Biologic Response–Modifying and Antirheumatic Drugs Chapter 47 Biologic Response–Modifying and Antirheumatic Drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Biologic Response–Modifying Drugs Alter the body’s response to diseases such as cancer and autoimmune, inflammatory, and infectious diseases Hematopoietic drugs Immunomodulating drugs Interferons Monoclonal antibodies interleukin receptor agonists and antagonists Miscellaneous drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Immunomodulating Drugs Medications that therapeutically alter a patient’s immune response to malignant tumor cells Drugs that modify the body’s own immune response so that it can destroy various viruses and cancerous cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Biologic Response Modifiers (BRMs) Fourth part of cancer therapy, in addition to: Surgery Chemotherapy Radiation Also used for other diseases Autoimmune Inflammatory Infectious Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. BRMs: Subclasses Hematopoietic drugs Interferons (IFNs) Monoclonal antibodies Interleukin receptor agonists and antagonists Disease-modifying antirheumatic drugs Miscellaneous drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

BRMs: Mechanisms of Action Enhancement or restoration of the host’s immune system defenses against the tumor Direct toxic effect on the tumor cells, which causes them to lyse, or rupture Adverse modification of the tumor’s biology, which makes it harder for the tumor cells to survive and reproduce Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. The Immune System Two components of the immune system work together to recognize and destroy foreign particles and cells in the blood or other body tissues Humoral immunity Mediated by B-cell functions (antibodies) Cell-mediated immunity (CMI) Mediated by T-cell functions Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

The Immune System (cont’d) Tumor antigens (chemical or tumor “markers”) label tumor cells as abnormal cells Antibodies attack tumor cells B-lymphocytes (B cells) from the humoral immune system T-lymphocytes (T cells) from the cell-mediated immune system Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Humoral Immune System B-lymphocytes (B cells) Originate from bone marrow When a foreign substance (antigen) is present, these turn into plasma cells, which in turn produce antibodies Antibody-antigen complex Memory cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Humoral Immune System (cont’d) Antibodies also known as immunoglobulins (Ig) Monoclonal antibodies Five major types of naturally occurring immunoglobulins IgA, IgD, IgE, IgG, IgM Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Cell-Mediated Immune System T-lymphocytes (T cells) Originate from bone marrow but mature in the thymus gland Three types with different functions Cytotoxic T cells T-helper cells T-suppressor cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Cell-Mediated Immune System (cont’d) Cytotoxic T cells directly kill their targets by causing cell lysis or rupture T-helper cells direct the actions of many other components of the immune system T-suppressor cells serve to limit or control the immune response Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Cell-Mediated Immune System (cont’d) A healthy immune system has about twice as many T-helper cells as T-suppressor cells at any one time Overactive T-suppressor cells may be responsible for clinically significant cancer cases by permitting tumor growth beyond immune system control Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Cell-Mediated Immune System (cont’d) Other cells of the cell-mediated immune system help to destroy cancer cells Macrophages (derived from monocytes) Natural killer (NK) cells Polymorphonuclear (PMN) leukocytes (neutrophils) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Therapeutic Effects of BRMs Regulation or enhancement of the immune response Cytotoxic or cytostatic activity against cancer cells Inhibition of metastases, prevention of cell division, or inhibition of cell maturation Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (HDs) HDs promote the synthesis of various types of major blood components by promoting the growth, or differentiation, and function of their precursor cells in the bone marrow Produced by rDNA technology Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (cont’d) HDs are used to: Decrease the duration of chemotherapy-induced anemia, neutropenia, and thrombocytopenia Enable higher doses of chemotherapy to be given Other uses Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (cont’d) Erythropoietic drugs epoetin alfa (Epogen, Procrit) darbepoetin alfa (Aranesp) Colony-stimulating factors (CSFs) filgrastim (Neupogen) pegfilgrastim (Neulasta) sargramostin (Leukine) Platelet-promoting drugs oprelvekin (Neumega) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs: Mechanism of Action Decrease the duration of chemotherapy-induced anemia, neutropenia, and thrombocytopenia Allow for higher dosages of chemotherapy Decrease bone marrow recovery time after bone marrow transplantation or irradiation Stimulate other cells in the immune system to destroy or inhibit the growth of cancer cells, as well as virus- or fungus-infected cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (cont’d) filgrastim (Neupogen) Granulocyte colony-stimulating factor (G-CSF) Stimulates precursor cells for the type of WBCs known as granulocytes Administered before patient develops infection pegfilgrastim (Neulasta) Longer-acting form of filgrastim Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (cont’d) sargramostim (Leukine) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Stimulates bone marrow precursor cells that make both granulocytes and phagocytic (cell-eating) cells; known as monocytes Indicated for promoting bone marrow recovery after autologous (own marrow) or allogenic (donor marrow) bone marrow transplantation in patients with leukemia and lymphoma Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs (cont’d) oprelvekin (Neumega) Both a hematopoietic drug and one of the interleukins (IL-11) Enhances synthesis of platelets Indicated for the prevention of chemotherapy-induced severe thrombocytopenia and avoidance of the need for platelet transfusions Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs: Indications Used in patients who have experienced destruction of bone marrow cells as a result of cytotoxic chemotherapy Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs: Indications (cont’d) Decrease the duration of low neutrophil counts, thus reducing the incidence and duration of infections Enhance the functioning of mature cells of the immune system, resulting in greater ability to kill cancer cells as well as viral- and fungal-infected cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Hematopoietic Drugs: Indications (cont’d) Also enhance RBC and platelet counts in patients with bone marrow suppression resulting from chemotherapy Allow for higher doses of chemotherapy, resulting in the destruction of a greater number of cancer cells Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Classroom Response Question A patient’s chemotherapy has ended at 1800 on a Tuesday afternoon. When is it appropriate to start therapy with filgrastim? 1800 on Tuesday 0600 on Wednesday 1800 on Wednesday 1 week later, 1800 the next Tuesday Correct answer: C Rationale: Filgrastim and sargramostim have significant drug interactions when given with myelosuppressive antineoplastic drugs. Typically filgrastim and sargramostim are not given within 24 hours of administration of myelosuppressive antineoplastics. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Hematopoietic Drugs: Adverse Effects Usually mild Most common include: Fever Muscle aches Bone pain Flushing Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interferons (IFNs) Proteins with three basic properties Antiviral Antitumor Immunomodulating Used to treat certain viral infections and cancer Alpha, beta, and gamma interferons Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interferons (cont’d) Manufactured from Escherichia coli bacteria with rDNA technology Also obtained from pooled human leukocytes that have been stimulated by synthetic and natural antigens Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interferons (cont’d) Recombinantly made IFNs are identical to the IFNs that are present within the human body and have the same properties IFNs protect human cells from viruses and prevent cancer cells from dividing and replicating Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interferons: Effects on Immune System Restore the immune system’s function if it is impaired Augment the immune system’s ability to function as the body’s defense Inhibit the immune system from working Helpful in autoimmune disorders Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interferons: Indications Viral infections Genital warts, hepatitis Cancer Chronic myelogenous leukemia, follicular lymphoma, hairy-cell leukemia, Kaposi’s sarcoma, malignant melanoma Autoimmune disorders Multiple sclerosis Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interferons: Adverse Effects Flulike effects Fever, chills, headache, myalgia Dose-limiting adverse effect is fatigue Other adverse effects Anorexia Dizziness Nausea Vomiting Diarrhea Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interferons (cont’d) Interferon alfa products: “leukocyte interferons”—produced from human leukocytes interferon alfa-2a interferon alfa-2b interferon alfa-n3 interferon alfacon-1 peginterferon alfa-2a peginterferon alfa-2b Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interferons (cont’d) Interferon beta products interferon beta-1a interferon beta-1b Interferon gamma products interferon gamma-1b (Actimmune) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Monoclonal Antibodies (MABs) Treatment of cancer, rheumatoid arthritis, multiple sclerosis, and organ transplantation Specifically target cancer cells and have minimal effect on healthy cells Fewer adverse effects than traditional antineoplastic medications Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Monoclonal Antibodies (MABs) (cont’d) Cancer treatment alemtuzumab (Campath) bevacizumab (Avastin) cetuximab (Erbitux) gemtuzumab ozogamicin (Mylotarg) Other disease processes, including rheumatoid arthritis adalimumab (Humira) infliximab (Remicade) natalizumab (Tysabri) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Classroom Response Question Which statement regarding use of monoclonal antibodies in the treatment of cancer does the nurse identify as being true? Monoclonal antibodies are not as effective as other chemotherapy drugs. have few adverse effects. may cause flulike effects but do not cause the typical adverse effects associated with chemotherapy. are only used in cases of last resort when other chemotherapy drugs have failed. Correct answer: C Rationale: Because these drugs only target cancer cells, they do not have the adverse effects that are typically associated with chemotherapy. However, they do cause acute symptoms that are similar to classic allergy or flulike symptoms. As a result, these symptoms are managed during therapy. