Pharmacotherapy

in inflammatory arthritis

ARIFA MUSTIKA
PHARMACOLOGY DEPARTMENT
FACULTY OF MEDICINE UNIVERSITAS
AIRLANGGA
 Medicine
• NSAID
• Corticosteroide
• DMARD
• Cytokine inhibitors
Mechanism of action NSAID
 NSAID
Drug Dose ( mg) Rute Interval

Acetosal 500-1000 peroral 3-4 dd

Ibuprofen 200-400 peroral 3-4 dd
Indomethacin 25-50 peroral 3-4 dd
Ketoprofen 50-200 Peroral/supp/im 3-4 dd

Naproxen 275-550 peroral 2-3 dd

Ketorolac 15-60 im 3-4 dd
Piroxicam 10-40 Peroral/im/supp 1 dd

Tenoxicam 20-40 peroral 1 dd

Diclofenac Na 25-50 Peroral/im 3-4 dd
Nimesulid 100-200 peroral 2 dd
Meloxicam 7,5 – 15 Peroral/im/supp 1 dd

Celoxib 100-200 peroral 1-2 dd

Etodolac 200-300 mg peroral 3 dd
 Dr. Luar biasa Dr. Luar biasa
SIP No.1a SIP No.1a
Alamat praktek Alamat praktek
Surabaya,………………….. Surabaya,…………………..

R / Tab. Acetosal 500 mg No XX R / Cap Piroxicam 20 mg No XV

S 3 dd tab I S 1 dd Cap I
₰ ₰

R/ Ibuprofen 300 mg R/ Ketoprofen 100 mg supp No X

m f pulv da in caps td no XX S 2 dd supp I
S 3 dd cap I ₰
₰ R/ Inj Ketorolac 30 mg/mL 2 mL ampul No V
₰ S i.m.m
₰

Pro : Pro :
Usia: Usia:
Alamat: Alamat:
 Corticostroids
• Corticosteroids have been used in 60–70%
• slowing the appearance of new bone erosions.
• gradual reduction of the dose should be
encouraged.
• Thus glucocorticosteroids produce a delayed
but profound anti-inflammatory effect
Corticosteroids
• Glucocorticosteroids combine with a cytoplasmic
glucocorticosteroid receptor causing its dissociation
from a phosphorylated heat shock protein complex.
• The receptor glucocorticosteroid complex translocates
to the nucleus, where it binds to glucocorticosteroid
response elements (GREs) in DNA and acts as a
transcription factor.

• This increases the transcription of various

signal transduction proteins.
• In addition, the glucocorticosteroid receptor
interacts with both NFκB and AP-1 and
inhibits them from enhancing transcription of
many pro-inflammatory proteins.
Anti-inflammatory, immunosuppressive, and vasoconstrictive effects of
topical corticosteroids
Corticosteroids medicine
 Dr. Luar biasa Dr. Luar biasa
SIP No.1a SIP No.1a
Alamat praktek Alamat praktek
Surabaya,………………….. Surabaya,…………………..

R / Tab. Deksametason 0,5 mg No XX R / Tab. Metilprednisolon 4 mg mg No XX

S 3 dd tab I S uc
₰ ₰

R/ Inj Deksametason 5mg/mL 2 mL ampul No V R / Tab. Metilprednisolon 16 mg mg No XX

S i.m.m S uc
₰ ₰

Pro : Pro :
Usia: Usia:
Alamat: Alamat:
 Disease-modifying antirheumatic
drugs (DMARDs)
• is a category of otherwise unrelated drugs
defined by their use in rheumatoid arthritis to
slow down disease progression.
• The term is often used in contrast to nonsteroidal
anti-inflammatory drug (which refers to agents
that treat the inflammation but not the
underlying cause) and steroids (which blunt the
immune response but are insufficient to slow
down the progression of the disease).
• are not analgesic and do not inhibit COX, but they do
suppress the inflammatory process in inflammatory
arthritis.
• Their mechanisms are generally poorly understood.
• They are used in patients with progressive disease.
• Response (though unpredictable) is usually maximal in
four to ten weeks.
• Unlike NSAIDs, DMARDs reduce inflammatory markers
(historically, it was this effect that led to them being
referred to as ‘disease modifying’).
 Type of DMARDs
• These therapies include
– nonbiologic
– biologic.
• The nonbiologic agents include small molecule
drugs such as methotrexate, azathioprine,
chloroquine and hydroxychloroquine,
cyclophosphamide, cyclosporine, leflunomide,
mycophenolate mofetil, and sulfasalazine.
• Tofacitinib, though marketed as a biologic, is
actually a well-tolerated nonbiologic DMARD.
• Gold salts, which were once extensively used, are
no longer recommended because of their
significant toxicities and questionable efficacy.
• Biologics are large-molecule therapeutic agents,
usually proteins, that are often produced by
recombinant DNA technology.
• The biologic DMARDs approved for RA include:
– a T-cellmodulating biologic (abatacept),
– a B-cell cytotoxic agent (rituximab),
– an anti-IL-6 receptor antibody (tocilizumab),
– IL-1- inhibiting agents (anakinra, rilonacept,
canakinumab), and
– the TNF-α-blocking agents (five drugs)
Drug Dose ( mg)

