Department of Orthopaedics, Father Muller Medical College

Disease modifying anti-rheumatoid drugs(DMARDs)

Moderator: Dr. Rajesh Bhat
Presented by: Dr. Terence Dsouza

DMARDs are so named because of their ability to slow or prevent structural progression of RA.
1. Traditional DMARDs:
Methotrexate
Hydroxychhloroquine
Sulfasalazine
Leflunomide
Azathioprine, cyclophosphamide,cyclosporine,mycophenolate mofetil.
2. TNF Inhibitors (infliximab, adalimumab, etancercept)
3. Newer biologics (abatacept, rituximab)

Methotrexate:

Methotrexate mainly inhibits DHFRase that inhibits conversion of folateDHF &

DHFTHF.
This inhibition deprives the cell of folate coenzymes and leads to decreased production
of compounds that depend on these coenzymes for their biosynthesis. Although these
molecules include the nucleotides adenine, guanine and thymidine and the amino acids
methionine and serine, depletion of thymidine is the most prominent effect.
This leads to depressed DNA, RNA, and protein synthesis and, ultimately, to cell death.
The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural
substrate: dihydrofolate, or by administration of N5 formyl THF( leucovorin, Folinic acid,
citrovorum factor) which bypasses the blocked enzyme and replenishes the folate pool.

Dose and Administration:

Dose ranges from 7.5 to 25 mg
ONLY GIVEN ONCE A WEEK
2.5 mg Tablets or Subcutaneous Injection 25 mg/mL
Onset of Action: 6-8 weeks
Pharmacokinetics:
Up to 90% of a given dose is excreted unchanged in the urine within 48 hours, mostly
within the first 8 to 12 hours.
Metabolism of Mtx in humans is usually minimal.
After high doses, however, metabolites are readily detectable; these include 7-hydroxy-,
which is potentially nephrotoxic. Renal excretion of Mtx occurs through a combination

of glomerular filtration and active tubular secretion. Therefore, the concurrent use of
drugs that reduce renal blood flow (e.g., nonsteroidal antiinflammatory agents), that are
nephrotoxic (e.g.,cisplatin), or that are weak organic acids (e.g., aspirin or piperacillin)
can delay drug excretion. Particular caution must be exercised in treating patients with
renal insufficiency

MOA in RA:
Methotrexate's principal mechanism of action at the low doses used in the rheumatic diseases probably
relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and
thymidylate synthetase, with 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, inhibition of proinflammatory cytokines linked to
rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid
arthritis.

Adverse effects:

Commonly observed toxicities: In addition to nausea, vomiting, and diarrhea, the

most frequent toxicities occur in tissues that are constantly renewing. Thus, MTX
causes stomatitis, myelosuppression, erythema, rash, urticaria, and alopecia.
Renal damage: Although uncommon during conventional therapy, renal damage
is a complication of high-dose MTX and its 7-OH metabolite, which can
precipitate in the tubules. Alkalinization of the urine and hydration help to
prevent this problem.
Hepatic function: Hepatic function should be monitored. Long-term use of MTX
may lead to cirrhosis.
Pulmonary toxicity: This is a rare complication. Children who are being
maintained on MTX may develop cough, dyspnea, fever, and cyanosis. Infiltrates
are seen on radiographs. This toxicity is reversible on suspension of the drug.

Chloroquine & Hydroxychloroquine:

MOA:
the intracellular pH, interferes with the cells ability to process & degrade proteins.

Pharmacokinetics:
Antimalarials are 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:
Antimalarials are approved for rheumatoid arthritis, but they are not considered very
effective DMARDs. Dose-response and serum concentration-response relationships
have been documented for HCQ and dose-loading may increase rate of response.
It usually takes 36 months to obtain a response.
Adverse Effects:
Although ocular toxicity may occur at dosages greater than 250 mg/d for chloroquine
and greater than 6.4 mg/kg/d for HCQ, it rarely occurs at lower doses. Nevertheless,
ophthalmologic monitoring every 612 months is advised.
Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and
nightmares. These drugs appear to be relatively safe in pregnancy.

Sulfasalazine:
Mechanism of Action:
Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid(ASA), and it is
thought that the sulfapyridine is probably the active moiety when treating rheumatoid
arthritis. Some authorities believe that the parent compound, sulfasalazine, also has an

effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are
decreased. Suppression of T & Bcell responses are also seen.
Pharmacokinetics:
Only 1020% 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 excreted after hepatic acetylation and hydroxylation. Sulfasalazine's
half-life is about 17 hours.
Indications
. The usual regimen is 23 g/d.
The drug does not appear to be teratogenic.
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 15% of patients, while thrombocytopenia is very rare.
Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women.
The drug does not appear to be teratogenic.
Sulfasalazine 500 mg tablets
o Week 1: Take 1 OD
o Week 2: Take 1-0-1
o Week 3: Take 2-0-1
o Week 4 & therafter: 2-0-2
Lab Monitoring (week 2, 4 and then monthly)

Leflunomide:
Mechanism of Action:
Leflunomide 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.Consequently, leflunomide inhibits T-cell proliferation and
production of autoantibodies by B cells.
Pharmacokinetics:
A77-1726, the active metabolite of leflunomide, is thought to have approximately the same
half-life and is subject to enterohepatic recirculation.
Adverse Effects:
Diarrhea occurs in approximately 25% of patients given leflunomide, although only
about 35% discontinue the drug because of this effect. Elevation in liver enzymes also
occurs. 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

Gold:
Mechanism of action: Chemotaxis, CMI.
It lowers RF & ESR & prevents joint destruction.
Given in both parenteral & oral forms(Auranofin)
Parenteral gold is heavily bound to plasma proteins & stays in the body for years,
Adverse effects: Hypotension,dermatitis,stomatitis, BM depression , kidney & liver damage.
Oral gold compound has 29% gold with 25% bioavailability, Main adverse effect is
diaarhoea(30%)
Rarely used now
d-Pencillamine:
similar action & adverse effects like gold, not preferred now

