DMARDs

Disease Modifying Anti-Rheumatic Drugs

Dr Usman Nawaz
Pharmacology & Therapeutics
 Learning Objectives

1. Classify anti-inflammatory drugs

2. Describe the role of DMARDs as anti-inflammatory agents
3. Describe the role of glucocorticoids as anti-inflammatory agents
 Classification of Anti-Inflammatory Drugs

1. Corticosteroids
2. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
3. DMARDs (Disease Modifying Anti-Rheumatic Drugs)
4. Immunosuppressants
 Classification of Anti-Inflammatory Drugs

Corticosteroids NSAIDs
• Prednisolone • Aspirin (Dispirin)
• Dexamethasone • Ibuprofen (Brufen)
• Triamcinolone – Intraarticular • Flurbiprofen (Froben)
• Fluticasone – Inhaled • Diclofenac (Artifen)
• Mafenamic Acid (Ponstan)
 Classification of Anti-Inflammatory Drugs
Immunosuppressants (Biological
DMARDs Agents)
• Methotrexate • TNF-α Blockers
• Chloroquine & Hydroxychloroquine • Infliximab
• Etanercept
• Leflunomide
• Adalimumab
• Cyclophosphamide • Non TNF Agents
• Sulfasalazine • Abatacept
• Azathioprine • Rituximab
• Tocilizumab
 Inflammation
• Inflammation is a normal protective response to tissue injury – trauma,
chemicals, or microbiologic agents
• Inflammation is the body’s effort to inactivate or destroy invading
organisms, remove irritants, and set the stage for tissue repair
• Stimulation of the neutrophil membranes produces oxygen-derived free
radicals
• Interaction of these substances with arachidonic acid results in the
generation of chemotactic substances – propagating the inflammatory
process
 Inflammation

• Prostaglandins • Prostacyclin
• Promote edema and • Vasodilation
leukocyte infiltration • Reduces platelet
• Increase vascular aggregation
permeability • Thromboxane A2
• Enhance pain producing • Platelet aggregation
properties of bradykinin
• Vasoconstriction
 Cyclooxygenase (COX)

COX 1 COX 2
• Regulates normal cellular • Production of prostanoids at
processes the site of inflammation
• Gastric cytoprotection • Induced by inflammatory
• Vascular homeostasis – mediators like TNF-α & IL-1
Platelet aggregation • Inhibited by glucocorticoids
• Kidneys and reproduction
 Lipoxygenase

• Yields leukotrienes
• Powerful chemotactic effect on eosinophils, neutrophils and macrophages
• Promote bronchoconstriction and alterations in vascular permeability
 Immune Mediated Inflammation

• Inappropriate activation of the immune system can result in inflammation

leading to immune mediated diseases
• Auto Immune Diseases
• Rheumatoid Arthritis (RA)
• Systemic Lupus Erythematosus (SLE)
• Normally, the immune system can differentiate between self and non-self
• In RA – WBCs view the synovium as non-self and initiate an inflammatory
attack
 Cell Mediated Immunity

• WBC activation leads to stimulation of T lymphocytes (Cell mediated

immunity) which recruit and activate monocytes and macrophages

• These cells secrete proinflammatory cytokines like TNF-α and IL-1 into the
synovial cavity
 Effects of Cytokines

1. ↑ proinflammatory cellular infiltration into the endothelium due to release

of histamines, kinins, and vasodilatory prostaglandins
2. ↑ production of CRP by hepatocytes (marker of inflammation)
3. ↑ production and release of proteolytic enzymes by chondrocytes, leading
to degradation of cartilage and joint space narrowing
4. ↑ osteoclast activity, resulting in focal bone erosions and bone
demineralization around joints
5. Systemic manifestations in certain organs such as the heart, skin etc.
 Antibody Mediated Immunity

• In addition to T-lymphocytes (Cell mediated immunity), B lymphocytes are

also activated (Antibody mediated immunity)

• Produce Rheumatoid Factor (inflammatory marker) and other

autoantibodies

• To maintain inflammation
 Ultimate Effects of Immune Response

• Progressive tissue injury

• Joint damage and erosions
• Functional disability
• Significant pain
• Reduction in quality of life
 Rheumatoid Arthritis

• RA is an autoimmune disease that results in a chronic systemic inflammation

that affect many tissues and organs, but principally attacks synovial joints

• Lungs, pleura, pericardium, kidneys, eyes etc.

