[03.25] Disease-Modifying Anti-Rheumatic Drugs (DMARDs) V2

Chronic progressive immunologic disease

What is Rheumatoid Arthritis (RA) described as?

Symmetric, peripheral polyarthritis

What is the main jointChronic progressive immunologic disease

Symmetric, peripheral polyarthritis

What is the main joint manifestation of Rheumatoid Arthritis?

Systemic effects

What significant type of effects does RA cause, besides joint inflammation?

Subcutaneous nodules, pericarditis, leukocytosis, peripheral neuropathy, difficulty breathing, pericardial effusion, and vasculitis

Name three nonspecific extra-articular manifestations of RA.

Symmetrical

What type of manifestation distinguishes RA from other types of arthritis like septic arthritis and osteoarthritis?

Females of reproductive age (25-55 y.o.)

Which demographic does RA usually affect?

Most common form of chronic inflammatory arthritis

How is RA characterized regarding its prevalence among chronic inflammatory arthritis types?

Hematologic Abnormalities

What might the majority of people with autoimmune disorders normally manifest with?

Anemia

Which hematologic abnormality is common among those with auto-immune diseases?

Morning Joint Stiffness

What is a common presentation of RA related to time of day?

More than one hour

How long does the pain from morning joint stiffness in RA last?

Improvement with physical activity takes a very long time

How does physical activity affect RA joint stiffness?

Small joints of the hand, specifically the PIP

What are the earliest joint involvements in RA?

Osteoarthritis

Where is DIP involvement more common, although it is seen in RA?

No inflammation

Why is Osteoarthritis considered a misnomer for arthritis?

Decrease inflammation, improve symptoms, slow down bone damage

Name two ways DMARDs modify the disease process.

DMARDs

Which drugs affect the inflammatory mechanisms more than steroids and NSAIDs?

More toxic

Compared to steroids and NSAIDs, what characteristic makes DMARDs different in terms of safety?

Slowing or even reversal of joint damage

What effect can DMARDs cause on joint damage?

2 weeks to 6 months

How long may it take for the benefits of DMARDs to become apparent?

SAARDs (Slow Acting Antirheumatic Drugs)

What is another name for DMARDs?

Conventional Synthetic DMARDs (csDMARDs) and Biologics

What are the two classes of DMARDs?

Monoclonal Antibodies

What is the primary type of Biologic DMARD?

-mabs

What suffix do Biologic DMARD names usually contain?

Aspirin, COX-2 inhibitors (e.g., Meloxicam), and other non-selective NSAIDs

Name two drugs included under NSAIDs.

Methotrexate, Azathioprine, Chloroquine, Cyclophosphamide, Cyclosporine, Leflunomide, Mycophenolate Mofetil, Sulfasalazine

Name four Conventional Synthetic DMARDs.

Hydatidiform moles and psoriasis

What are two uses of Methotrexate outside of being a DMARD?

Inhibit organ rejection for kidney transplant patients

What is a use for Azathioprine and Cyclosporine outside of being DMARDs?

Antimalarials

What is the use of Chloroquine and Hydroxychloroquine outside of being DMARDs?

Anti-cancer agent

What is the use of Cyclophosphamide outside of being a DMARD?

Lupus Erythematosus

Which disease is Mycophenolate Mofetil very good for?

Maintenance phase of Inflammatory bowel disorder/disease (IBD)

What is Sulfasalazine most commonly used for?

Gold salts (e.g. sodium thiomalate)

What was used in the past to treat RA?

High propensity to cause toxicities because of the heavy metal content

What was the problem with gold salts?

Methotrexate

Which csDMARD is also a Cancer chemotherapeutic drug?

Inhibits aminoimidazole carboxamide ribonucleotide (AICAR) transformylase and thymidylate synthase

What is one mechanism of action of Methotrexate?

Increase in adenosine

Inhibition of AICAR transformylase and thymidylate synthase leads to what change in a potent inhibitor of inflammation and polymorphonuclear chemotaxis?

