DMARD

Question 1

DRUGS FOR RHEUMATOID ARTHRITIS

Answer 1

• NSAIDs
• Corticosteroids
• DMARDs

Note: NSAIDs and corticosteroids do not prevent disease progression or joint destruction.

Question 2

DMARD Drug list

Answer 2

• miscellaneous group of drugs with the potential to reduce or prevent joint damage.
• have no immediate analgesic effects, but can control symptoms and can delay and possibly stop progression of the disease.

Non-Biologicals

• Methotrexate
• Leflunomide
• Hydroxychloroquine
• Sulfasalazine
• Cyclosporine
• Azathioprine
• Cyclophosphamide
• Gold Compounds

Biologicals

• Anti-TNF Drugs: Adalimumab, Infliximab, Etanercept
• Anti-Interleukin Drugs: Anakinra
• Rituximab
• Abatacept

Question 3

METHOTREXATE

Answer 3

DMARD of first choice to treat rheumatoid arthritis.

1o MOA: Inhibits amino imidazole carboxamide ribonucleotide (AICAR) transformylase.

• AICAR Transformylase catalyzes the penultimate and final steps in de novo purine biosynthesis which lead to synthesis of inosine monophosphate (IMP).
• The inhibition of AICAR transformylase results in the accumulation and release of adenosine.

Other MOA:

• Adenosine is a potentanti-inflammatory mediator. Adenosine, acting on A2b receptors, suppresses NF-kappaB activation induced by TNF and other inflammatory stimuli.
• DHF Reductase inhibition: thymidylate synthase pathway also may be involved.

Adverse

• Nausea
• Mucosalulcers
• Hepatotoxicity
• Cirrhosisisrare
• Toxicity can be reduced with leucovorin or folic acid
• Contraindicated in pregnancy.

Question 4

LEFLUNOMIDE

Answer 4

• Leflunomide undergoes conversion to an active metabolite which inhibits dihydroorotate dehydrogenase, leading to lower levels of UMP.
• Cells arrest in the G1 phase.
• Thus, leflunomide inhibits autoimmune T cell proliferation and production of autoantibodies by B cells.
• Other cells are not affected because they can use the salvage pathways to maintain their basal requirements for pyrimidines.
• Activated lymphocytes depend on the de novo synthesis of pyrimidine because their need is increased eightfold.

Adverse

• Diarrhea.
• Reversible alopecia, rash, myelosuppression and increases in aminotransferase activity.
• CBC and LFT should be monitored.
• Carcinogenic and teratogenic in animals.
• Contraindicated in pregnancy.

Question 5

HYDROXYCHLOROQUINE

Answer 5

• mechanism of anti-inflammatory action is unclear.
• Often used with methotrexate and sulfasalazine.

Adverse

• Hemolysis may occur in patients with G6PD deficiency.
• Retinal damage is a rare complication.
• Ophthalmologic exam is recommended before treatment, and regularly afterwards.

Question 6

SULFASALAZINE

Answer 6

Consists of sulfa pyridine and 5-aminosalicylic (5-ASA) connected by a diazo bond.

Metabolized by bacteria in the colon to the constituent moieties.

The 5-ASA moiety is thought not to be very important in rheumatoid arthritis (unlike in ulcerative colitis).

Adverse

• Nausea, anorexia and rash are common.
• Hepatitis,leukopenia and agranulocytos is are rare.
• A lupus-like syndrome has been reported.
• Hemolysis may occur in patients with G6PD deficiency.
• Probably safe in pregnancy.

Question 7

CYCLOSPORINE

Answer 7

• inhibits antigen-triggered signal transduction in T lymphocytes.
• Calcineurin is a phosphatase necessary for activation of a T- cell-specific transcription factor: NFAT.
• NFAT is required for the induction of cytokine genes.
• forms a complex with cyclophilin, an immunophilin. This complex inhibits calcineurin.
• Cyclosporine can be helpful in some patients with rheumatoid arthritis.

