This document summarizes the management of rheumatoid arthritis. It discusses the disease etiology, which involves genetic factors like the HLA-DRB1 gene and environmental triggers. The pathogenesis involves an autoimmune reaction mediated by T cells and autoantibodies. Symptoms include joint stiffness and deformities. Diagnosis is based on clinical features and tests like rheumatoid factor. Treatment involves NSAIDs, glucocorticoids, and disease-modifying antirheumatic drugs like methotrexate, TNF inhibitors, and B cell-depleting agents. The goal of treatment is to reduce joint damage and disability based on measures like ACR20 response criteria.

1. Management of
Rheumatoid Arthritis
Dr Zafar
Masood Ansari
Deptt. of
Pharmacology
JNMC,
AMU

2. INTRODUCTION
 Rheumatoid arthritis is a chronic systemic
inflammatory disease of unknown etiology, that
may affect many tissues and organs, but
principally affects the joints, producing symmetric
peripheral polyarthritis.
 Target - synovial membrane, nonsuppurative
proliferative and inflammatory synovitis that often
progresses to destruction of the articular cartilage
and bone.
 Joint damage and physical disability

3.  Affects 0.5-1% of adult population.
 Women : Men – 3:1.
 40-70 yrs.

4. ETIOLOGY
 HLA-DRB1 gene, which encodes the MHC II -
chain molecule.
 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).
 *0401, *0101, *0404, *1001, *0405 and *0901.
 Non MHC gene PTPN22 is also implicated in RA.
 PTPN22 encodes for lymphoid tyrosine
phosphatase, a protein that regulates T and B cell
function.

5.  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.
 EBV, Mycoplasma, Parvovirus B19.
 Smoking.

6. PATHOGENESIS
 Rheumatoid arthritis is triggered by exposure of a
genetically susceptible host to an arthritogenic
antigen resulting in a breakdown of
immunological self-tolerance and a chronic
inflammatory reaction.
 Arthritogenic antigen may be Epstein-Barr virus,
retroviruses, parvoviruses, mycobacteria,
Borrelia, Proteus mirabilis, Mycoplasma and
citrullinated proteins.
 Autoimmunity – RF, Anti CCP antibodies, type 2
collagen and glycosaminoglycans.

8.  CD4+ T cells become activated by antigen
presenting cells (APCs) through interactions
between the T cell receptor and class II major
histocompatibility complex (MHC)-peptide antigen
(signal 1) with co-stimulation through the CD28-
CD80/86 pathway, as well as other pathways
(signal 2).
 Ligands binding Toll-like receptors (TLRs) may
further stimulate activation of APCs inside the
joint.
 Synovial CD4+ T cells differentiate into TH1 and
TH17 cells, each with their distinctive cytokine
profile.

9.  CD4+ TH cells in turn activate B cells, some of
which are destined to differentiate into
autoantibody-producing plasma cells.
 Immune complexes, possibly comprised of
rheumatoid factors (RFs) and anti–cyclic
citrullinated peptides (CCP) antibodies, may form
inside the joint, activating the complement
pathway and amplifying inflammation.
 T effector cells stimulate synovial macrophages
(M) and fibroblasts (SF) to secrete
proinflammatory mediators, among which is tumor
necrosis factor (TNF α), interleukin 1 (IL-1), IL-6,
and granulocyte-macrophage colony-stimulating
factor (GM-CSF).
 TNF α upregulates adhesion molecules on
endothelial cells, promoting leukocyte influx into

10. Genetic predisposition
+
Environmental factors

11. CLINICAL FEATURES
 Early morning joint stiffness lasting more than 1 hour
and easing with physical activity.
 The earliest involved joints are typically the small
joints of the hands and feet. The initial pattern of joint
involvement may be monoarticular, oligoarticular (4
joints), or polyarticular (>5 joints), usually in a
symmetric distribution.
 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
 Joint imaging : Juxtaarticular osteopenia, soft tissue
swelling, symmetric joint space loss, and subchondral
erosions. In late stages X-ray reveals joint subluxation
and collapse.
 MRI and ultrasound : Synovitis, tenosynovitis, and
effusions as well as greater sensitivity for identifying
bony abnormalities.

