Management of

Rheumatoid Arthritis

Dr Zafar Masood Ansari

Deptt. of Pharmacology

JNMC, AMU

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

Affects 0.5-1% of adult population.

Women : Men – 3:1.

40-70 yrs.

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.

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.

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.

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.

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 tumornecrosis 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 the joint.

Genetic predisposition + Environmental factors

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").

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.

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.

ACR- EULAR 2010

TREATMENT

NSAIDS

GLUCOCORTICOIDS

DMARD’s.

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.

GLUCOCORTICOIDS Bridge therapy.

Negatively regulates the genes for cyclooxygenase-2 and inflammatory cytokines.

Negatively regulates the transcription factors NF-kBwhich regulate the expression of a number of components of the immune system.

Long term use: side effects (peptic ulcer, osteoporosis, infection, hyperglycemia, hypertension).

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

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 carboxamideribonucleotide transformylase and thymidylatesynthase, 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.

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.

LEFLUNOMIDE Active metabolite A77-1726.

Competitive inhibitor of dihydroorotatedehydrogenase, 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.

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.

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.

Sulfapyridine is excreted in urine.

ADRs -

Drug induced lupus.

Nausea, vomiting, headache.

Hemolytic anemia and methemoglobinemia .

Reversible infertility occurs in men.

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.

They are very extensively tissue-bound,

particularly in melanin-containing tissues such

as the eyes.

Irreversible retinal damage, Cardiotoxicity,

Nausea, Diarrhea, Headache, Rash.

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

Pharmacokinetics-

• Can be given i.v or orally.

• Absorption is incomplete hence bioavailabiltyis 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

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

TNF-α ANTAGONISTS

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 proinflammatorycytokines.

Iv infusion 3-5 mg/kg at 0 ,2 and 6 week interval.

It can be administered at an interval of 8 wksthereafter.

Half life 9 days.

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.

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.

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

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.

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 proinflammatorycytokines.

100mg s.c. daily.

ADRs

Risk -bacterial, viral infections

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.

NEWER TARGETS

Newer TNF antagonists in clinical trials:

Certolizumab., Don’t cross placenta so used

in pregnancy.

Anti-IL-17(secukinumab) under trial.

THANK YOU

TREATMENT STRATEGY

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

GOLD COMPOUNDS Aurothiomalate and Aurothioglucose contain 50%

elemental gold.

Auranofin contains 29% elemental gold.

Reduces chemotaxis, phagocytosis, lysosomalactivity, 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.

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.

CYCLOSPORINE

Calcineurin inhibitors

MOA:

Target T cell signal transduction

Inhibit expression of IL2

Inhibit IL2 mediated T cell activation,

proliferation & differentiation

Pharmacokinetic features:

Given orally or i.v.

ADRs:

renal dysfunction, tremor, hirsutism, hypertension,

hyperlipidemia, gum hyperplasia, hyperuricemia

Monitoring:

BP, Creatinine

CBC every 3 months.

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

ADR:

Myelosupression

Hepatotoxicity

Infections & hematological malignancies

Monitoring: CBC, LFT every 3 monthly