Adverse

• Nephrotoxicity and many interactions with drugs and foods limit its use.
• Main adverse reactions: Nephrotoxicity, tremor, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, hirsutism, gum hyperplasia.
• Nephrotoxicity is limiting and occurs in the majority of patients treated. It is the major indication for cessation or modification of therapy.
• Very little bone marrow toxicity.

Question 8

AZATHIOPRINE

Answer 8

• Purine antimetabolite.
• Azathioprine is converted to 6-mercaptopurine, which, in turn, is converted to additional metabolites, which inhibit de novo purine synthesis.
• This leads to suppression of B and T cell function.
• Indications: used for patients with refractory rheumatoid arthritis.

Adverse

• Bone marrow suppression
• GI disturbances
• Infections and malignancies.

Question 9

CYCLOPHOSPHAMIDE

Answer 9

• Cross-links DNA, thereby preventing cell replication.
• Cyclophosphamide is generally limited to the most severe cases of rheumatoid arthritis.

Adverse

• Bone marrow suppression, infertility and hemorrhagic cystitis.
• Long-term use increases risk of infection and malignancy.

Question 10

GOLD COMPOUNDS

Answer 10

• Gold sodium thiomalate. Given IM.
• Auranofin. Given orally.
• Gold salts are taken up by macrophages and suppress phagocytosis and lysosomal enzyme activity.
• This mechanism retards progression of bone and articular destruction.
• Because of their toxicity gold compounds are used infrequently today.

Question 11

ADALIMUMAB

Answer 11

• ANTI-TNF DRUGS
• Fully human IgG1 anti-TNF monoclonal antibody.
• Binds to soluble TNF-alpha and prevents its interaction with TNF receptors.
• This results in down- regulation of macrophage and T cell function.

Question 12

INFLIXIMAB

Answer 12

• ANTI-TNF DRUGS
• Chimeric monoclonal anti-TNF-alpha antibody.
• Binds to human TNF-alpha

Question 13

ETANERCEPT

Answer 13

• ANTI-TNF DRUGS
• Recombinant fusion protein: two TNF receptors linked to the Fc portion of human IgG1.
• Binds TNF-alpha molecules

Question 14

ADVERSE EFFECTS OF THE ANTI-TNF-alpha DRUGS

Answer 14

• Cytopenias can occur. CBC should be monitored regularly.
• Serious infections are the most important potential adverse effects of TNF inhibition.
• These drugs should not be given to patients with an active infection.
• Patients should be screened for latent TB infection before and during treatment with a TNF inhibitor.

Question 15

ANAKINRA

Answer 15

• ANTI-INTERLEUKIN DRUGS
• IL-1 receptor antagonist

Question 16

RITUXIMAB

Answer 16

• ANTI-INTERLEUKIN DRUGS
• Chimeric monoclonal antibody that targets CD20 B lymphocytes.
• Causes B-cell depletion.

Question 17

ABATACEPT

Answer 17

• ANTI-INTERLEUKIN DRUGS
• Fusion protein that interferes with T-cell activation.

Question 18

CHOICE OF DRUGS

Answer 18

• For initial treatment most clinicians prescribe a non-biological DMARD plus a NSAID or a corticoid to control symptoms.
• Methotrexate is generally the DMARD of choice.
• In patients with moderate to severe disease, combining a biologic DMARD with a non-biologic DMARD for initial treatment may provide better disease control than a DMARD alone.
• TNF inhibitors are the first-line biologic agents prescribed.

Question 19

COMBINATION THERAPY

Answer 19

• NEVER COMBINE 2 BIOLOGICAL DMARDS
• Combination DMARD therapy may be more effective than monotherapy without a significant increase in toxicity.
• Combination therapy typically includes weekly methotrexate, to which other agents are added.
• Leflunomide in combination with methotrexate increases risk of hepatotoxicity: patients must be monitored closely.