DMARDs and Rheumatoid Arthritis

Learning Outcomes for DMARDs

• Describe mechanisms of action and roles of anti-rheumatic drugs (methotrexate, leflunomide, hydroxychloroquine, gold salts) in treating rheumatic conditions
• List indications and main side effects of these drugs
• Describe the roles of glucocorticosteroids in autoimmune diseases
• Describe unwanted effects of long-term glucocorticoid use and prevention
• Identify and describe the mechanism of action of immune modulators (etanercept, infliximab, adalimumab, anakinra) and their indications and side effects

Rheumatoid Arthritis (RA)

• RA is a chronic systemic inflammatory disease with unknown cause
• Usually presents as bilateral symmetric polyarthritis affecting hands and feet
• Any joint lined by a synovial membrane can be affected
• Extra-articular involvement of organs like skin, heart, lungs, and eyes can be significant

Rheumatoid Arthritis: Diagnosis

• The American College of Rheumatology requires at least four of the following criteria to confirm RA:
• Arthritis of hand joints for at least six weeks
• Arthritis on both sides of the body for at least six weeks
• Rheumatoid nodules under the skin
• Rheumatoid factor in blood testing
• Morning stiffness around the joint lasting at least one hour
• Arthritis of three or more joints for at least six weeks
• Evidence of rheumatoid arthritis on X-rays

Treatment of Rheumatoid Arthritis

• Joint destruction occurs early
• Begin DMARDs on diagnosis
• Combinations of drugs may be used
• The first and second years are critical

DMARDs for RA

• First-line agents: methotrexate and leflunomide
• Second-line agents: chloroquine, hydroxychloroquine, glucocorticosteroids
• Third-line agents: sulfasalazine, gold compounds, D-Penicillamine
• Biological agents: TNF inhibitors and others (immunomodulators)

DMARDs Mechanisms

• Act by various mechanisms to suppress proliferation and activity of lymphocytes and polymorph-nuclear leukocytes
• Counteract their ability to cause joint inflammation and destruction
• Joint erosion is usually found within 2 years of RA
• DMARDs should be prescribed at the time of diagnosis

Important Considerations for DMARDs

• Toxicity
• Loss of efficacy with time
• Anti-rheumatic drugs slow down disease progression
• Steroids suppress the immune system, but not disease progression
• NSAIDs suppress inflammation, but not disease progression
• Moderate inhibition of joint destruction occurs with drugs like sulphasalazine, hydroxychloroquine, or cyclosporin
• Delayed onset of action, requiring weeks to months to observe anti-rheumatic benefits

Traditional DMARDs

• Methotrexate
• Hydroxychloroquine
• Glucocorticosteroids
• Leflunomide
• Gold salts inhibit proliferation and activity of lymphocytes and polymorphonuclear leukocytes
• Capable of slowing down disease progression of joint erosion

Methotrexate

• Indications include rheumatoid arthritis, psoriasis, and as an antineoplastic agent
• Drug of choice for RA and still most effective
• More effective than other traditional DMARDs in limiting joint damage
• Start early, rapid dose escalation
• Significant toxicity reported in long-term treatment, causing 75% of patients to stop within 5 years

Methotrexate: Administration and Pharmacokinetics

• Well absorbed orally
• Plasma half-life of 8-10 hours
• Relatively rapid onset of action: 2-3 weeks
• Excreted unchanged in the urine; may accumulate in renal impairment
• Effective for up to 15 years
• More effective in combination with other DMARDs than as single-drug therapy

Methotrexate: Mechanism

• Anti-neoplastic and immune-modulating drug
• Several mechanisms exist:
• Inhibits folate reductase, reducing DNA synthesis
• Inhibits lymphocyte proliferation and production of cytokines and Rheumatoid Factor
• Inhibits leukocyte chemotaxis
• Decreases the production of free radicals and cytotoxins

Methotrexate: Contraindications

• Pre-existing blood dyscrasias
• Existing renal or hepatic impairment
• Previous or existing herpes or varicella infections
• Presence of a serous effusion (ascites or pleural effusion)
• Pregnancy and lactation