Chloroquine/ 200-400 mg/day

Hydroxychloroquine

Sulphasalazin 500-2000mg/day
Methotrexate 5-30 mg/week
Azathiprine 1-2 mg/kgbb
Leflunomide 100mg/day for 3 days,
continue with 10-20 mg/day

Cyclosporine 5 mg/kgbw/day
 CHLOROQUINE & HYDROXYCHLOROQUINE
• Mechanism of Action:
– suppression of T-lymphocyte responses to mitogens,
– inhibition of leukocyte chemotaxis,
– stabilization of lysosomal enzymes,
– processing through the Fc-receptor,
– inhibition of DNA and RNA synthesis, and
– the trapping of free radicals.
• Pharmacokinetics:
– rapidly absorbed and 50% protein-bound in the plasma.
They are very extensively tissue-bound, particularly in
melanin-containing tissues such as the eyes. The drugs are
deaminated in the liver and have blood elimination half-
lives of up to 45 days.
Indications
– approved for RA, but they are not considered very
effective DMARDs.
– Dose-loading may increase rate of response. There
is no evidence that these compounds alter bony
damage in RA at their usual dosages (up to 6.4
mg/kg/d for hydroxychloroquine or 200 mg/d for
chloroquine). It usually takes 3–6 months to obtain
a response.
– used very commonly in SLE because they decrease
mortality and the skin manifestations, serositis, and
joint pains of this disease.
– They have also been used in Sjögren’s syndrome.
Adverse Effects

– ocular toxicity may occur at dosages greater

than 250 mg/d for chloroquine and greater than
6.4 mg/kg/d for hydroxychloroquine, it rarely
occurs at lower doses.
– ophthalmologic monitoring every 12 months
– dyspepsia, nausea, vomiting, abdominal pain,
rashes, and nightmares.
– These drugs appear to be relatively safe in
pregnancy.
 AZATHIOPRINE

Mechanism of Action:
• a synthetic nonbiologic DMARD that acts
through its major metabolite, 6-thioguanine.
• 6-Thioguanine suppresses inosinic acid
synthesis, B-cell and
• T-cell function, immunoglobulin production,
and IL-2 secretion
 Pharmacokinetics

• Orally or parenterally.
• Its metabolism is bimodal in humans, with rapid
metabolizers clearing the drug four times faster
than slow metabolizers.
• Production of 6-thioguanine is dependent on
thiopurine methyltransferase (TPMT), and
patients with low or absent TPMT activity (0.3%
of the population) are at particularly high risk of
myelosuppression by excess concentrations of
the parent drug, if dosage is not adjusted.
 Indications

• Azathioprine is approved for use in RA at a

dosage of 2 mg/kg/d. It is also used for the
prevention of kidney transplant rejection in
combination with other immune suppressants.
• Controlled trials show efficacy in PA, reactive
arthritis, polymyositis, SLE, maintenance of
remission in vasculitis, and Behçet’s disease.
• Azathioprine is also used in scleroderma;
however, in one study, it was found to be less
effective than cyclophosphamide in controlling
the progression of scleroderma lung disease.
 Adverse Effects

• bone marrow suppression,

• GI disturbances,
• increase in infection risk.
• lymphomas may be increased
• Rarely, fever, rash, and hepatotoxicity
• signal acute allergic reactions
 CYCLOSPORINE