14. Diagnostic criteria ( ACR 1987)
 Four out of seven are required :
 Morning stiffness( at least 1 hr).
 Arthritis of 3 or more joint areas.
 Arthritis of hand joints.
 Symmetric arthritis.
 Rheumatoid nodules.
 RF.
 Radiological changes.

15. ACR- EULAR 2010

16. TREATMENT
 NSAIDS
 GLUCOCORTICOIDS
 DMARD’s.

17. NSAIDS
 Adjunctive therapy to manage the symptoms.
 NSAIDs inhibit the COX enzymes and PG
production, thereby inhibiting the local
inflammation.
 Do not retard the progression of disease.

18. GLUCOCORTICOIDS
 Bridge therapy.
 Negatively regulates the genes for cyclooxygenase-2
and inflammatory cytokines.
 Negatively regulates the transcription factors NF-kB
which regulate the expression of a number of
components of the immune system.
 Long term use: side effects (peptic ulcer,
osteoporosis, infection, hyperglycemia, hypertension).

19. DMARDs
 SYNTHETIC
DMARDs
 Methotrexate
 Leflunomide
 Sulfasalazine
 Hydroxychloroquine
 Cyclosporine
 Azathioprine
 BIOLOGICAlS
 TNF antagonist:
infliximab,
adalimumab
 IL1 antagonist:
anakinra
 IL6 antagonist:
tosilizumab
 CD20 antagonist:
rituximab
 TNF receptor fusion
protein: Etanercept
 Fusion protein :
Abatacept

20. METHOTREXATE
 First line DMARD.
 Inhibits Dihydrofolate reductase enzyme which is
required in the synthesis of methylene
tetrahydrofolate which in turn is a cofactor for
thymidine synthesis and amino acids.
 Inhibits aminoimidazole carboxamide
ribonucleotide transformylase and thymidylate
synthase, thus inhibiting the synthesis of DNA in
T helper cells and B cells and amino acids.
 Inhibits cytokine production, chemotaxis and cell
mediated immune reaction.
 Dose 7.5mg-25 mg orally weekly.

21.  Orally absorbed - food hinders absorption.
 Metabolised to polyglutamate derivatives, which
are retained in the cell for weeks.
 Renal excretion 70% and Bile excretion 30%.
 Folinic acid (5 tetrahydrofolate) should be given
to restore the folic acid levels in normal cells.
 Myelosuppresion, Oral ulcers, Hepatotoxicity,
Nausea, Diarrhoea.
 Displaced from plasma albumin by a number of
drugs, including sulfonamides, salicylates,
tetracycline, chloramphenicol and phenytoin.
 C/I in pregnancy and lactation.

22. LEFLUNOMIDE
 Active metabolite A77-1726.
 Competitive inhibitor of dihydroorotate
dehydrogenase, enzyme involved in
pyrimidine synthesis.(UMP).
 Arrests cells in G1 phase of cell growth and
as a result inhibits T cell proliferation and
production of autoantibodies by B cells.
 Half life 19 days.

23.  Enterohepatic circulation.
 Loading dose is given 100mg/daily for 3 days
followed by 10 mg/daily .
 Hepatotoxicity, weight loss, alopecia.
 C/I in pregnancy and lactation.
 Cholestyramine is used to increase the
clearance of Leflunomide.

24. SULFASALAZINE
 Sulfapyridine and 5-aminosalicylic acid.
 Sulfapyridine is the active moiety
 Inhibition of IL8, IL2, TNFα expression.
 Decreased production of Ig M & Ig G.
 Decreased angiogenesis.
 Decreased free radical production & cellular injury.
 Half life-6-15 hr
 Dose- 500 mg OD x 7 days, increased by 500 mg
every wk to a maximum of 3 g/ day in 2-3 divided
doses.

