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Pearls and Practical Considerations for Biologic Agents
Scott Vogelgesang, MD Shane Madsen, PharmD, BCPS Division of Immunology, Rheumatology and Allergy Department of Pharmaceutical Care University of Iowa University of Iowa Hospitals & Clinics
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Disclosure Scott Vogelgesang and Shane Madsen report no actual or potential conflicts of interest associated with this presentation.
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Learning Objectives Upon successful completion of this activity, participants should be able to: Differentiate between biologic agents Identify potential short and long-term adverse events that may occur with biologic agents Develop an appropriate screening and monitoring plan for various biologic agents Discuss pertinent patient counseling points for patients who are prescribed biologic agents
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Outline Introduction Rheumatoid arthritis Psoriatic arthritis
TNF antagonists abatacept rituximab tocilizumab tofacitinib anakinra Psoriatic arthritis ustekinumab secukinumab apremilast Systemic Lupus Erythematosus belimumab Screening prior to initiation labs medical considerations vaccines On treatment considerations Pipeline Take home points
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Introduction Therapy of Rheumatoid Arthritis – interesting history
Gold Everyone “knew” RA was caused by infection No antibiotics – experimentation with heavy metals as therapy Gold – those with arthritis got better Hydroxychloroquine – 1940’s antimalarial - those w/ arthritis got better First “designer drug” – sulfasalazine Everyone “knew” RA was an infection so use an antibiotic (sulfapyradine) Everyone knew aspirin helped RA so use salicylate Combined the two: sulfasalazine Skip ahead to 1990s – Immunologists recognized that TNF and IL-1 were responsible for the inflammatory response in RA – Development of anti-TNF and anti-IL-1 drugs Since: Understand and target pieces of the immune system…
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Summary
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Rheumatoid Arthritis Rheumatoid arthritis is a systemic inflammatory disease which manifests itself in multiple joints of the body. The inflammatory process primarily affects the lining of the joints (synovial membrane), but can also affect other organs. The pathophysiology involves antibody, B cells, T cells and cytokines.
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TNF Antagonists Inhibits Tumor Necrosis Factor Adverse Effects
Infections Upper respiratory infections Urinary tract infections Reactivation of TB Fungal infections Reactivation of hepatitis B Demyelinating Disease / Neuropathies Malignancy (Lymphoma)? Lupus-like reactions Avoid in heart failure
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TNF Antagonists Etanercept (Enbrel) Infliximab (Remicade)
Soluble TNF receptor Subcutaneous Short half-life Infliximab (Remicade) Chimeric TNF antibody Infusion Longest half-life Certolizumab (Cimzia) Humanized TNF antibody Moderate half-life Adalimumab (Humira) Humanized TNF antibody Subcutaneous Moderate half-life Golimumab (Simponi & Simponi Aria) Subcutaneous & infusion Long half-life
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Abatacept (Orencia) CTLA4 Ig – Blocks T cell signaling and therefore T cell activation Subcutaneous & infusion Side Effects Infusion Reactions Infection ? Increased cancer (lymphoma) risk
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Rituximab (Rituxan) Monoclonal antibody directed against CD20 - Depletes B cells IV infusion Side Effects Infusion reactions Infections? PML (progressive multifocal leukoencephalopathy) Hepatitis B reactivation Hypogammaglobulinemia Decreased CD4 counts
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Tocilizumab (Actemra)
Monoclonal antibody - inhibits IL-6 Subcutaneous & infusion Dose modifications for LFTs, platelets, and ANC Side Effects Infection Reactivation of TB Fungal infections Reactivation of Hepatitis B Cytopenias Increased liver tests Increased lipids GI perforations
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Tofacitinib (Xeljanz)
Inhibits Janus Kinase – involved with T cell signaling/ activation/ proliferation Oral tablet Renal & hepatic dosing Dose modifications: neutropenia, lymphopenia & anemia Drug interactions Side Effects Infection Reactivation TB Fungal infections Cytopenias GI symptoms; Liver irritation Elevated lipids Increased risk for cancer (Lymphoma)?
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Anakinra (Kineret) Inhibits IL-1, decreasing inflammation
Daily (perhaps multiple times daily) subcutaneous injection Limited distribution: 1 pharmacy Side Effects Injection site reactions Not so much…
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Questions?
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Psoriatic Arthritis Psoriatic arthritis is a type of arthritic inflammation that occurs in about 15 percent [25%?] of patients who have a skin rash called psoriasis. This particular arthritis can affect any joint in the body, and symptoms vary from person to person. The pathophysiology is not clear (or perhaps not the same for all). Abnormalities are similar to rheumatoid arthritis (Antibody, B cells, T cells and cytokines) however there may be similarities to the spondyloarthropathies (like ankylosing spondylitis).
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Ustekinumab (Stelara)
Human antibody against IL-12 and IL-23 Subcutaneous injection at week 0, then week 4 then every 12 weeks Side Effects URI Headache Fatigue Infection TB reactivation Seizures CNS changes Increased cancer risk?
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Secukinumab (Cosentyx)
Monoclonal antibody –inhibits IL-17A Subcutaneous injection weeks 0,1,2,3 and 4; then every 4 weeks Side effects URI Diarrhea Reactivation of TB Worsening of Crohn’s Disease
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Apremilast (Otezla) Inhibits phosphodiesterase 4 leading to increased cAMP levels Downregulatory signal in immune cells Decreased TNF and IL-17 Oral tablet Renal dosing Drug interactions Side Effects Diarrhea, nausea and vomiting Upper Respiratory Infection Headache Worsening depression
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Systemic Lupus Erythematosus
Systemic Lupus Erythematosus is an autoimmune disease in which the immune system produces antibodies to cells within the body leading to widespread inflammation and tissue damage. The pathophysiology involves antibody predominantly (and plasma cells and B cells by extension).