Mechanism of Action:
• Cyclosporine is a peptide antibiotic but is
considered a nonbiologic DMARD. Through
regulation of gene transcription, it inhibits IL-1
and IL-2 receptor production and secondarily
inhibits macrophage-T-cell interaction and T-
cell responsiveness
• T-cell dependent B-cell function is also
affected.
Adverse Effects

• Leukopenia, thrombocytopenia, and to a

lesser extent, anemia are predictable.
• High doses can be cardiotoxic and sterility may
occur after chronic dosing at antirheumatic
doses, especially in women.
• Bladder cancer is very rare but must be looked
for, even 5 years after cessation of use.
Pharmacokinetics
• absorption is incomplete and somewhat
erratic, although a microemulsion formulation
improves its consistency and provides 20–30%
bioavailability.
• Grapefruit juice increases cyclosporine
bioavailability by as much as 62%.
• Cyclosporine is metabolized by CYP3A and
consequently is subject to a large number of
drug interactions
 indications

• Cyclosporine is approved for use in RA and

retards the appearance of new bony erosions.
• Its usual dosage is 3–5 mg/kg/d divided into
two doses.
• it may be useful in SLE, polymyositis and
dermatomyositis, Wegener’s granulomatosis,
and juvenile chronic arthritis.
 LEFLUNOMIDE
Mechanism of Action:
• active metabolite, A77-1726 inhibits dihydroorotate
dehydrogenase, leading to a decrease in ribonucleotide
synthesis and the arrest of stimulated cells in the G1
phase of cell growth.
• Consequently, leflunomide inhibits T-cell proliferation
and reduces production of autoantibodies by B cells.
Secondary effects include increases of IL-10 receptor
mRNA, decreased IL-8 receptor type A mRNA, and
decreased TNF-α-dependent nuclear factor kappa B
(NF-κB) activation.
Pharmacokinetics
• completely absorbed from the gut and has a
mean plasma half-life of 19 days.
• Its active metabolite, A77-1726, has
approximately the same half-life and is subject
to enterohepatic recirculation.
• Cholestyramine can enhance leflunomide
excretion and increases total clearance by
approximately 50%.
 Indications
• as effective as methotrexate in RA,
• including inhibition of bony damage.
• In one study, combined treatment with
methotrexate and leflunomide resulted in a
46.2% ACR20 response compared with 19.5%
in patients receiving methotrexate alone.
Adverse Effects
• Diarrhea occurs in approximately 25% of patients given
leflunomide, although only about 3–5% of patients
discontinue the drug because of this side effect.
Elevation
• in liver enzymes can occur. Both effects can be reduced
by decreasing the dose of leflunomide.
• Other adverse effects associated with leflunomide are
mild alopecia, weight gain, and increased blood
pressure.
• Leukopenia and thrombocytopenia occur rarely.
• This drug is contraindicated in pregnancy
 METHOTREXATE
Mechanism of Action:
• Methotrexate’s principal mechanism of action at the low doses
used in the rheumatic diseases probably relates to inhibition of
amino-imidazolecarboxamide ribonucleotide (AICAR)
transformylase and thymidylate synthetase. AICAR, which
accumulates intracellularly, competitively inhibits AMP
deaminase, leading to an accumulation of AMP.
• The AMP is released and converted extracellularly to
adenosine, which is a potent inhibitor of inflammation.
• As a result, the inflammatory functions of neutrophils,
macrophages, dendritic cells, and lymphocytes are suppressed.
• Methotrexate has secondary effects on
polymorphonuclear chemotaxis. There is some
effect on dihydrofolate reductase and this affects
lymphocyte and macrophage function, but this is
not its principal mechanism of action.
• Methotrexate has direct inhibitory effects on
proliferation and stimulates apoptosis in
immune-inflammatory cells. Additionally, it
inhibits proinflammatory cytokines linked to
rheumatoid synovitis
Pharmacokinetics
• The drug is approximately 70% absorbed after oral
administration
• It is metabolized to a less active hydroxylated product.
Both the parent compound and the metabolite are
polyglutamated within cells where they stay for
prolonged periods.
• Methotrexate’s serum half-life is usually only 6–9
hours. Hydroxychloroquine can reduce the clearance or
increase the tubular reabsorption of methotrexate.
Methotrexate is excreted principally in the urine, but
up to 30% may be excreted in bile.
 Indications
• Although the most common methotrexate dosing
regimen for the treatment of RA is 15–25 mg
weekly, there is an increased effect up to 30–35
mg weekly.
• The drug decreases the rate of appearance of
new erosions.
• Evidence supports its use in juvenile chronic
arthritis, and it has been used in psoriasis, PA, AS,
polymyositis, dermatomyositis, Wegener’s
granulomatosis, giant cell arteritis, SLE, and
vasculitis
Adverse Effects
• Nausea and mucosal ulcers are the most common
toxicities.
• Additionally, many other side effects such as
leukopenia, anemia, stomatitis, GI ulcerations, and
alopecia are probably the result of inhibiting cellular
proliferation.
• Progressive dose-related hepatotoxicity in the form of
enzyme elevation occurs frequently, but cirrhosis is
rare (<1%).
• Liver toxicity is not related to serum methotrexate
concentrations.
• A rare hypersensitivity-like lung reaction with
acute shortness of breath has been documented,
as have pseudo-lymphomatous reactions.
• The incidence of GI and liver function test
abnormalities can be reduced by the use of
leucovorin 24 hours after each weekly dose or by
the use of folic acid, although this may decrease
the efficacy of the methotrexate by about 10%.
• This drug is contraindicated in pregnancy
 SULFASALAZINE