25.  Sulfapyridine is excreted in urine.
 ADRs -
 Drug induced lupus.
 Nausea, vomiting, headache.
 Hemolytic anemia and methemoglobinemia .
 Reversible infertility occurs in men.

26. HYDROXYCHLOROQUINE
 Suppression of T lymphocyte responses to
mitogens, decreased leukocyte chemotaxis,
reduced production of TNF, IFN, IL6 ,
stabilization of lysosomal enzymes, inhibition
of DNA and RNA synthesis, and the trapping
of free radicals.
 Mild RA along with Methotrexate.
 200–400 mg/d orally.
 50% protein-bound in the plasma.

27.  They are very extensively tissue-bound,
particularly in melanin-containing tissues such
as the eyes.
 Irreversible retinal damage, Cardiotoxicity,
Nausea, Diarrhea, Headache, Rash.

28.  CYCLOSPORIN:
It is a peptide antibiotic.
MOA-
• Cyclosporin binds with cyclophilin and form a complex
• The complex inhibits cytoplasmic phosphatase- Calcineurin
• Calcineurin involved in activation of T-cell specific
transcription factor (NF-AT)→ Involved in synthesis of ILs,
IFN-γ by activated T-cells
• No activation of NF-AT → Hence no synthesis of ILs, IFN-γ

29. Pharmacokinetics-
• Can be given i.v or orally.
• Absorption is incomplete hence bioavailabilty
is very low.
• Metabolized by CYP 3A4 enzyme in liver.
Dose- 3-5mg/kg/day i.v ( 2 divided doses)
Adverse effects- Nephrotoxicity,
Hyperkalemia, Hepatotoxicity, Gingival
hyperplasia

30.  Azathioprine (AZA):
Prodrug
MOA- AZA → 6-MP →→→→→→ 6-Thio GTP
• 6-Thio GTP falsely incorporated in genetic
material of T- & B-cell lymphocytes → Non-
functional cells
Dose- 2mg/kg/day orally
Adverse effects- Bone marrow suppression,
hepatotoxicity, alopecia, GIT disturbances

31. TNF-α ANTAGONISTS

32. INFLIXIMAB
 Chimeric anti–TNF- monoclonal antibody containing a
human constant region and a murine variable region.
 It forms complexes with soluble as well as membrane
bound TNF α receptors and inhibits interaction of
TNF α with its receptors and hence blocking all its
actions.
 Down-regulation of macrophage and T cell function
and prevents the release of proinflammatory
cytokines.
 Iv infusion 3-5 mg/kg at 0 ,2 and 6 week interval.
 It can be administered at an interval of 8 wks
thereafter.
 Half life 9 days.

33. ADRs
 Infection : opportunistic infection, activation of
latent tuberculosis.
 Long term use leads to development of anti-
infliximab antibodies.
 Lymphomas.
 Infusion & injection related reactions.
 Drug induced lupus.
 Demyelinating syndromes.

34. ETANERCEPT
 Etanercept is a recombinant fusion protein consisting
of two soluble TNF p75 receptor moieties linked to the
Fc portion of human IgG1.
 Acts as exogenously administered TNFα receptor
and prevents TNF α from binding to its membrane
bound receptors.
 25 mg twice weekly or 50 mg weekly given s.c.
ADRs
 Activation of latent tuberculosis.
 Bacterial infections is slightly increased, especially
soft tissue infections and septic arthritis.

35. ABATACEPT
 Costimulation modulator that inhibits the
activation of
T cells.
 Abatacept binds to CD80 and 86 on APC,
thereby inhibiting the binding to CD28 and
preventing the activation of T cells.
 500mg biweekly i.v.
 Along with other DMARDs in moderate to severe
rheumatoid arthritis.
ADRs
Increased risk of infection, URTI
 Increase in lymphomas

36. RITUXIMAB
 Chimeric monoclonal antibody that targets CD20
B lymphocytes.
 Cell-mediated and complement-dependent
cytotoxicity and stimulation of cell apoptosis.
 It has been approved for RA patients who
have failed TNF inhibitor therapy.
 Given by iv infusion.
 ADRs: infusion reactions, pulmonary fibrosis,
infections, Hepatitis B reactivation.

