Management of rheumatoid arthritis

1. MANAGEMENT OF
RHEUMATOID ARTHRITIS
Dr. Irfan Ahmad Khan
Senior Resident
Department of Pharmacology

2. INTRODUCTION
• Is chronic systemic inflammatory disorder that may
affect many tissues and organs—skin, blood vessels,
heart, lungs, and muscles—but principally attacks the
joints, producing a nonsuppurative proliferative and
inflammatory synovitis that often progresses to
destruction of the articular cartilage and ankylosis of
the joints.

3. • 0.5-1% of the population worldwide
• Incidence increases 25-55 years after which it
remains same upto 75 years of age.
• More common in females as compared to males (2:1
– 3:1).

4. ETIOLOGY
• Etiology of RA is unknown but the studies suggest
that environmental and genetic factors both are
necessary for full expression of the disease.
• Genetic factor:
Genes play a key role in susceptibility to RA and
disease severity.

5. 1. HLA-DRB1 gene, which encodes the MHC II -chain
molecule Most prominent genetic association.
• Disease-associated HLA-DRB1 alleles share an amino
acid sequence at positions 70–74 in the third
hypervariable regions of the HLA-DR -chain, which is
termed the shared epitope (SE).

6. 2. Non MHC gene implicated in RA.
i. Protein tyrosine phosphatase non-receptor 22
(PTPN22) gene encodes for lymphoid tyrosine
phosphatase, a protein that regulates T and B cell
function.
ii. Peptidyl arginine deiminase type IV (PADI4) gene.
• Encodes an enzyme involved in the conversion of
arginine to citrulline.
• Risk allele is postulated to play a role in the
development of antibodies to citrullinated antigens.

7. • Environmental factor:
Smoking- confers a relative risk for developing RA of
1.5–3.5.
 Smoking induces citrullination of cellular proteins
→ expression of neoepitopes → self reactivity.
Infections- EBV, Mycoplasma, Parvovirus B19

8. PATHOGENESIS
IFN-γ, TNF-,
Lymphotoxin-β
•IL-17, 21, 22, 26, 6
•TNF-
•GM-CSF
•Recruitment of neutrophils
& monocytes
Signal -I
Signal -II

10. CLINICAL PRESENTATION
• Early morning joint stiffness lasting >1 hour and
easing with physical activity.
• Earliest involved  small joints of the hands and
feet.
• Initial pattern  monoarticular, oligoarticular (4
joints) or polyarticular (>5 joints), usually in a
symmetric distribution.

11. • Hyperextension of the PIP joint with flexion of the
DIP joint (“Swan-neck deformity").
• Flexion of the PIP joint with hyperextension of the
DIP joint (“Boutonnière deformity").
• Subluxation of the first MCP joint with
hyperextension of the first interphalangeal (IP) joint
("Z-line deformity").

13. DIAGNOSIS
• CBC – Normocytic anemia, ↑ ESR
• ↑ CRP
• Presence of RF.
• Presence of anti-CCP.
• Synovial fluid analysis : 5000 and 50,000 WBC/µ3
• X ray:
• Juxtaarticular osteopenia, soft tissue swelling, symmetric
joint space loss and subchondral erosions.
• In late stages - joint subluxation and collapse.
• MRI and ultrasound: Synovitis, tenosynovitis, effusions as well
as identify bony abnormalities.

14. CLASSIFICATION CRITERIA FOR RA (ACR- EULAR 2010)
SCORE
Joint involvement 1 large joint (shoulder, elbow, hip, knee, ankle) 0
2–10 large joints 1
1–3 small joints (MCP, PIP, Thumb IP, MTP, wrists) 2
4–10 small joints 3
>10 joints (at least 1 small joint) 5
Serology Negative RF and negative ACPA 0
Low-positive RF or low-positive anti-CCP antibodies
(3 times ULN)
2
High-positive RF or high-positive anti-CCP antibodies
(>3 times ULN)
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

15. TREATMENT
• The current therapies for RA are -
1.NSAIDs
2.Glucocorticoids
3.Disease Modifying Antirheumatic drugs
(DMARDs)

16. • NSAIDs:
 Usually employed as bridge therapy while waiting for
DMARDs to become effective.
 Inhibit the COX enzymes → ↓PG production, thereby
inhibiting the local inflammation.
 Do not retard the progression of disease.

17. • GLUCOCORTICOIDS:
 Bridge therapy to control symptoms until the DMARDs or
biological agents become effective.
 Effectively suppress severe inflammation
 MOA:- they result in the down-regulation of proinflammatory
chemokines, adhesion molecules and cytokines (TNF, IL-1, IL-6).
 Prednisolone 7.5mg/day to standard DMARDs.

18. DMARDs
• NON-BIOLOGICAL
DMARDs
– Methotrexate
– Leflunomide
– Sulfasalazine
– Hydroxychloroquine
• BIOLOGICS
– TNF- α inhibitors:
Infliximab, Adalimumab,
Etanercept, Golimumab,
Certolimumab
– IL-1 antagonist: Anakinra
– IL-6 antagonist:
Tocilizumab
– CD20 antagonist (B-cell
depletor): Rituximab
– T-cell inhibitor: Abatacept

19. • NON-BIOLOGICAL DMARDs:
 METHOTREXATE:
First line DMARD.
MOA- Inhibits aminoimidazole carboxamide
ribonucleotide transformylase (AICAR) and
thymidylate synthetase → Inhibits replication and
function of T-cells.

