Management of Rheumatoid Arthritis Dr Zafar Masood Ansari Deptt. of Pharmacology JNMC, AMU
Jul 16, 2015
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