Methotrexate: Side Effects

• Hematologic: bone marrow suppression, megaloblastic anaemia (reversed with leucovorin)
• GIT: mucosal ulceration and bleeding, stomatitis, diarrhoea which may require stopping the drug
• Hepatotoxicity and pulmonary toxicity
• Folic acid supplementation is important

Leflunomide

• Alternative to methotrexate in treatment of RA
• Clinical indications include:
  • Rheumatoid arthritis in adults
  • Systemic lupus erythematosus (SLE)

Leflunomide: Mechanism

• Potent inhibition of leukocyte and T-cell proliferation
• Active metabolite (teriflunomide) prevents DNA, RNA, and protein synthesis in immune cells
• Inhibits dihydroorotate dehydrogenase, which is involved in pyrimidine synthesis
• Anti-proliferative effect on T cells provides anti-inflammatory action by reducing pro-inflammatory cytokines like IL-1 and TNF
• As effective as sulphasalazine and MTX
• Concern over possible hepatotoxicity

Leflunomide: Side Effects

• Diarrhoea
• Alopecia (reversible)
• Hepatotoxicity
• Inhibits CYP450, causing drug interactions
• Teratogenic- avoid in pregnancy

Chloroquine and Hydroxychloroquine

• Clinical indications include:
  • Rheumatoid arthritis
  • Systemic lupus erythematosus

Chloroquine and Hydroxychloroquine: Mechanisms

• Inhibits lymphocytes
• Stabilizes lysosomal membranes
• Reduces chemotaxis and phagocytosis of PMN
• Reduces production of superoxide radicals
• Slow onset of action: 6 months

Chloroquine and Hydroxychloroquine: Side Effects

• Ocular side effects:
  • Blurred vision
  • Scotomas
  • Night blindness
  • Photosensitivity
• Six monthly ophthalmologist follow-up is important
• Doesn't generally produce myelosuppression, hepatic and renal toxicity

Glucocorticoids

• Suppress the activation of T lymphocytes
• Suppress the production of cytokines by activated helper T cells
• Cytokines play a major role in inflammation
• Decrease the release of various chemical mediators of inflammation
• Stabilize lysosomal membranes of neutrophils and prevent the release of catabolic enzymes
• Cause vasoconstriction and decrease capillary permeability

Glucocorticoids (Example)

• Example: Prednisone
• Clinical indications include:
  • RA and SLE
• Rapid onset (2-3 weeks)
• Used to induce remission and treat acute flare-ups
• Used as a low dose background therapy

Glucocorticoids: Side Effects

• Cushing's syndrome
• Hyperglycaemia
• Glucose intolerance
• Hypertension
• Osteoporosis
• Euphoria or psychosis
• Cataract
• Glaucoma

Sulphasalazine

• A pro-drug broken down to:
• Sulphapyridine (antibacterial and antirheumatic)
• 5-Aminosalicylic acid (anti-inflammatory)
• Indications:
• Ulcerative colitis
• Sulphapyridine is effective in RA, but the mechanism is unknown

Gold Salts

• Oral form: auranofin
• Parenteral forms: gold sodium thiomalate, aurothioglucose
• Indications include: rheumatoid arthritis
• Mechanism: unknown, but involves anti-mitochondrial activity and cell apoptosis
• Onset: 3-6 months

Gold Salts: Side Effects

• No longer a preferred drug due to its side effects:
• Hematologic
• Dermatologic
• GIT
• Renal
• Stomatitis
• 10% of patients develop membranous glomerulonephritis
• Orthostatic hypotension, bone marrow suppression, which lead to neutropenia and thrombocytopaenia

D-Penicillamine

• Chelating agent that modifies the formation of immunoglobulins (antibodies)
• Mechanism of action is not fully understood
• Reduces lymphocytes, inhibits macrophage action
• Reduces levels of inflammatory cytokines
• Onset of action: 3 months
• Side effects: aplastic anaemia, glomerulonephritis, toxic myopathy

