DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARDs)

Laura M. Aguirre-Aguinaldo, MD, DPPS February 14, 2014; 1:00-3:00 PM Pharmacology February 4, 2014,AND 3:00-5:00 PM THE IMMUNE RESPONSE RHEUMATOID ARTHRITIS (RA) Pediatrics Stimulation of the immune response is generally beneficial; protective Harmful if it results in chronic inflammation without resolution of underlying disease process In rheumatoid arthritis, chronic inflammation leads to destruction of bone cartilage resulting in pain, severe disability and systemic changes

CRITERIA FOR DIAGNOSIS 1. Morning stiffness 2. Arthritis of three or more joint areas 3. Arthritis of hand joints 4. Symmetric arthritis 5. Rheumatoid nodules 6. Serum rheumatoid factor 7. Radiographic changes
Note: Criteria 1-4 must be present for at least 6 weeks Criteria 2-5 must be observed by a physician SLIDE NOTES: Guidelines for classification Four of seven criteria are required to classify a patient as having rheumatoid arthritis (RA) Patients with two or more clinical diagnoses are not excluded Criteria 1. Morning stiffness Stiffness in and around the joints lasting 1 h before maximal improvement 2. Arthritis of three or more joint areas At least three joint areas, observed by a physician simultaneously, have soft tissue swelling or joint effusions, not just bony overgrowth The 14 possible joint areas involved are right or left proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal joints 3. Arthritis of hand joints Arthritis of wrist, metacarpophalangeal joint, or proximal interphalangeal joint 4. Symmetric arthritis Simultaneous involvement of the same joint areas on both sides of the body 5. Rheumatoid nodules Subcutaneous nodules over bony prominences, extensor surfaces, or juxtaarticular regions observed by a physician 6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects 7. Radiographic changes Typical changes of RA on posteroanterior hand and wrist radiographs that must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints

RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown cause. Although there are a variety of systemic manifestations, the characteristic feature of established RA is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution
Rheumatoid arthritis usually affects joints symmetrically (on both sides equally), may initially begin in a couple of joints only and most frequently attacks the wrists, hands, elbows, shoulders, knees, and ankles. The potential of the synovial inflammation to cause

cartilage damage and bone erosions and subsequent changes in joint integrity is the hallmark of the disease. Despite its destructive potential, the course of RA can be quite variable.
Some patients may experience only a mild oligoarticular illness of brief duration with minimal joint damage, but most will have a relentless progressive polyarthritis with marked functional impairment.

GOALS OF TREATMENT Pain relief Reduce inflammation Protection of articular structures Maintenance of function Control of systemic involvement

WHAT ARE DMARDs? Drugs that either affect the immune response or suppress the disease process. As well as improving the symptoms and signs of the arthritis, they may also improve the extra-articular manifestations such as vasculitis in addition to exerting systemic effects In contrast to NSAIDs which act by controlling pain and inflammation but have little effect on the progression of bone and cartilage destruction

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Shows the different inflammatory cytokines that are released when there is an injury or insult in the body. The role of TNF-a has been established in the development of RA and that is why there is a DMARD subgroup which targets the TNF-a

ANTITUMOUR NECROSIS FACTOR OR BIOLOGICAL AGENTS The term biological agents encompasses tumor necrosis factor (TNF)-alpha blockers (infliximab, etanercept, and adalimumab) and other agents, including abatacept, anakinra, and rituximab A revolution has occurred in treating RA due to the realization that the pro-inflammatory cytokine TNFalpha plays a central role. In the last 10 years several agents have been developed that block this molecule and TNF inhibitors significantly improve symptoms and reduce disease activity and joint inflammation INFLAMMATORY MEDIATORS

Biologicals mostly act on the mediators of inflammation and specifically targets TNF-a
(please see table on the last page for the different drugs)

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 Tumor necrosis factor- (TNF-) is a cytokine central to many aspects of the inflammatory response Macrophages, mast cells, and activated TH cells (especially TH1 cells) secrete TNF-. TNF- stimulates macrophages to produce cytotoxic metabolites, thereby increasing phagocytic killing activity TNF- has been implicated in numerous autoimmune diseases. Rheumatoid arthritis, psoriasis, and Crohns disease are three disorders in which inhibition of TNF- has demonstrated therapeutic efficacy. Rheumatoid arthritis illustrates the central role of TNF- in the pathophysiology of autoimmune diseases.