 Pharmacotherapy for RA – Goals

1. Relief of symptoms (pain etc.) and the maintenance of function

• NSAIDs
• Corticosteroids
2. Slowing or arrest of the tissue-damaging process
• DMARDs
• Corticosteroids
• Immunosuppressants
 Corticosteroids

• Prednisolone – Oral, IV
• Triamcinolone – Intraarticular – preferable as compared to increasing oral
dose of steroids
• Delayed Release Prednisolone
• Morning stiffness and joint pain follow a circadian rhythm - ↑ cytokines in the early
morning
• The outer layer dissolves over 4–6 hours, releasing the prednisone
• Taking the drug at 9–10 pm results in a small pulse of prednisone at 2–4 am
 Corticosteroids

• Used in 60-70% of RA patients

• Prompt and dramatic effects
• Serious adverse effects
• Useful for exacerbation of RA and extra articular complications
• Prednisolone – max dose 7.5 mg/day
• Tapering of dose
• Alternate day corticosteroid therapy – unsuccessful in RA
 Corticosteroids – Adverse Effects

• Adrenal Suppression • Osteoporosis

• Iatrogenic Cushing's syndrome • Muscle wasting

• Peptic ulcers • Growth retardation in children

• Superimposed bacterial & • Cataract

fungal infections • Glaucoma
• Diabetes Mellitus • Psychosis or Depression
• Salt retention And Hypertension
 Anti-Inflammatory & Immunosuppressive Effects

• Inhibition of phospholipase A2
• ↓ Prostaglandin
• ↓ Leukotriene
• ↓ Platelet-activating factor

• Antibody production can be reduced by large doses of steroids

• Also decrease capillary permeability by reducing the amount of histamine
released by basophils and mast cells
 Anti-Inflammatory & Immunosuppressive Effects

• ↓ Lymphocytes (T and B cells)

• ↓ Monocytes
• ↓ Eosinophils
• ↓ Basophils
• ↑ Neutrophils
 Anti-Inflammatory & Immunosuppressive Effects

• The increase in neutrophils is both due to the increased influx into the blood
from the bone marrow and to the decreased migration from the blood
vessels, leading to a reduction in the number of cells at the site of
inflammation

• The reduction in circulating lymphocytes, monocytes, eosinophils, and

basophils is primarily the result of their movement from the vascular bed to
lymphoid tissue
 Anti-Inflammatory & Immunosuppressive Effects

• Glucocorticoids also inhibit the functions of tissue macrophages and other

antigen-presenting cells
• ↓ response to antigens and mitogens
• ↓ phagocytosis and killing of microorganisms
• ↓ production of TNF, IL-1, metalloproteinases, and plasminogen
activator
• ↓ IL-12 and interferons – Important inducers cellular immunity
 Corticosteroids Uses as Anti-Inflammatory

• RA • Asthma
• SLE • IBD
• Gout • Giant cell arteritis
• Vasculitis
• Wegener’s granulomatosis
• Sarcoidosis
 DMARDs

• Disease Modifying Anti Rheumatoid Drugs

• Onset of Action – 6 weeks to 6 months
• Slow the course of the disease
• Stop progression of diseases
• Induce remission
 DMARDs

• DMARDs should be started within 3 months to help stop the progression of

the disease at the earlier stages.
• NSAIDs or corticosteroids may also be used for relief of symptoms if needed
• All DMARDs can cause severe or fatal toxicities
• Careful monitoring of patients who take these drugs is mandatory
 Choice of Drug

