1. Scott Vogelgesang, MD Division of Immunology, Rheumatology and Allergy University of Iowa BIOLOGIC AGENTS: CURRENT AND FUTURE No conflicts of interest

2. OBJECTIVES Recognize and manage common infections in those taking biologics Understand indications for use and basic mechanisms of action of the commonly used biologics List common side effects of the commonly used biologics List one biologic being actively investigated

3. Introduction Rheumatoid Arthritis Rituximab Belimumab Abatacept TNF antagonists Tocilizumab Tofacitinib Systemic Lupus Erythematosus Belimumab Psoriatic Arthritis Ustekinumab Apremilast Secukinumab Autoinflammatory Disorders Anakinra Canakinumab Osteoporosis Denosumab Summary OUTLINE

4. 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 but those with 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…

5. 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. http://www.cdc.gov/arthritis/basics/rheumatoid.htm RHEUMATOID ARTHRITIS

6. Inhibits Tumor Necrosis Factor Adverse Effects Infections Upper respiratory infections Urinary tract infections Reactivation of TB Fungal Infections Reactivation of hepatitis B Demyelinating Dis/Neuropathies Malignancy (Lymphoma)? Lupus-like reactions Avoid in Heart failure TNF ANTAGONISTS

7. Etanercept (Enbrel) soluble TNF Receptor Subcutaneous short half life Infliximab (Remicade) Chimeric TNF antibody Infusion Longest half life Certolizumab (Cimzia) Humanized TNF Antibody Subcutaneous Moderate half-life Adalimumab (Humira) Humanized TNF aby Subcutaneous Moderate Half life Golimumab (Simponi) Humanized TNF aby Long Half Life Long half life

8. CTLA4 Ig – Blocks T cell signaling and therefore T cell activation IV infusion Side Effects Infusion Reactions Infection ? Increased cancer (lymphoma) risk ABATACEPT (ORENCIA)

9. 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 RITUXIMAB (RITUXAN)

10. Monoclonal antibody Inhibits IL-6 IV infusion Side Effects Infection Reactivation of TB Fungal infections Reactivation of Hepatitis B Cytopenias Increased Liver tests Increased lipids TOCILIZUMAB (ACTEMRA)

11. Inhibits Janus Kinase – involved with T cell signaling/ activation/ Proliferation Oral tablet Side Effects Infection Reactivation TB Fungal infections Cytopenias GI symptoms; Liver irritation Elevated lipids Increased risk for cancer (Lymphoma)? TOFACITINIB (XELJANZ)

12. 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). https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Psoriatic_Arthritis/ PSORIATIC ARTHRITIS

13. 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?

14. 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 SECUKINUMAB (COSENTYX)

15. Inhibits phosphodiesterase 4 leading to increased cAMP levels Downregulatory signal in immune cells Decreased TNF and IL-17 Oral tablet Side Effects (new) Diarrhea, nausea and vomiting Upper Respiratory Infection Headache Worsening depression APREMILAST (OTEZLA)

16. 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). http://www.cdc.gov/arthritis/basics/lupus.htm SYSTEMIC LUPUS ERYTHEMATOSUS

17. Inhibits B cell activating Factor (BAFF) IV infusion Side Effects Infection Urinary tract infection Pulmonary infections Depression Increased risk for cancer (Lymphoma)? BELIMUMAB (BENLYSTA)

18. AUTOINFLAMMATORY DISORDERS

19. Newly described group of disorders Abnormalities of innate immune system - Typical autoantibodies absent Often with abnormalities of IL-1 Examples: Familial Mediterranean Fever TRAPS Maybe? Still’s Disease Behcet’s Gout??? AUTOINFLAMMATORY DISORDERS

20. Inhibits IL-1, decreasing inflammation Daily (perhaps multiple times daily) subcutaneous injection Side Effects Injection site reactions Not so much… ANAKINRA (KINERET)

21. Inhibits IL-1, decreasing inflammation “Long-acting anakinra” CANAKINUMAB (ILARIS)

22. Osteoporosis means “porous bone” and is a disease when you lose too much bone, make too little bone or both. As a result, bones lose density, become weak and may break from minor trauma. Postmenopausal osteoporosis happens when osteoblasts are unable to make new bone as fast as the osteoclasts resorb “old” bone. OSTEOPOROSIS

23. Monoclonal antibody that inhibits RANK ligand Inhibits osteoclast formation Inhibits bone resorption Biologic bisphosphonate Subcutaneous injection every 6 mos Side effects Injection site reactions Initial concern for infections – less than expected (so far) Brittle fractures Urinary symptoms DENOSUMAB (PROLIA)

24. Atacicept soluble receptor that binds both BLyS (BAFF) and TACI “Paralyzes” B cells In Phase 2 and 3 clinical trials for Systemic Lupus Speculation that because it binds both BAFF and TACI it will work better than Belimumab However, side effects have accompanied the clinical trials …more to come. MOVING FORWARD…

25. TAKE HOME POINTS Biologic Agents – fast growing group of therapeutic agents that have specific targets within the immune system. 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 Perioperative Management Little or no data Hold perioperatively based on treatment schedule Adalimumab – stop 1 wk after last injection, restart when wound shows healing Avoid live-virus vaccines: Zoster, Varicella, Measles, Mumps, Rubella, Nasal influenza No Biologic Combinations: combining therapy is common (e.g. methotrexate + etanercept) HOWEVER, biologics are NOT combined (e.g. infliximab + anakinra = infections)