Biologic Response Modulators

• These are also known as Immune modulators

Tumor Necrosis Factor Alpha (TNFα) Inhibitors

• Examples include: etanercept, infliximab, adalimumab
• Inhibit TNFα, which is a major pro-inflammatory cytokine that mediates the pathology of RA
• Proven efficacy in inhibiting radiologic progression of the disease
• Side effects: severe infections and lymphomas

Immune Modulators: Others

• Anakinra:
• A human Interleukin 1 receptor antagonist
• IL-1 is a major inflammatory cytokine that mediates cartilage degradation, bone resorption, and loss of peptidoglycans in RA
• Abatacept:
• Inhibits T-cell activation
• Has similar side effects as TNFα blockers

Gout

• A metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage

Uric Acid

• End product of purine metabolism in humans
• Causes problems due to its limited solubility
• More soluble in alkaline urine
• Uric acid crystals LEAD to severe inflammatory response
• Tophi (chalky deposits) deposit in cool extremities (e.g. pinna of the ear, toes)
• Renal stones and/or renal tubular obstruction can also occur

Pathophysiology of Gout

• Uric acid precipitates in joints and kidneys
• Crystals are phagocytosed by cells
• The cells then release PG’s, IL-1 and lysosomal enzymes causing the pH of joint fluid to fall
• Leukocytes and phagocytes migrate to the joint and amplify inflammatory response
• Leukocytes release more mediators

Classification of Hyperuricemia

• Primary hyperuricaemia:
• Poor excretors of uric acid
• Over-producers of uric acid
• Secondary hyperuricaemia:
• Drugs (Loop and thiazide diuretics, ethambutol, pyrazinamide)
• Myeloproliferative disease
• Chronic renal failure

Increased Urate Production

• Nutritional factors include: excess purine, ethanol, and fructose consumption
• Hematologic conditions include: myeloproliferative and lymphoproliferative disorders, polycythaemia
• Drugs: Ethanol, cytotoxic drugs, vitamin B12 (treatment of pernicious anaemia)
• Miscellaneous: Obesity, psoriasis, hypertriglyceridemia

Decreased Renal Excretion of Urate

• Drugs: ethanol, cyclosporine, thiazides, furosemide and other loop diuretics, ethambutol, pyrazinamide, aspirin (low-dose), levodopa, nicotinic acid
• Renal: hypertension, polycystic kidney disease, chronic renal failure (any etiology)
• Metabolic/endocrine: dehydration, lactic acidosis, ketosis, hypothyroidism, hyperparathyroidism
• Miscellaneous: obesity, sarcoidosis, toxemia of pregnancy

Clinical Features of Gout

• Sudden pain, erythema, limited motion, swelling of the joint
• Peak occurrence: 30-50 years
• 90% of first attacks are monoarticular
• 50%+: first MTP joint initial joint involved = podagra
• MTP joint >instep/forefoot >ankle> knee> wrist> fingers
• In women: exclusively post-menopause
• Onset < 30 in men, premenopausal in women = atypical and can be associated with an inherited enzyme defect or renal disease

Drugs Preventing Gout Attack

• Prevented by drugs lowering uric acid
• Probenecid and lesinurad:
  • Increase excretion of uric acid
• Allopurinol:
  • Inhibit synthesis of uric acid
• Catabolic enzyme to reverse hyperuricemia

Uricosuric Drugs

• These drugs are used to prevent gout attacks in patients
• Used in patients that, under excrete uric acid, and have a 24-hr uric acid excretion < 800mg

Probenecid

• Probenecid is a weak acid
• Competitively inhibit the reabsorption of uric acid by renal tubules
• Administered orally
• Must drink a full glass of water to ensure adequate fluid intake

Probenecid Considerations

• Start slowly and gradually increase the dose
• Generally well-tolerated
• Drug-drug interactions:
  • Aspirin and salicylates- interfere with the uricosuric effect, so avoid concomitant use
  • High doses of salicylates have uricosuric effects
• Lesinurad- inhibits the functioning of the transporters