• No DMARD is efficacious and safe

• Trials of several different drugs may be necessary.
• Low disease – Monotherapy may be initiated with any of the DMARDs
• Moderate to high disease – combination DMARD therapy or use of anti-TNF
drugs
• More established disease – Biologic therapies (abatacept, rituximab) can be
considered
 DMARDs

• Methotrexate • Azathioprine
• Chloroquine & Hydroxychloroquine • Penicillamine
• Mycophenolate mofetil • Leflunomide
• Cyclophosphamide • Gold salts (Auranofin)
• Cyclosporine • Sulfasalazine
• Abatacept • Miocycline
 Methotrexate (MTX)

• DMARD of first choice

• It is anticancer drug but the dose used for RA is very low
• 15–25 mg - given once a week
• Alone or in combination
• Response to methotrexate occurs within 3 to 6 weeks of starting treatment
 Methotrexate – MOA

• Folic acid antagonist

• At low dose, some inhibition of
dihydrofolate reductase
• This affects lymphocyte and
macrophage function
• But this is not its principal
mechanism of action
 Methotrexate – MOA

• Inhibition enzymes
• Amino-imidazole-carboxamide ribonucleotide (AICAR)
transformylase
• Thymidylate synthetase
• AICAR inhibits AMP deaminase (normally destroy AMP) – accumulation of
AMP intracellularly – AMP released and converted extracellularly into
adenosine – which is potent inhibitor of inflammation
 Methotrexate – MOA

• Secondary effect on polymorphonuclear chemotaxis

• Direct inhibition of proliferation of inflammatory cells

• Stimulates apoptosis in inflammatory cells
• Inhibition of proinflammatory cytokines
 Methotrexate – Clinical Indications

• Rheumatoid Arthritis (RA) • Polymyositis

• Juvenile chronic arthritis • Dermatomyositis
• Systemic lupus erythematous • Vasculitis
(SLE)
• Wegener's granulomatosis
• Psoriatic arthritis • Giant cell arteritis
• Psoriasis
• Ankylosing spondylitis
 Methotrexate – Adverse Effects
• Nausea and mucosal ulcers (most • Hepatotoxicity
common)
• Pneumonia like syndrome
• Result of inhibiting cellular
proliferation • Hypersensitivity (rarely)
• Leukopenia • Can be reduced by the use of
• Anemia • Leucovorin (Folinic Acid)
• Alopecia • 24 hour after weekly dose
• Stomatitis • This may decrease the efficacy
of the methotrexate by 10%
• GI Ulceration
• Contraindicated in pregnancy
 Chloroquine & Hydroxychloroquine

• Used for malaria

• Anti-inflammatory mechanism – unclear
• Extensively tissue bound – large Vd
• Deposited particularly in melanin containing tissues such as eyes
• Half-lives up to 45 days
• For RA, SLE etc.
 Chloroquine & Hydroxychloroquine

• The following mechanisms have been proposed:

1. Suppression of T-lymphocyte responses to mitogens
2. Decreased leukocyte chemotaxis
3. Stabilization of lysosomal enzymes
4. Inhibition of DNA and RNA synthesis
5. Trapping of free radicals
 Chloroquine & Hydroxychloroquine

• Adverse Effects
• Ocular toxicity (irreversible retinal damage and corneal deposits) –
monitoring every 12 month
• Dyspepsia, nausea, vomiting, abdominal pain, rashes and nightmares
• These drugs appear to be relatively safe in pregnancy
 Sulfasalazine

• Sulfasalazine is metabolized to Sulfapyridine and 5-aminosalicylic acid (5-

ASA)
• Sulfapyridine is the active moiety when treating rheumatoid arthritis (unlike
5-ASA in inflammatory bowel disease)
• For early mild RA in combination with MTX
• Onset of action 1-3 months
• Safe in pregnancy
 Sulfasalazine