Although the initial stimulus for joint inflammation is still debated, it is thought that macrophages in a diseased joint secrete TNF-, which activates endothelial cells, other monocytes, and synovial fibroblasts. Activated endothelial cells up-regulate adhesion molecule expression, resulting in recruitment of inflammatory cells to the joint. Monocyte activation has a positive feedback effect on T-cell and synovial fibroblast activation. Activated synovial fibroblasts secrete interleukins, which recruit additional inflammatory cells. With time, the synovium hypertrophies and forms a pannus that leads to destruction of bone and cartilage in the joint, causing the characteristic deformity and pain of rheumatoid arthritis

TNF- BLOCKERS ADALIMUMAB MOA: interacts with p55 and p75 cell surface receptors resulting in down regulation of macrophage and T cell function Is a fully human IgG1 anti-TNF monoclonal antibody. Subcutaneous Injection; Half-life of 10-20days INFLIXIMAB 25% mouse, 75% human IgG1 monoclonal antibody Same MOA as Adalimumab Given as IV infusion 3-5 mg/kg every 8 weeks ETANERCEPT It binds TNF molecules and also inhibits lymphotoxin. Given Subcutaneously, 25mg 2x/week or 50mg weekly Slowly absorbed and peaks 72 hours after administration Adverse effects: increased incidence of bacterial infections especially soft tissue infections and septic arthritis

An algorithm to guide you in choosing what treatment modality to start in the patient

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DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDs) DRUG SULFASALAZINE CHLOROQUINE AND HYDROXYCHLOROQUINE CONTRAINDICATIONS
Salicylate hypersensitivity Pre-existing retinopathy Hepatic impairment Pregnancy (a woman or man should avoid conception for at least three

METHOTREXATE

AZATHIOPRINE

CYCLOSPORINE

LEFLUNOMIDE

months after stopping medication) Breast-feeding Active infection Immunodeficiency syndromes Hypersensitivity to azathioprine Breast-feeding Renal Impairment Uncontrolled hypertension Uncontrolled infections Malignancy Severe immunodeficiency Serious infection Liver dysfunction Sever hypoproteinaemia Pregnancy (significant teratogenic risk effective contraception essential during
treatment and for at least 2 years after treatment in women and at least 3 months after treatment in men)

INFLIXIMAB

ETANERCEPT

Breast-feeding Severe infections Pregnancy Breast-feeding Active infection Pregnancy Breast-feeding

COMMON COMPLICATIONS OF DMARDs USE Potential for myelosuppression Prone to opportunistic infections Reactivation or development of TB

Worsening of demyelinating disease Liver toxicity, GI disturbance Skin rash Other idiosyncratic reaction

-ENDTRANSCRIPTION DETAILS
BASIS REMARKS
Latest PPT RECORDINGS + NOTES + DEVIATIONS 8-10% CREDITS Arrangement of contents not similar to the PPT, some are group according to their classification for easier understanding

-DLSHSI Medicine Batch 2016 Transcriptions. Version 1.0.0.0.0 Build 2201-

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METHOTREXATE
Considered as the DMARD of first choice to treat RA MOA: inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. Affects proliferation and enhances apoptosis in immuneinflammatory cells May be used in the treatment of RA, psoriatic arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, Wegeners granulomatosis, giant cell arteritis, SLE and vasculitis Adverse effects: nausea, mucosal ulcers, elevated Liver Function Tests to hepatotoxicity, hypersensitivity lung reaction (rare), CONTRAINDICATED IN PREGNANCY

