 6 to 12 months.
 Total joint arthroplasties , particularly of the knee, hip, wrist, and
elbow, are highly successful.
 Other operations include release of nerve entrapments (e.g., carpal
tunnel syndrome), arthroscopic procedures, and, occasionally,
removal of a symptomatic rheumatoid nodule.

63. RA IN PREGNANCY
 Most patients with RA go into remission during pregnancy.
 Methotrexate and leflunomide should be discontinued for at least 3
months before trying to conceive.
 Paracetamol is the oral analgesic of choice during pregnancy.
 Corticosteroids may be used to control disease flares
 DMARDs that may be used: sulfasalazine, hydroxychloroquine,
azathioprine or ciclosporin if required to control inflammation.
 DMARDs that must be avoided: methotrexate,
leflunomide,cyclophosphamide, gold and penicillamine.
 Biological therapies: safety during pregnancy is currently
unclear.

70. References
 Edwards JW et al Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients
with Rheumatoid Arthritis N Engl J Med 2004;350:2572-81
 Indian Rheumatology Association consensus statement on the management of
adults with rheumatoid arthritis Indian Journal of Rheumatology 2008
:3(3);(Suppl); pp. S1–S16