Scott Vogelgesang, MD

Division of Immunology, Rheumatology and Allergy

University of Iowa

BIOLOGIC AGENTS: CURRENT AND FUTURE

No conflicts of interest

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

• 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

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…

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

• 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

TNF ANTAGONISTS

• 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

• CTLA4 Ig – Blocks T cell signaling and therefore T cell activation

• IV infusion

• Side Effects• Infusion Reactions

• Infection

• ? Increased cancer (lymphoma) risk

ABATACEPT (ORENCIA)

• 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)

• 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)

• 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)

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

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?

• 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)

• 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)

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

• Inhibits B cell activating Factor (BAFF)

• IV infusion

• Side Effects

• Infection

• Urinary tract infection

• Pulmonary infections

• Depression

• Increased risk for cancer (Lymphoma)?

BELIMUMAB (BENLYSTA)

AUTOINFLAMMATORY DISORDERS

• 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

• Inhibits IL-1, decreasing inflammation

• Daily (perhaps multiple times daily) subcutaneous injection

• Side Effects

• Injection site reactions

• Not so much…

ANAKINRA (KINERET)

• Inhibits IL-1, decreasing inflammation

• “Long-acting anakinra”

CANAKINUMAB (ILARIS)

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

• 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)

• 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…

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)