Disease Modifying Anti-Rheumatic

Agents (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)
that triggers an autoimmune reaction, leading to synovial
hypertrophy and chronic joint inflammation along with
potential for extra-articular manifestations.
No lab test results but the presence of anti-cyclic citrullinated
protein antibody (ACPA) and rheumatoid factor (RF) is highly
specific.
 Etiology
Genetic
-Human leukocyte antigen (HLA-DR4) cluster
constitutes 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
RA.
Note: Cytokine plays a central role in the perpetuation of
synovial inflammation.
Infectious factors
-Mycoplasma organisms, Epstein-Barr virus (EBV) and
rubella virus
-Periodontopathic bacteria including Porphyromonas
gingivalis
Socio-economic,psychological and lifestyle factors influence
disease development and outcome.
 DMARDs
Non-biologic
azathioprine, chloroquine and hydroxychloroquine,
cyclosphophamide, cyclosporine, leflunomide, methotrexate,
mycophenolate mofetil 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
significant toxicities.
 Non-biologic
Azathioprine
MOA: acts through its major metabolite, 6-thioguanine. It suppresses
anosinic acid synthesis, B-cell and T-cell function, immunoglobulin
production, and IL-2 secretions.
Indication:
for use in RA at 2mg/kg/d
for the prevention of kidney transplant rejection in combination
with other immune suppressants
A/E:
Bone marrow suppression, GI disturbances, lymphomas, and
increase in infection risks
 Chloroquine and Hydroxychloroquine
MOA: Suppression of T lymphocyte responses to mitogens, decreased leukocyte
chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA
sysnthesis, and the trapping of free radicals.
Indications:
mainly used for malaria
often used for skin manifestations, serositis, and joint pains of SLE, and
Sjgrens 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
hyrdoxychloroquine
dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares.

Note: safe for pregnant women

 Cyclosphophamide
MOA:
major active metabolite is phosphoramide mustard, which cross-
links DNA to prevent cell replication. It suppresses T-cell and B-
cell function.
Indication:
active against RA when given orally at dosages of 2mg/kg/d but not
when given IV.
treat SLE, vasculitis, Wegeners granulomatosis, other severe RD.
A/E:
Infertility in both men and women, bone marrow supression,
alopecia, hemorrhagic cystitis, and bladder carcinoma.
 Cyclosporine
MOA
Through regulation of gene transcription, it inhibits interleukin-1 and
interleukin-2 receptor production and secondarily inhibits macrophage
T- cell interaction and T-cell responsiveness
Indication
for RA and retards the appearance of new bony erosions. Maybe useful
in SLE, polymyositis and dermatomyositis, Wegeners granulomatosis,
and juvenile chronic arthritis.
A/E
neohrotoxicity, hypertension, hyperkalemia, hepatotoxicity, gingival
hyperplasia, 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
active metabolite A77-1726. This metabolite inhibits dihydroorotate
dehydrogenase, leading to a decrease in ribonucleotide synthesis and the
arrest of stimulated cells in the G1 phase of cell growth. It inhibits T cell
proliferation and production of autoantibodies by B cells. Secondary effects
include interleukin-10 receptor mRNA, decreased interleukin-8 receptor type
A mRNA, and decreased 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
gain, increased blood pressure, leukopenia, thrombocytopenia
 Methotrexate
MOA
Inhibit aminoimidazolecarboxamide ribonucleotide transfomylase
and thymidylate synthetase, with secondary effects
onpolymorphonuclear chemotaxis. Some effect on dihydrofolate
reductase and this affects lymphocyte and macrophage function
Indication
juvenile chronic arthritis, psoriasis, psoriatic arthritis, ankylosing
spondylitis, polymyositis, dermatomyositis, Wegeners
granulomatosis, giant cell aneritis, SLE, and vasculitis
A/E
Nausea and mucosal ulcers, hepatotoxicity, cirrhosis,
hypersensitivity, pseudolymphomatous reactions
 Mycophenolate mofetil
MOA
MMF is converted to mycophenolic acid, the active form of the
drug. This inhibits cytosine monophossphate dehydrogenase and
secondarily inhibits T cell lymphocyte proliferation; it interferes
with leukocyte adhesion to endothelial cells through inhibition of E-
selectin, P-selectin, and intracellular adhesion molecule 1.
Indication
effective for treatment of renal disease due to SLE and may be
useful 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
thought that the sulfapyridine is probably the active moiety when
treating RA. IgA and IgM RF production are decreased. Suppression of
T cell responses to concanavalin and inhibition of in vitro B cell
proliferation.
Indication
Treat RA and reduces radiologic disease progression, for juvenile
chronic arthritis and ankylosing spondylitis and its associated uveitis.
A/E
nausea, vomiting, headache, rash, hemolytic anemia,
methemoglobinemia, neutropenia, thrombocytopenia, pulmonary
toxicity, reversible infertility
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
cytokine produced by different cell types including T cells, B cells,
monocytes, fibroblasts, and synovial and endothelial cells. IL-6 is
involved in a variety of physiologic processes such as T cell activation,
hepatic acute-phase protein synthesis, and stimulaton of the
inflammatory processes involved in diseases 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,
hypersensitivity
 B-cell cytotoxic agent (rituximab)
MOA
chimeric monoclonal antibody biologic agent that targets CD20 B
lymphocytes. This depletion takes place through cell-mediated and
complement-dependent cytotoxicity and stimulation of cell apoptosis.
Depletion of B lymphocytes reduces inflammation by decreasing the
presentation of antigens to T lymphocytes and inhibiting the secretion of
proinflammatory cytokines. It rapidly depletes peripheral B cells, although
this depletion correlates neither with efficacy 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
affinity to soluble and possibly membrane-bound TNF-alpha.
MOA
same with adalimumab
Indication
treat RA, ankylosing spondylitis, Crohns disease, and psoriatic arthritis, psoriasis,
ulcerative colitis, juvenile chronic arthritis, Wegeners granulomatosis, giant cell arteritis,
sarcoidosis
A/E
URTI, nausea, headache, sinusitis, rash, cough
 Etanercept
recombinant fusion protein consisting of twosoluble TNF p75 receptor moieties linked to
the 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