Disease Modifying Anti-Rheumatic Agent

s (DMARDs)
 Rheumatoid Arthritis
chronic systemic inflammatory disease of unknown cause.
causes significant systemic effects, shortens life, and reduces
mobility and quality of life.
External trigger (eg., cigarette smoking, infection or trauma) th
at triggers an autoimmune reaction, leading to synovial hypertr
ophy and chronic joint inflammation along with potential for e
xtra-articular manifestations.
No lab test results but the presence of anti-cyclic citrullinated p
rotein antibody (ACPA) and rheumatoid factor (RF) is highly s
pecific.
 Etiology
Genetic
-Human leukocyte antigen (HLA-DR4) cluster co
nstitutes one of the peptide-binding sites of certain
HLA-DR molecules associated with RA.
Environmental
Hormonal
-Hyperprolactinemia maybe a risk factor.
 Immunologic
-production and regulation of both proinflammatory and anti-
inflammatory cytokines and cytokine pathways are formed in R
A.
Note: Cytokine plays a central role in the perpetuation of synovi
al inflammation.
Infectious factors
-Mycoplasma organisms, Epstein-Barr virus (EBV) and rubel
la virus
-Periodontopathic bacteria including Porphyromonas gingiva
lis
Socio-economic,psychological and lifestyle factors influence d
isease development and outcome.
 DMARDs
Non-biologic
azathioprine, chloroquine and hydroxychloroquine, cyclosphopham
ide, cyclosporine, leflunomide, methotrexate, mycophenolate mofet
il and sulfasalazine, tofacitinib (marketed as biologic)
Biologic
T-cell modulating biologic (abatacept)
B-cell cytotoxic agent (rituximab)
IL-1inhibiting agents (anakinra)
TNF-alpha blocking agents
Gold salts were once used but are no loner recommended because of s
ignificant toxicities.
 Non-biologic
Azathioprine
MOA: acts through its major metabolite, 6-thioguanine. It suppresses
anosinic acid synthesis, B-cell and T-cell function, immunoglobulin p
roduction, and IL-2 secretions.
Indication:
for use in RA at 2mg/kg/d
for the prevention of kidney transplant rejection in combination wit
h other immune suppressants
A/E:
Bone marrow suppression, GI disturbances, lymphomas, and increa
se in infection risks
 Chloroquine and Hydroxychloroquine
MOA: Suppression of T lymphocyte responses to mitogens, decreased leukocyte c
hemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA sysnth
esis, and the trapping of free radicals.
Indications:
mainly used for malaria
often used for skin manifestations, serositis, and joint pains of SLE, and Sjgr
ens syndrome.
usually takes 3-6 months to obtain a response
A/E:
Ocular toxicity at dosages >250mg/d for chloroquine and >6.4mg/kg/d hyrdox
ychloroquine
dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares.