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Belimumab (Benlysta) Inhibits B cell activating factor (BAFF)
IV infusion Side Effects Infection Urinary tract infection Pulmonary infections Depression Increased risk for cancer (Lymphoma)?
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Questions?
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Screening prior to initiation
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Prior to starting: labs
Medication / Class Hep B panel Hep C TB SCr LFTs CBC CBC w/ diff Lipid panel TNFi x abatacept rituximab tocilizumab (ANC & Plt) tofacitinib (neutrophils, lymphocytes, anemia)
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Prior to starting: labs
Medication / Class Hep B panel Hep C TB SCr LFTs CBC CBC w/ diff Lipid panel anakinra x ustekinumab secukinumab apremilast belimumab
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Prior to starting: medical issues
Medication / Class Cancer Heart Failure Demyelinating nervous system disease Lupus Serious infections COPD Recent abdominal surgery / hx of diverticulitis Weight TNFi x abatacept rituximab tocilizumab tofacitinib
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Prior to starting: Medical issues
Medication / Class Cancer Serious infections Weight Depression Crohn’s Disease anakinra x ustekinumab secukinumab apremilast belimumab
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Prior to starting: vaccines
American College of Rheumatology Recommendations Killed vaccines Recombinant vaccine Live attenuated vaccine Pneumococcal Influenza Hepatitis Ba Human Papillomavirusb Herpes zosterc* Before initiating therapy DMARD monotherapy X Combination DMARDs TNFi biologics Non-TNF biologics Abbreviations: disease-modifying antirheumatic drugs (DMARDs); tumor necrosis factor inhibitor (TNFi); Rheumatoid arthritis (RA) * Deviates from CDC recommendations a. Given if known hepatitis B risk factors are present (intravenous drug abuse, multiple sex partners in previous six months, health care personnel) b: Human Papillomavirus Vaccine- Given to people who are normally eligible (in individuals years old). c: RA patients > 50 years old should receive herpes zoster vaccine prior to starting biologic therapy. Can start therapy 2 weeks after vaccine. Chart adapted by Emily Prinz, Pharm.D., from Figure 8, 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis.
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Prior to Starting: other considerations
Pregnancy Have a discussion: risks vs benefits RA often improves during pregnancy Insurance formulary Ability to self administer injections
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On treatment considerations
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On treatment: Vaccines
American College of Rheumatology Recommendations Killed vaccines Recombinant vaccine Live attenuated vaccine Pneumococcal Influenza Hepatitis Ba Human Papillomavirusb Herpes zosterc* While already taking therapy DMARD monotherapy X Combination DMARDs TNFi biologicsd Non-TNFi biologicsd Abbreviations: disease-modifying antirheumatic drugs (DMARDs); tumor necrosis factor inhibitor (TNFi); Rheumatoid arthritis (RA) * Deviates from CDC recommendations a. Given if known hepatitis B risk factors are present (intravenous drug abuse, multiple sex partners in previous six months, health care personnel) b: Human Papillomavirus Vaccine- Given to people who are normally eligible (in individuals years old). c: RA patients > 50 years old should receive herpes zoster vaccine prior to starting biologic therapy. Can received therapy 2 weeks after vaccine. d: RA patients currently receiving biologics should not receive live attenuated vaccines Chart adapted by Emily Prinz, Pharm.D., from Figure 8, 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis.
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On treatment: labs Laboratory monitoring
Mostly without recommendations / guidelines Primarily with clinical suspicion Tofacitinib: 4-8 weeks post initiation: CBC w/ diff, LFTs, and lipids Q3 months: CBC w/ diff, LFTs Tocilizumab: Q6 months: lipids
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On treatment Hold the medication for a week (or perhaps two) when fever is present; Patient looks sick NOT necessary for apremilast Injection site reactions Lasts 2-7 days Usually worse with 2nd and 3rd injection Usually minimize by 6 weeks Ensure allowing to warm up prior to administration (30-45 minutes) Cold pack – before and / or after Antihistamines Topical steroids Rule out skin infection – good hygiene practices for injection
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On treatment Perioperative Management Most recent guidance
etanercept hold 2 weeks adalimumab hold 3 weeks infliximab hold 6 weeks golimumab hold 6 weeks certolizumab hold 6 weeks tocilizumab subcut hold 3 weeks tociluzmab IV hold 4 weeks abatacept subcut hold 2 weeks abatacept IV hold 4 weeks rituximab no recommendation to hold Goodman, S. Rheumatoid Arthritis: Perioperative Management of Biologics and DMARDS. Sem Arth and Rheum 2015;44:
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Pipeline for rheumatology
Biosimilars: infliximab, etanercept, & adalimumab – approved by FDA rituximab – application submitted to FDA IL-17 inhibitors: brodalumab, ixekizumab (both currently approved for psoriasis) JAK inhibitors: baricitinib, filgotinib IL-6 inhibitors: sarilumab, sirukumab CD20 inhibitor: obinutuzumab CD22 inhibitor: epratuzumab Anti-interferon-α: anifrolumab, sifalimumab BAFF/Blys inhibitor: blisibimod Blys & APRIL inhibitor: atacicept Synthetic cannabinoid: ajulemic acid FCX-013 gene therapy
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Summary
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Take Home Points Infection risk is likely higher in general for biologic agents Hold the medication for a week (or perhaps two) when Fever is present Patient looks sick Vaccinations are critical to minimize preventable infections Assess vaccination status at PCP or pharmacy visits Avoid live-virus vaccines: Zoster, Varicella, Measles, Mumps, Rubella, Nasal influenza No biologic combinations
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Questions?
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