ABATACEPT
A costimulation modulator that inhibits activation of T cells IV infusions 3 initial doses (day 0, week 2, week 4) followed by monthly infusions: < 60kg: 500mg 60-100kg: 750mg 100 kg: 1000mg Can be used as monotherapy or in combination with other DMARDs

AZATHIOPRINE
Acts through its major metabolite, 6thioguanine Suppresses T and B cell function, Ig production and IL-2 secretion Metabolism is bimodal in humans (rapid vs slow metabolizers); TPMT (thiopurine methyltransferase) Approved for RA at a dose of 2mg/kg/day Adverse effects: Myelosuppression GI disturbances increased risk for infections
Note: It was proposed that patients taking Azathioprine should be screened genetically whether they are rapid or slow metabolizer because if a patient is a slow metabolizer the suppression of the bone marrow will be more severe. So, instead of the disease killing you it might be the drug killing you

CHLOROQUINE AND HYDROXYCHLOROQUINE

MOA: Suppression of T-lymphocyte response; decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis trapping of free radicals Rapidly absorbed and 50% protein bound NOT considered to be very effective DMARDs Also used to treat skin manifestations of SLE Adverse effects: ocular toxicity dyspepsia nausea, vomiting, abdominal pain, rashes nightmares RELATIVELY SAFE IN PREGNANCY

CYCLOSPORINE
MOA: It is a powerful immunosuppressant that appears to act specifically on lymphocytes (mainly helper T cells) resulting in depression of the cell-mediated immune response Dose: 3-5mg/kg BID Adverse effects: NEPHROTOXIC, monitor creatinine; increased toxicity with drugs inhibiting CYP3A. Others: HPN, Hyperkalemia, hepatotoxicity, gingival hyperplasia, hirsutism Indications: It is licensed for the treatment of severe active rheumatoid arthritis, retards bone erosions
Note: Should be very careful in giving this drug because almost all medications are involved with CYP3A

CYCLOPHOSPHAMIDE
MOA: suppresses T and B cell function; its active metabolite is phosphoramide mustard; also prevents cell replication For RA, dose is at 2 mg/kg/day orally. Not IV. Other uses: SLE Vasculitis Wegeners granulomatosis other severe rheumatic diseases

LEFLUNOMIDE
MOA: its active metabolite, A77-1726 inhibits dihydroorotate dehydrogenase leading to inhibition of T cell proliferation and autoantibody production by B cells Loading dose: 100 mg once daily for 3 days. Maintenance: 10 to 20 mg daily. > 25 mg/ day increases AR Completely absorbed Half-life is 19 days undergoes enterohepatic cycling Adverse effects: diarrhea, increase in LFT, mild alopecia, weight gain, increase BP, rarely leukopenia and thrombocytopenia CONTRAINDICATED IN PREGNANCY

MYCOPHENOLATE MOFETIL
(PRODRUG)

RITUXIMAB
A monoclonal Ab that targets CD20 B lymphocytes resulting in reduced inflammation, and inhibition of proinflammatory cytokine secretion Given as 2 IV infusions of 1g 2 weeks apart Used in the treatment of RA in combination with methotrexate Adverse effects: Rashes decrease IgM and IgA levels cardiovascular effects

SULFASALAZINE
MOA: suppression of T cell response It is licensed for the treatment of RA which has failed to respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Dose: 2-3 g/d Adverse effects: nausea and vomiting headache rash hemolytic anemia methemoglobinemia neutropenia thrombocytopenia pulmonary toxicity (rare) reversible infertility in men DOES NOT APPEAR TO BE TERATOGENIC

Mycophenolic acid is the active form of the drug. It inhibits cytosine monophosphate dehydrogenase resulting in T-cell lymphocyte inhibition Indications: SLE Vasculitis Wegeners granulomatosis NO well controlled data for the treatment of RA

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