First line csDMARD for treating rheumatoid arthritis

What is the primary clinical use designation for Methotrexate?

SLE, JRA, Psoriatic Arthritis, Ankylosing spondylitis, Polymyositis, Dermatomyositis, Wegener’s granulomatosis, Giant cell arteritis, Vasculitis

Name three clinical uses of Methotrexate besides RA.

Nausea, Mucosal Ulcer, Hepatotoxicity, Hypersensitivity, Pseudolymphomatous Reaction, Leukopenia, Anemia, Stomatitis, GI Ulcerations, Alopecia

Name three toxicities of Methotrexate.

Leucovorin (Folinic Acid)

What is the rescue agent for Methotrexate?

Within 24 hours

When must Leucovorin be given after Methotrexate administration?

Inhibitor of dihydrofolate reductase

Methotrexate is considered an inhibitor of what enzyme?

Sulfamethoxazole and Trimethoprim combination (Co-trimoxazole)

What combination drug works similarly to Methotrexate by inhibiting folate?

6-thioguanine

What does Azathioprine form?

Suppression of inosinic acid synthesis, B-cell, and T-cell function, immunoglobulin production, and interleukin-2 secretion

What is one mechanism of action of Azathioprine?

Rheumatoid arthritis, Inflammatory bowel disease (IBD), Psoriatic arthritis, Reactive arthritis, Polymyositis, SLE, Behçet’s disease, Prevention of kidney transplant rejection

Name three clinical uses of Azathioprine.

Bone marrow suppression, Increased risk of infections, Increased incidence of lymphoma, Fever, Rash, Hepatotoxicity, Allergic Reactions, GI Upset

Name three toxicities of Azathioprine.

Allopurinol

Which xanthine oxidase inhibitor should not be given with Azathioprine?

Severe leukopenia or bone marrow suppression

What can result from the accumulation of 6-thioguanine nucleotides when Azathioprine is combined with Allopurinol?

Thiopurine methyltransferase (TPMT)

The production of 6-thioguanine nucleotides is dependent on what enzyme?

Hydroxychloroquine

What is a similar drug to Chloroquine?

Suppression of T-lymphocyte responses to mitogens, Decreased leukocyte chemotaxis, Stabilization of lysosomal enzymes, Inhibitor of DNA and RNA synthesis, Trapping of free radicals

Name two mechanisms of action of Chloroquine.

Rheumatoid arthritis, SLE, Sjögren's syndrome, Malaria

Name two clinical uses of Chloroquine.

Ocular toxicity (corneal and retinal pigmentation)

What is the most notable side effect of Chloroquine?

Check baseline ophthalmological function

What is important to do before starting Chloroquine treatment due to ocular toxicity?

Forms phosphoramide mustard

What does Cyclophosphamide form?

Cross-links DNA to prevent cell replication; Suppresses T-cell and B-cell function

What is one mechanism of action of Cyclophosphamide?

Rheumatoid arthritis, SLE, Vasculitis, Wegener's granulomatosis, Severe rheumatic diseases

Name three clinical uses of Cyclophosphamide.

Hemorrhagic cystitis

What is the very distinct side effect of Cyclophosphamide that is often asked in board exams?

Accumulation of acrolein (necrotoxic metabolite)

What causes hemorrhagic cystitis from Cyclophosphamide?

MESNA

What is the rescue agent for Cyclophosphamide?

Take in lots of water

What must patients taking Cyclophosphamide do to prevent hemorrhagic cystitis?

Inhibits interleukin-1 and interleukin-2 receptor production

What is the mechanism of action of Cyclosporine?

Inhibits macrophage–T-cell interaction and T-cell responsiveness

Inhibition of IL-1 and IL-2 receptor production leads to what effect?

Rheumatoid arthritis, SLE, Polymyositis, Dermatomyositis, Wegener’s granulomatosis, Juvenile rheumatoid arthritis, Tissue transplantation, Behcet’s Disease (eye involvement)

Name three clinical uses of Cyclosporine.