• Enterohepatic recirculation – Reduced by intestinal bacteria to liberate

Sulfapyridine and 5-aminosalicylic acid

• Sulfapyridine is well absorbed while 5-aminosalicylic acid remains

unabsorbed
 Miscellaneous DMARDs

• Azathioprine → 6-Thioguanine – Suppresses inosinic acid synthesis, B-cell

and T-cell function, immunoglobulin production, and IL-2 secretion
• Cyclophosphamide – Cross-links DNA to prevent cell replication –
Suppresses T-cell and B-cell function by 30–40%
• Cyclosporine – Antibiotic – regulate gene transcription - ↓ IL-1 & IL-2
receptors production - ↓ T Cell activation
 Miscellaneous DMARDs

• Leflunomide – Inhibits dihydroorotate dehydrogenase (DHODH) required

for pyrimidine synthesis - ↓ proliferation of lymphocytes
• Minocycline – Antibiotic – Mild RA
• Mycophenolate mofetil → mycophenolic acid - Inhibits IMP dehydrogenase
– suppression of T- and B-lymphocyte proliferation – Also interferes with
leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-
selectin & and intercellular adhesion molecule 1
 Biological Therapies

• IL-1, IL-6 and TNF-α are proinflammatory cytokines involved in the

pathogenesis of RA
• Stimulate synovial cells to proliferate and synthesize collagenase,
degrading cartilage, stimulating bone resorption, and inhibiting
proteoglycan synthesis
 Inflammation

• T lymphocytes need two interactions to become activated

1. The APCs (i.e. macrophages or B cells) must interact with the receptor on
the T cell
2. The CD80/CD86 protein on the APC must interact with the CD28 protein
on the T cell
 Inflammation

• B lymphocytes propagate the inflammatory process in the synovium by

1. Activating T lymphocytes by presenting antigen
2. Producing autoantibodies and rheumatoid factor
3. Producing proinflammatory cytokines such as TNF-α and IL-1
 Biological Therapies

TNF α blockers Non TNF biological therapy

• Infliximab • Tocilizumab – IL-6 Antagonist
• Etanercept • IL-1 Antagonists
• Adalimumab • Anakinra, Canakinumab,
• Certolizumab Rilonacept

• Golimumab • Abatacept
• Rituximab
• Tofacitinib
 Infliximab

• Chimeric monoclonal antibody composed of human and murine regions

• The antibody binds to human TNF-α and inhibits binding with its receptors
• Combined with MTX
• Not indicated for monotherapy – development of anti-infliximab antibodies
• IV infusion every 8 weeks
 Adverse Effects

• Infusion reactions (fever, chills, pruritus, urticaria)

• Immunosuppression - ↑ risk for infections (activation of latent tuberculosis,
fungal opportunistic infections, and pancytopenia)
• ↑ risk of lymphoma and other cancers
• Can worsen heart failure
• Live vaccinations should not be administered while on TNF-a inhibitor
therapy
 Clinical Uses

• Rheumatoid arthritis • IBD

• Juvenile chronic arthritis • Crohn's disease
• Ankylosing spondylitis • Ulcerative colitis
• Psoriatic arthritis • Wegener's granulomatosis
• Psoriasis • Giant cell arteritis
• Sarcoidosis
 Rituximab

• Chimeric murine/human monoclonal antibody

• Directed against CD20 antigen found on the surface of B lymphocytes
• Resulting in B-cell depletion through cell mediated and complement-
dependent cytotoxicity and stimulation of cell apoptosis
• Decrease presentation of antigens to T lymphocytes and inhibiting the
secretion of proinflammatory cytokines.
• IV infusion 4-6 monthly – methylprednisolone to avoid infusion reaction
 Tocilizumab

• Monoclonal antibody
• IL-6 receptor blocker
• IV every 4 week
• Neutropenia, lipid disturbance, GL perforation, multiple sclerosis, rarely
anaphylaxis, anti tocilizumab antibodies
 Miscellaneous

• Abatacept – fusion protein – contains the endogenous ligand CTLA-4 –

binds to CD80 and 86 on APC, thereby inhibiting the binding to CD28 on T
cell and preventing the activation of T cells
• Tofacitinib – Oral inhibitor of intracellular Janus kinases enzymes
interrupting JAK-STAT
• IL-1 Antagonists
• Anakinra, Canakinumab, Rilonacept