Mechanism of Action:
• Sulfasalazine, a synthetic nonbiologic DMARD, is
metabolized to sulfapyridine and 5-aminosalicylic acid.
• The sulfapyridine is probably the active moiety when
treating RA
• Some authorities believe that the parent compound,
sulfasalazine, also has an effect. Suppression of T-cell
responses to concanavalin and inhibition of in vitro B-
cell proliferation are documented. In vitro,
sulfasalazine or its metabolites inhibit the release of
inflammatory cytokines produced byby monocytes or
macrophages, eg, IL-1, -6, and -12, and TNF-α.
 Pharmacokinetics
• Only 10–20% of orally administered sulfasalazine
is absorbed, although a fraction undergoes
enterohepatic recirculation into the bowel where
it is reduced by intestinal bacteria to liberate
sulfapyridine and 5-aminosalicylic acid
• Sulfapyridine is well absorbed while 5-
aminosalicylic acid remains unabsorbed.
• Some sulfasalazine is excreted unchanged in the
urine whereas sulfapyridine is excreted after
hepatic acetylation and hydroxylation.
• Sulfasalazine’s half-life is 6–17 hours.
 Indications
• Sulfasalazine is effective in RA and reduces
radiologic disease progression.
• It has also been used in juvenile chronic
arthritis, PA, inflammatory bowel disease, AS,
and
• spondyloarthropathy-associated uveitis. The
usual regimen is 2–3 g/d
 Adverse Effects
• Approximately 30% of patients using sulfasalazine
discontinue the drug because of toxicity.
• Common adverse effects include nausea, vomiting,
headache, and rash.
• Hemolytic anemia and methemoglobinemia also occur, but
rarely. Neutropenia occurs in 1–5% of patients, while
thrombocytopenia is very rare.
• Pulmonary toxicity and positive double- stranded DNA
(dsDNA) are occasionally seen, but drug-induced lupus is
rare.
• Reversible infertility occurs in men, but sulfasalazine does
not affect fertility in women.
• The drug does not appear to be teratogenic
 ABATACEPT
Mechanism of action:
• Abatacept is a co-stimulation modulator biologic
that inhibits the activation of T cells
• After a T cell has engaged an antigen-presenting
cell (APC), a second signal is produced by CD28
on the T cell that interacts with CD80 or CD86 on
the APC, leading to T-cell activation.
• Abatacept (which contains the endogenous ligand
CTLA-4) binds to CD80 and 86, thereby inhibiting
the binding to CD28 and preventing the activation
of T cells.
Pharmacokinetics
• The recommended dose of abatacept for the treatment of adult
patients with RA is three intravenous infusion “induction” doses
(day 0, week 2, and week 4), followed by monthly infusions.
• The dose is based on body weight; patients weighing less than 60 kg
receiving 500 mg, those 60–100 kg receiving 750 mg, and those
more than 100 kg receiving 1000 mg.
• Abatacept is also available as a subcutaneous formulation and is
given as 125 mg subcutaneously once weekly. JIA can also be
treated with abatacept with an induction schedule at day 0, week 2,
and week 4, followed by intravenous infusion every 4 weeks.
• The recommended dose for patients 6–17 years of age and
weighing less than 75 kg is 10 mg/kg, while those weighing 75 kg or
more follow the adult intravenous doses to a maximum not to
exceed 1000 mg.
• The terminal serum half-life is 13–16 days.
 Indications
• Abatacept can be used as monotherapy or in
combination with methotrexate or other
DMARDs in patients with moderate to severe
RA or severe PJIA.
• It is being tested in early RA and
methotrexate-naïve patients.
 Adverse Effects:
• There is a slightly increased risk of infection (as with other biologic
DMARDs), predominantly of the upper respiratory tract.
• Concomitant use with TNF-α antagonists or other biologics is not
recommended due to the increased incidence of serious infection.