Nephrotoxicity, Hypertension, Hyperkalemia, Hepatotoxicity, Gingival hyperplasia, Hirsutism, Bladder cancer, Cardiotoxicity, Neurotoxicity

Name three toxicities of Cyclosporine.

Gingival hyperplasia or thickening of gums and Hirsutism

Name two distinct physical side effects of Cyclosporine that make patients look like "monsters".

Grapefruit juice

What food increases Cyclosporine bioavailability by as much as 62%?

CYP3A4 inhibitor

Why does grapefruit juice increase Cyclosporine bioavailability?

Retards the appearance of new bony erosions in RA

What specific effect of Cyclosporine is noted in RA?

A77-1726

What is the active metabolite of Leflunomide?

Inhibits dihydroorotate dehydrogenase

What enzyme does the active metabolite of Leflunomide inhibit?

Decrease in ribonucleotide synthesis

Inhibition of dihydroorotate dehydrogenase leads to what?

T-cell proliferation and reduction of autoantibodies by B cells

What does Leflunomide inhibit and reduce?

Diarrhea, Elevated liver enzymes, mild alopecia, weight gain, increased blood pressure, leukopenia, and thrombocytopenia

Name three toxicities of Leflunomide.

19 days

What is the mean plasma half-life of Leflunomide?

Once a week or every 2 weeks only

What is the usual administration frequency of Leflunomide due to its long half-life?

CI in pregnancy

What is a major contraindication for Leflunomide?

Mycophenolic acid

What is the active product of Mycophenolate Mofetil?

Inhibits cyclosine monophosphate dehydrogenase

What enzyme does Mycophenolic acid inhibit?

Inhibits T-cell and beta-cell lymphocyte proliferation

Inhibition of cyclosine monophosphate dehydrogenase leads to what?

SLE nephritis

What is Mycophenolate Mofetil famous in the treatment of?

Vasculitis, Wegener’s granulomatosis, Rheumatoid Arthritis

Name two clinical uses of Mycophenolate Mofetil besides SLE nephritis.

Gastrointestinal disturbances, Reversible myelosuppression (neutropenia), Hepatotoxicity

Name two primary toxicities of Mycophenolate Mofetil.

Sulfapyridine

What is the active metabolite of Sulfasalazine?

Inhibits the release of inflammatory cytokines (Ex. IL-1, -6, and -12, and TNF-α) produced by monocytes or macrophages

What is the mechanism of action of Sulfasalazine?

Rheumatoid arthritis (reduces radiologic disease progression), Inflammatory bowel disease, JRA, Ankylosing spondylitis, juvenile chronic arthritis, Psoriatic Arthritis, Spondyloarthropathy-associated uveitis

Name three clinical uses of Sulfasalazine.

Hemolytic anemia, Methemoglobinemia, Neutropenia, Thrombocytopenia, Pulmonary toxicity, Autoantibody formation (anti-dsDNA), Reversible infertility in men

Name three toxicities of Sulfasalazine.

Reversible infertility in men

What is a notable side effect of Sulfasalazine related to reproduction?

Maintenance agent/treatment for inflammatory bowel disease (IBD)

What is the primary use of Sulfasalazine?

Sulfapyridine

Which metabolite of Sulfasalazine is well absorbed?

5-aminosalicylic acid

Which metabolite of Sulfasalazine remains unabsorbed and is excreted via bile?

G6PD deficiency

For which patient condition is Sulfasalazine not recommended?

Large-molecule therapeutic agents, usually proteins

What are Biologic DMARDs?

Recombinant DNA technology

How are Biologic DMARDs often produced?

Expensive

What is a major characteristic of Biologic DMARDs that affects their use?

Tocilizumab, Rituximab, Adalimumab, and Etanercept

Name four Biologic DMARDs mentioned as common or used for other diseases (like COVID-19 or leukemia).

T & B cell inhibitors, IL-1 inhibitors, TNF-alpha blocking agents, and other biologics

What are the four groups of Biologic DMARDs?