Note: safe for pregnant women

 Cyclosphophamide
MOA:
major active metabolite is phosphoramide mustard, which cross-lin
ks DNA to prevent cell replication. It suppresses T-cell and B-cell f
unction.
Indication:
active against RA when given orally at dosages of 2mg/kg/d but no
t when given IV.
treat SLE, vasculitis, Wegeners granulomatosis, other severe RD.
A/E:
Infertility in both men and women, bone marrow supression, alope
cia, hemorrhagic cystitis, and bladder carcinoma.
 Cyclosporine
MOA
Through regulation of gene transcription, it inhibits interleukin-1 and int
erleukin-2 receptor production and secondarily inhibits macrophage T- c
ell interaction and T-cell responsiveness
Indication
for RA and retards the appearance of new bony erosions. Maybe useful i
n SLE, polymyositis and dermatomyositis, Wegeners granulomatosis, a
nd juvenile chronic arthritis.
A/E
neohrotoxicity, hypertension, hyperkalemia, hepatotoxicity, gingival hyp
erplasia, and hirsutism
DI
increased toxicity with diltiazem, potassium-sparing diuretics, andother
drugs inhibiting CYP3A
 Leflunomide
MOA
undergoes rapid conversion both in the intestine and in the plasma, to its activ
e metabolite A77-1726. This metabolite inhibits dihydroorotate dehydrogenas
e, leading to a decrease in ribonucleotide synthesis and the arrest of stimulate
d cells in the G1 phase of cell growth. It inhibits T cell proliferation and prod
uction of autoantibodies by B cells. Secondary effects include interleukin-10 r
eceptor mRNA, decreased interleukin-8 receptor type A mRNA, and decrease
d TNF-alpha-dependent NF-KB activation
Indication
for RA, including inhibition of bony damage
A/E
Diarrhea or loose bowels, elevation in liver enzymes, mild alopecia, weight g
ain, increased blood pressure, leukopenia, thrombocytopenia
 Methotrexate
MOA
Inhibit aminoimidazolecarboxamide ribonucleotide transfomylase a
nd thymidylate synthetase, with secondary effects onpolymorphonu
clear chemotaxis. Some effect on dihydrofolate reductase and this a
ffects lymphocyte and macrophage function
Indication
juvenile chronic arthritis, psoriasis, psoriatic arthritis, ankylosing sp
ondylitis, polymyositis, dermatomyositis, Wegeners granulomatosi
s, giant cell aneritis, SLE, and vasculitis
A/E
Nausea and mucosal ulcers, hepatotoxicity, cirrhosis, hypersensitivi
ty, pseudolymphomatous reactions
 Mycophenolate mofetil
MOA
MMF is converted to mycophenolic acid, the active form of the dru
g. This inhibits cytosine monophossphate dehydrogenase and secon
darily inhibits T cell lymphocyte proliferation; it interferes with leu
kocyte adhesion to endothelial cells through inhibition of E-selecti
n, P-selectin, and intracellular adhesion molecule 1.
Indication
effective for treatment of renal disease due to SLE and may be usef
ul in vasculitis and Wegeners granulomatosis.
treats RA at a dose of 2g/d
A/E
Gastrointestinal, hematopoietic, and hepatic toxicity
 Sulfasalazine
MOA
It is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is tho
ught that the sulfapyridine is probably the active moiety when treating R
A. IgA and IgM RF production are decreased. Suppression of T cell resp
onses to concanavalin and inhibition of in vitro B cell proliferation.
Indication
Treat RA and reduces radiologic disease progression, for juvenile chroni
c arthritis and ankylosing spondylitis and its associated uveitis.
A/E
nausea, vomiting, headache, rash, hemolytic anemia, methemoglobinemi
a, neutropenia, thrombocytopenia, pulmonary toxicity, reversible infertil
ity
Anti-IL-6 receptor antibody (tocilizumab)
MOA
binds to soluble and membrane bound IL-6 receptors, and inhibit the IL-6-
mediated signaling via these receptors. IL-6 is a proinflammatory cytokin
e produced by different cell types including T cells, B cells, monocytes, fi
broblasts, and synovial and endothelial cells. IL-6 is involved in a variety
of physiologic processes such as T cell activation, hepatic acute-phase pro
tein synthesis, and stimulaton of the inflammatory processes involved in d
iseases such as RA.
Indication
Treat RA
A/E
TB, fungal, viral and other opportunistic infections.
 Biologic
T-cell modulating biologic (Abatacept)
MOA
Inhibits the activation of T cells
Indication
Moderate to severe RA who have an inadequate response to
DMARDs or TNF antagonist.
A/E
Increased risk of infection, predominantly URT, hypersensiti
vity
 B-cell cytotoxic agent (rituximab)
MOA
chimeric monoclonal antibody biologic agent that targets CD20 B lymphocyt
es. This depletion takes place through cell-mediated and complement-depend
ent cytotoxicity and stimulation of cell apoptosis. Depletion of B lymphocyte
s reduces inflammation by decreasing the presentation of antigens to T lymp
hocytes and inhibiting the secretion of proinflammatory cytokines. It rapidly
depletes peripheral B cells, although this depletion correlates neither with eff
icacy nor with toxicity.
Indication
Treat RA
A/E
rashes
 IL-1INHIBITING AGENTS (ANAKINRA)
MOA
antagonizes human IL-1 receptors
Indication
Treat RA
A/E
Headache, sinusitis, nausea and diarrhea
TNF-ALPHA BLOCKING AGENTS (ADALIMUMAB, INFLIXIMAB,
ETANERCEPT)
MOA
fully human IgG1 anti-TNF monoclonal antibody. It complexes with soluble TNF-alpha
and prevents its interaction with p55 and p75 cell surface receptors.
Indication
Treat RA, ankylosing spondylitis, and psoriatic arthritis.
It decreases the rate of formation of new erosions.
A/E
risk of macrophage-dependent infection, leukopenia and vasculitis
 Infliximab
-chimeric (25% mouse, 75% human) IgG1 monoclonal antibody that binds with high affin
ity to soluble and possibly membrane-bound TNF-alpha.
MOA
same with adalimumab
Indication
treat RA, ankylosing spondylitis, Crohns disease, and psoriatic arthritis, psoriasis, ulcerat
ive colitis, juvenile chronic arthritis, Wegeners granulomatosis, giant cell arteritis, sarcoi
dosis
A/E
URTI, nausea, headache, sinusitis, rash, cough
 Etanercept
recombinant fusion protein consisting of twosoluble TNF p75 receptor moieties linked to t
he Fc portion of human IgG1
MOA
binds to TNF-alpha molecules and also inhibits lymphotoxin-alpha
Indication
Treat RA, juvenile chronic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis
A/E
latent TB