Xanthine Oxidase Inhibitors

• Used to treat gout by inhibiting xanthine oxidase

Allopurinol facts

• It is used to prevent gout attacks
• Used in individuals who overproduce uric acid
• Used to prevent hyperuricemia and gout
• Used in patients undergoing chemotherapy who have a high rate of purine catabolism

Allopurinol: MOA

• Decrease uric acid production
• Inhibits xanthine oxidase- an enzyme that converts hypoxanthine to xanthine and then xanthine to uric acid
• It is a competitive inhibitor of xanthine oxidase

Allopurinol other facts

• Causes a decrease in uric acid excretion
• Increase in the urinary excretion of hypoxanthine.
• Increase reutilisation of hypoxanthine and xanthine
• Inhibits nucleic acid synthesis
• Prevents the urate deposition
• Prevents the recurrence or progression of both gouty arthritis and nephropathy

Allopurinol pharmacokinetic

• Administered orally
• Rapidly converted into its active metabolite known as oxypurinol
• Oxypurinol has a plasma half-life of around 20 hours
• Mostly eliminated unchanged in the urine

Allopurinol Side Effects

• 25% of patients are unable to tolerate allopurinol
• Common side effects are nausea and vomiting
• Other side effects are hepatitis and skin rashes

Febuxostat

• First new drug to treat gout in less than 40 years
• It is a competitive inhibitor of xanthine oxidase
• Advantages over allopurinol:
• Once a day administration
• Greater efficacy
• More selective for xanthine oxidase than allopurinol

Febuxostat Side Effects

• Adverse effects are rare
• However reported effects consist of minor liver enzyme elevation, nausea, arthralgia, and rash

Catabolic Enzyme Agents

Pegloticase

• Recently approved for patients with refractory chronic gout
• Given as an intravenous infusion
• It is a recombinant uricase

Pegloticase MOA

• Catalysing the oxidation of uric acid to allantoin
• Allantoin- is an inert-water soluble purine metabolite that is renally excreted
• Administer under careful monitoring- increased risk of life-threatening allergic reaction

Rasburicase

• Recombinant uricase enzyme
• Indications
• Initial management of plasma uric acid levels in Paediatrics patients
• Is also used in Adults who are receiving chemotherapy
• Is commonly given for, Leukaemia, Lymphoma, and Solid tumour malignancies

Rasburicase and Chemotherapy

• Used for Chemotherapy induced Tumor lysis and cell death caused by ELEVATED URIC ACID LEVELS

Drugs for Treating Gout Attacks

Indomethacin

• It is a Non-steroidal anti-inflammatory drug
• Indications for gout
• Is a Potent anti-inflammatory used to relief pain

Colchicine

• Traditionally used to treat acute gout attach

Colchicine MOA

• Acts by disrupting microtubules
• Inhibit the motility of inflammatory leukocytes
• Blocking their ability to cause urate crystal-induced joint inflammation

Colchicine Pharmacokinetics

• Rapidly absorbed orally
• Partially metabolised in the liver
• Drug and its metabolite excreted via bile and faeces

Colchicine Effects

• Nausea and vomiting can occur
• Diarrhoea and abdominal cramps can occur

Colchicine other side effects -Therapeutic doses-

• Diarrhea, vomiting
• Abdominal pain
• Hair loss
• Hone marrow depression
• Peripheral neuropathy

Colchicine side effects -In overdose-

• Massive Gl damage
• Blood loss from Gl tract and shock

Corticosteroids in Gout

• Can be given Intra-articularly, intravenously, intramuscularly or orally.
• Indicated when one or two accessible joints are involved
• Before performing Intra-articular injection, one must ASPIRATE the joint for diagnosis and synovial fluid cultures to rule out contraindications for intra-articular steroid administration.
• Oral prednisone or Triamcinolone is common options if NSAIDs are contraindicated