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Interleukins Beneficial antitumor action Interleukin receptor agonists aldesleukin (IL-2) oprelvekin (IL-11)* denileukin diftitox tocilizumab (IL-6) anakinra *Also classified as an HD Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interleukins: Capillary Leak Syndrome Severe toxicity of aldesleukin therapy Capillaries lose ability to retain vital colloids in the blood; these substances are “leaked” into the surrounding tissues Result: massive fluid retention Respiratory distress Heart failure MI Dysrhythmias Reversible after interleukin therapy is discontinued Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interleukins (cont’d) aldesleukin (Proleukin) Treatment of metastatic renal cell carcinoma and metastatic melanoma Off-label uses include HIV infection and AIDS, and non-Hodgkin’s lymphoma Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Interleukins (cont’d) anakinra (Kineret) IL-1 receptor antagonist Used to control symptoms of rheumatoid arthritis Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Rheumatoid Arthritis Autoimmune disorder causing inflammation and tissue damage in joints Diagnosis primarily symptomatic Treatment consists of NSAIDs and disease-modifying antirheumatic drugs Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Osteoarthritis Another type of arthritis Age-related degeneration of joint tissues Pain and reduced function   Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Disease-Modifying Antirheumatic Drugs (DMARDs) Modify the disease of rheumatoid arthritis Exhibit antiinflammatory, antiarthritic, and immunomodulating effects Inhibit the movement of various cells into an inflamed, damaged area, such as a joint Slow onset of action of several weeks, versus minutes to hours for NSAIDs Also referred to as slow-acting antirheumatic drugs (SAARDs) Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Nonbiologic DMARDs methotrexate leflunomide (Arava) hydroxychloroquine sulfasalazine Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Biologic DMARDs adalimumab anakinra etanercept infliximab abatacept rituximab tocilizumab Others Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Disease-Modifying Antirheumatic Drugs (DMARDs) (cont’d) etanercept (Enbrel) Used to treat rheumatoid arthritis (including juvenile RA) and psoriasis Patients must be screened for latex allergy (some dosage forms may contain latex) Onset of action: 1 to 2 weeks Contraindicated in presence of active infections Reactivation of hepatitis and TB have been reported Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Disease-Modifying Antirheumatic Drugs (DMARDs) (cont’d) abatacept (Orencia) Used to treat rheumatoid arthritis Caution if history of recurrent infections or COPD Patients must be up to date on immunizations before starting therapy May increase risk of infections associated with live vaccines May decrease response to vaccines Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Nursing Implications Assess for allergies, specifically allergies to egg proteins, IgG, or neomycin Assess for conditions that may be contraindications Assess baseline blood counts; perform cardiac, renal, and liver studies Assess for presence of infection Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Nursing Implications (cont’d) Follow specific guidelines for preparation and administration of drugs Monitor the patient’s response during therapy Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Nursing Implications (cont’d) Teach patients to report signs of infection immediately Sore throat Diarrhea Vomiting Fever over 100.5° F (38.1° C) or higher Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Nursing Implications (cont’d) Monitor for therapeutic responses Decrease in growth of lesion or mass Improved blood counts Absence of infection, anemia, and hemorrhage Monitor for adverse effects Copyright © 2014 by Mosby, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Case Study A 40-year-old female patient is seen in the clinic. She has been newly diagnosed with rheumatoid arthritis. Which medication does the nurse anticipate being ordered for the patient? methotrexate adalimumab infliximab etanercept Correct answer: A Rationale: For the treatment of rheumatoid arthritis, the recommend therapy with nonbiologic DMARDs usually begins with methotrexate or leflunomide for most patients. Biologic DMARDs are generally reserved for those patients whose disease does not respond to methotrexate or leflunomide. The biologic DMARDs include etanercept, infliximab, adalimumab, abatacept, and rituximab. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Case Study (cont’d) Prior to administering methotrexate, it is most important for the nurse to assess the patient for allergy to eggs. congestive heart failure. latent tuberculosis. hypothyroidism. Correct answer: C Rationale: Prior to administering DMARDs, it is important for the nurse to assess the patient for contraindications to the use of DMARDs such as active bacterial infections, active herpes, active/latent tuberculosis, and acute or chronic hepatitis B or C. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Case Study (cont’d) The patient is scheduled for discharge. Which information does the nurse include when teaching the patient about methotrexate therapy? You can expect to develop mouth sores that will improve with time when taking this medication. Administer the methotrexate injection daily in the early morning. Mix the methotrexate with sterile saline prior to administration. Administer the methotrexate subcutaneously into the thigh, abdomen, or upper arm, rotating injection sites. Correct answer: D Rationale: Methotrexate should be administered subcutaneously into the thigh, abdomen, or upper arm, rotating injection sites. Methotrexate should not be administered with other solutions and without use of a filter. Methotrexate is taken weekly. The development of stomatitis should be reported to the prescriber immediately. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Case Study (cont’d) The patient improved within the first three months of treatment with methotrexate. Six months later, the patient experienced worsening of symptoms. The prescriber will most likely order which monoclonial antibody for the treatment of rheumatoid arthritis? adalimumab (Humira) trastuzumab (Herceptin) rituximab (Rituxan) cetuximab (Erbitux) Correct answer: A Rationale: Adalimumab (Humira) is indicated for the treatment of severe, progressive RA for which other RA therapies have failed. Trastuzumab (Herceptin) is indicated for the treatment of breast cancer. Rituximab (Rituxan) is used for the treatment of non-Hodgkin’s lymphoma, and cetuximab (Erbitux) is indicated for the treatment of metastatic colorectal cancer. Copyright © 2014 by Mosby, an imprint of Elsevier Inc. Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.