20. Dose- 15-25 mg weekly (orally/ s.c.)
Adverse effect- Nausea & Mucosal erosion
Hepatotoxicity (dose related)
Breathlessness
Leucovorin (24 hrs after each weekly dose)
C/I- Pregnancy
Initial Evaluation Monitoring
CBC, LFT, Viral hepatitis,
Chest X-ray
CBC, LFT every 2-3 months

21.  LEFLUNOMIDE:
MOA- Acts through its active metabolite- A77-1726
2 ATP + CO2 →→Dihydro-orotate →→→ Orotate
→→ ↓UMP →→ ↓RNA synthesis →→ growth arrest
at G1 phase (T- & B-cells)
Leflunomide
DHODH

22. Dose- 100mg/day (orally) loading dose for 3 days
followed by 10-20mg/day.
Adverse effects- Diarrhoea, ↑hepatic transaminase
levels, alopecia, myelosupression
C/I- Pregnancy & Lactation
Initial Evaluation Monitoring
CBC, LFT, Viral hepatitis,
Chest X-ray
CBC, LFT every 2-3 months

23. • HYDROXYCHLOROQUINE:
MOA- The proposed mechanisms are-
– Suppresses T lymphocyte response to mitogens
– ↓leukocyte chemotaxis
– Stabilize lysosomal enzymes
– Traps free radicals
• Mild RA along with Methotrexate.

24. Dose- Hydroxychloroquine
200-400 mg/day orally (<6.5mg/kg/day)
Adverse effects- Ocular toxicity, Greying of hairs,
Myopathy & Neuropathy
Initial Evaluation Monitoring
Eye examination if > 40
years old or prior ocular
disease
Fundus & visual field
testing every 12 months

25.  SULFASALAZINE:
Metabolised to Sulfapyridine & 5-ASA.
The beneficial effect in RA may be due to-
– Suppression of T & B-cell proliferation &
responses
– Inhibit release of inflammatory cytokines
– Decrease the production of rheumatoid factor
– Suppression of generation of superoxide free
radical

26. Dose- 500mg/day orally for 7days , increased by
500mg every week to 3g/day (2-3 divided doses)
Adverse effect- GIT disturbances, headache, rashes,
Neutropenia, Reversible ↓sperm count
Initial Evaluation Monitoring
CBC CBC every 2-3 weeks for
first 3 months, then every 3
months

27. • BIOLOGICAL DMARDs:
 TNF- ANTAGONISTS

28. o INFLIXIMAB:
MOA-

29. Dose- 3-5mg/kg as i.v infusion in at least 2hours at
weeks 0, 2, 6, then after every 8 weeks
More beneficial in combination with methotrexate.
Adverse effects- URTI, activation of latent TB
Initial Evaluation Monitoring
Purified peptide derivative
(PPD) skin test
LFT periodically

30. o ADALIMUMAB:
 MOA-

31. Dose- 40 mg s.c alternate week
Adverse effects- Risk of bacterial infection & other
opportunistic infections

32. o ETANERCEPT:
Fusion protein- 2 sTNF p75 receptor moieties linked
to Fc portion of human IgG1
MOA-Acts as exogenously administered TNFα
receptor and prevents TNF-α from binding to its
receptor.

33. Dose- 25mg s.c twice weekly or 50mg weekly
Adverse effects- same as infliximab
GOLIMUMAB
 Human monoclonal antibody
 High affinity for membrane bound and soluble TNF-α
 Given 50 mg s.c every 4 week in late RA.

34. CERTOLIZUMAB
• Pegylated Fc-free anti-TNF agent.
• Neutralizes membrane bound and soluble TNF- α
• Used in late stage of RA.
• 400 mg s.c weeks 0, 2, 4 then 200 mg every other
week

35.  IL-1 ANTAGONIST:
o ANAKINRA:
 Is a recombinant non-glycosylated version of human IL-1RA
prepared from cultures of genetically modified Escherichia coli.
MOA-

36. Dose- 100 mg s.c daily
Adverse effects- ↑Risk bacterial & viral infections,
Reactivation of latent TB, Neutropenia (CBC every
month for 3 months then every 4 months for 1 year)

37.  T-CELL INHIBITOR:
o ABATACEPT:
 Soluble fusion protein consisting of human cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) receptor linked to
modified portion of human IgG.
• MOA- Costimulation modulator that inhibits the activation of T
cells.

38.  Along with other DMARDs in moderate to severe RA
 Given i.v infusion as 3 initial doses (0, 2nd
& 4th
week) followed
by monthly infusion
-patient <60kg- 500mg
60-100kg- 750mg
>100kg- 1000mg
 Adverse effects- risk of infection-URTI, hypersensitivity
reactions, lymphomas
 C/I- with other anti-TNF drugs

39.  B-CELL DEPLETOR:
o RITUXIMAB:
 Chimeric murine-human monoclonal IgG1 antibody against
CD20 B-lymphocytes.
MOA-
Cell mediated & complement
mediated cytotoxicity
Stimulation of cell
apoptosis
Depletion of B-lymphocytes
↓ presentation of antigens to
T-cells hence, reduces
proinflammatory cytokines

40.  Approved for RA patients who have failed TNF inhibitor
therapy.
 Dose- Given 1000 mg i.v infusion twice separated by 2 weeks,
may be repeated every 6-9 months.
 Adverse effects- Infusion reactions, rashes, risk of infection

41. IL-6 antagonist:
 TOCILIZUMAB
• Humanized monoclonal antibody against IL6.
• Prevents activation of T cells, macrophages, osteoclast, B
cells.
• Given in early & late stage RA.
• Dose- 4-8mg/kg i.v every 4 week.
• ADRs: Infusion reaction, Risk of infection, neutropenia,
increased liver transaminases.

42. TREATMENT STRATEGY

43. Thank you