• All patients should be screened for latent tuberculosis and viral
hepatitis before starting this medication.
• Live vaccines should be avoided in patients while taking abatacept
and up to 3 months after discontinuation.
• Infusion related reactions and hypersensitivity reactions, including
anaphylaxis, have been reported but are rare.
• Anti-abatacept antibody formation is infrequent (<5%) and has no
effect on clinical outcomes.
• There is a possible increase in lymphomas but not other
malignancies when using abatacept
 RITUXIMAB
Mechanism of Action:
• Rituximab is a chimeric monoclonal antibody biologic agent
that targets CD20 B lymphocytes
• Depletion of these cells takes place through cellmediated
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.
• Rituximab rapidly depletes peripheral B cells, although this
depletion correlates neither with efficacy nor with toxicity
Pharmacokinetics
• Rituximab is given as two intravenous
infusions of 1000 mg, separated by 2 weeks. It
may be repeated every 6–9 months, as
needed. Repeated courses remain effective.
• Pretreatment with acetaminophen, an
antihistamine, and intravenous glucocorticoids
(usually 100 mg of methylprednisolone) given
30 minutes prior to infusion decreases the
incidence and severity of infusion reactions
 Indications
• Rituximab is indicated for the treatment of
moderately to severely active RA in combination
with methotrexate in patients with an inadequate
response to one or more TNF-α antagonists.
• Rituximab in combination with glucocorticoids is
also approved for the treatment of adult patients
with Wegener’s granulomatosis (also known as
granulomatosis with polyangiitis) and microscopic
polyangiitis and is used in other forms of
vasculitis as well
 Adverse Effects
• About 30% of patients develop rash with the first 1000 mg
treatment; this incidence decreases to about 10% with the second
infusion and progressively decreases with each course of therapy
thereafter.
• These rashes do not usually require discontinuation of therapy,
although an urticarial or anaphylactoid reaction precludes further
therapy.
• Immunoglobulins (particularly IgG and IgM) may decrease with
repeated courses of therapy and infections can occur, although they
do not seem directly associated with the decreases in
immunoglobulins.
• Serious, and sometimes fatal, bacterial, fungal, and viral infections
are reported for up to one year of the last dose of rituximab, and
patients with severe and active infections should not receive
rituximab.
• Rituximab is associated with reactivation of hepatitis B
virus (HBV) infection, which requires monitoring before and
several months after the initiation of the treatment.
• Rituximab has not been associated with either activation of
tuberculosis or the occurrence of lymphomas or other
tumors
• Fatal mucocutaneous reactions have been reported in
patients receiving rituximab. Different cytopenias can
occur, which require complete blood cell monitoring every
2–4 months in RA patients.
• Other adverse effects, such as cardiovascular events, are
rare.
 Dr. Luar biasa
SIP No.1a
Alamat praktek
Surabaya,…………………..

R / Tab. Leflunomid 20 mg No X
S 1 dd tab I
₰

R/ Tab Metotreksat 2,5 mg No x

S 1 dd tab I
₰

Pro :
Usia:
Alamat:
 Reference
• Trevor AJ, Katzung BG, Hall MK.
Pharmacodynamics. . In: Katzung. BG, editor.
Pharmacology 11: Mc Graw Hill; 2015.
• James M Ritter, Lionel D Lewis, Timothy GK Mant
and Albert Ferro, 2008. A Textbook of Clinical
Pharmacology and Therapeutics
• Pedoman diagnosis dan terapi Ilmu Penyakit
Dalam. RSUD Dr Soetomo Surabaya
• Jasvinder A. Singh et.al.,2015. American College
of Rheumatology Guideline for the Treatment of
Rheumatoid Arthritis