Immunosuppressants
Azathioprine:
Mechanism of Action:
Azathioprine acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses B-cell
and T-cell function, immunoglobulin production.
Pharmacokinetics
The metabolism of azathioprine 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 rheumatoid arthritis and is used at a dosage of 2 mg/kg/d.
Controlled trials show efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic
lupus erythematosus, and Behet's disease.
Adverse Effects:
Azathioprine's toxicity includes bone marrow suppression, gastrointestinal disturbances, and
some increase in infection risk & lymphomas may be seen with azathioprine use. Rarely, fever,
rash, and hepatotoxicity signal acute allergic reactions

Mycophenolate Mofetil:
Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug.
The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits
T-cell lymphocyte proliferation.
Although MMF is occasionally used at a dosage of 2 g/d to treat rheumatoid arthritis, there are
no well-controlled data regarding its efficacy in this disease.

Cyclophosphamide:
Mechanism of Action:

Cyclophosphamide's major active metabolite is phosphoramide mustard, which cross-links DNA

to prevent cell replication. It suppresses T-cell and B-cell function by 3040%; T-cell suppression
correlates with clinical response in the rheumatic diseases
Indications:
Cyclophosphamide is active against rheumatoid arthritis when given orally at dosages of 2
mg/kg/d but not when given intravenously

Cyclosporine:
Mechanism of Action:
Through regulation of gene transcription, cyclosporine inhibits interleukin-1 and interleukin-2
receptor production and secondarily inhibits macrophageT-cell interaction and T-cell
responsiveness.
Indications:Cyclosporine is approved for use in rheumatoid arthritis and retards the appearance
of new bony erosions. Its usual dosage is 35 mg/kg/d divided into two doses.
Adverse Effects:
Cyclosporine has significant nephrotoxicity, serum creatinine should be closely
monitored.
Other toxicities include hypertension, hyperkalemia, hepatotoxicity, gingival
hyperplasia, and hirsutism

Biologics
TNF Inhibitors
Adalimumab
Etanercept
Infliximab

IL-1 Inhibitors
Anakinra

T-Cell Co-Stimulatory Blockade

Abatacept (Orencia)

B-Cell Depletion
Rituximab (Rituxan)

TNF- Inhibitors
Mechanism of Action:
Infliximab and Adalimumab are antibodies directed against TNF
Etanercept is a soluble receptor decoy
Administration:
Infliximab is given intravenously
Etanercept and Adalimumab are given by subcutaneous injection
Adverse effects:
1. Infusion Reactions with Infliximab, Injection Site Reactions with Adalimumab and
Etanercept
2. Infection
Tuberculosis
Serious resulting in death
3. Malignancy
Increased risk of lymphoma early data
Solid tumors?
4. Neurologic
Multiple Sclerosis, seizures, inflammation of the ocular nerve
5. Autoimmune
Antibody formation SLE like illness
6. Worsening of Congestive Heart Failure
Abatacept(Orencia):
After a T cell has engaged an antigen
antigen-presenting
presenting cell (APC), a signal is produced by CD28 on the
T cell that interacts with CD80 or CD86 on the APC, leading to TT-cell
cell activation. Abatacept binds
to CD80 and 86, thereby inhibiting the binding to CD28 and preventing the activation of T cells.

Side Effects:
Infection
COPD exacerbation
Malignancy lung cancer
Rituximab:
Binds to CD 20 of B cells, and acts like a B cell depleter.
These B cells:
B-Cells cannot act as antigen presenting cells to activate T-Cells
B-Cells cannot produce Rheumatoid Factor
B-Cells cannot release cytokines
Drug dosage:
Given as two infusions of 1000mg spaced two weeks apart
All patients given 100 mg of solumedrol with each infusion
Takes about 3-4 months for onset of action
Time to re-treatment 6 to 9 months
Adverse reactions:
Infection, infusion reactions

Approach to the Patient: Rheumatoid Arthritis

The original treatment pyramid for RA is now considered to be obsolete and has evolved into a
new strategy that focuses on several goals:
(1) early, aggressive therapy to prevent joint damage and disability;
(2) frequent modification of therapy with utilization of combination therapy where appropriate;
(3) individualization of therapy in an attempt to maximize response and minimize side effects;

(4) achieving, whenever possible, remission of clinical disease activity. A considerable amount
of evidence supports this intensive treatment approach.
Mtx is the DMARD of first choice for initial treatment of moderate-to-severe RA. Failure
to achieve adequate improvement with Mtx therapy calls for consideration of an
effective combination regimen.
Effective combinations include:Mtx , sulfasalazine, and hydroxychloroquine (triple
therapy); Mtx and leflunomide; and Mtx plus a biological.
The combination of Mtx & an anti-TNF agent, for example, has been shown in
randomized, controlled trials to be superior to Mtx alone not only for reducing signs and
symptoms of disease, but also for retarding the progression of structural joint damage.
Remission:
Complete remission has been stringently defined as the total absence of all articular and
extraarticular inflammation and immunologic activity related to RA. However, evidence for this
state can be difficult to demonstrate in clinical practice. In an effort to standardize and simplify
the definition of remission for clinical trials, the ACR and EULAR developed two provisional
operational definitions of remission in RA.

ACR/Eular criteria for remission:

At any point, patient must satisfy all of the following:
Tender joint count 1
Swollen joint count 1
C reactive protein 1mg/dl
Patient global assessment 1(on a 0-10 scale)
OR
At any time point patient must have a simple disease activity index(SDAI) score of 3.3