37. IL-1 ANTAGONIST (ANAKINRA)
 All activated mononuclear cells generate IL-1,
which inturn enhances the production of IL-6, of
adhesion molecules and release of
metalloproteinase.
 Anakinra is a recombinant IL-1 receptor
antagonist.
 Non-glycosylated version of human IL-1RA
prepared from cultures of genetically
modified Escherichia coli.
 Competitively blocks the binding of IL-1α and IL-
1β to the IL-1 receptor and thereby inhibits the
activity of these two related proinflammatory
cytokines.
 100mg s.c. daily.
ADRs

38. IL-6 ANTAGONIST
(TOCILIZUMAB)
 Humanized monoclonal antibody against IL-6.
 Prevents activation of T cells, macrophages,
osteoclast, B cells.
 Given by iv infusion(4-8mg/kg) every 4 week.
 ADRs: headache, stomatitis, skin eruptions, fever,
serious infections, anaphylaxis, neutropenia,
increased liver transaminases.

39. NEWER TARGETS
 Newer TNF antagonists in clinical trials:
Certolizumab., Don’t cross placenta so used
in pregnancy.
 Anti-IL-17(secukinumab) under trial.

40. THANK YOU

41. TREATMENT STRATEGY

42. SUCCESS OF INTERVENTION
 American College of rheumatology criteria for
measure of disease activity and response of
treatment: (ACR20)
 Tender joint count:: >20% improvement
 Swollen joint count:: >20% improvement
 Patient assessment of pain
 Patient global assessment of disease activity
 Physician global assessment of disease
activity
 Patient assessment of physical function
 Markers of inflammation
 ACR50 & ACR70
>20%
improve
ment

43. GOLD COMPOUNDS
 Aurothiomalate and Aurothioglucose contain 50%
elemental gold.
 Auranofin contains 29% elemental gold.
 Reduces chemotaxis, phagocytosis, lysosomal
activity, inhibition of T cell differentiation & CMI,
interleukin-8, interleukin-1b production, and vascular
endothelial growth factor are all inhibited.
 Decrease RF & ESR, heal bony erosions.
 Hypotension, dermatitis, kidney & liver damage ,
myelosuppression, peripheral neuropathy,
pulmonary fibrosis.

44. PENICILLAMINE
 Metabolite of penicillin, analog of amino acid
cystine
 D -isomer was used in RA
 Also used as chelating agent in copper toxicity
 Rarely used due to toxicity
 Adrs include:
 Blood dyscrasias, rashes, nausea, proteinuria,
good pasture syndrome, myasthenia, myositis,
drug induced lupus
 MOA unknown, proposed:
 reduced chemotaxis, phagocytosis & lysosomal
activity, inhibit CMI.

45. CYCLOSPORINE
 Calcineurin inhibitors
 MOA:
 Target T cell signal transduction
 Inhibit expression of IL2
 Inhibit IL2 mediated T cell activation,
proliferation & differentiation

46.  Pharmacokinetic features:
Given orally or i.v.
 ADRs:
 renal dysfunction, tremor, hirsutism, hypertension,
hyperlipidemia, gum hyperplasia, hyperuricemia
 Monitoring:
 BP, Creatinine
 CBC every 3 months.

47. AZATHIOPRINE
 Prodrug converted to 6
mercaptopurine by TPMT
(thiopurine methyl
transferase)
 MOA:
 6MP is converted to 6IMP,
which is incorporated in
DNA, inhibit DNA synthesis
 Pharmacokinetics:
 Pharmacogenetics:
 80% : normal TPMT
 10% : low TPMT:
myelosupression
 10% high TPMT : hepatotoxicity

48.  ADR:
 Myelosupression
 Hepatotoxicity
 Infections & hematological malignancies
 Monitoring: CBC, LFT every 3 monthly