Download Approach to patient with polyarthralgia

BIOLOGIC AGENTS:
CURRENT AND FUTURE
Scott Vogelgesang, MD
Division of Immunology, Rheumatology and Allergy
University of Iowa
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
OUTLINE
• Introduction
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Ustekinumab
• Rituximab
• Apremilast
• Belimumab
• Secukinumab
• Abatacept
• TNF antagonists
• Tocilizumab
• Tofacitinib
• Systemic Lupus Erythematosus
•
Belimumab
• Autoinflammatory Disorders
• Anakinra
• Canakinumab
• Osteoporosis
• Denosumab
• Summary
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
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
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 Dis/Neuropathies
• Malignancy (Lymphoma)?
• Lupus-like reactions
• Avoid in Heart failure
TNF ANTAGONISTS
• Etanercept (Enbrel)
• Adalimumab (Humira)
•
soluble TNF Receptor
•
Humanized TNF aby
•
Subcutaneous
•
Subcutaneous
•
short half life
•
Moderate Half life
• Infliximab (Remicade)
•
Chimeric TNF antibody
•
Infusion
•
Longest half life
• Certolizumab (Cimzia)
•
Humanized TNF Antibody
•
Subcutaneous
•
Moderate half-life
• Golimumab (Simponi)
•
Humanized TNF aby
•
Long Half Life
•
Long half life
ABATACEPT (ORENCIA)
• CTLA4 Ig – Blocks T cell
signaling and therefore T cell
activation
• IV infusion
• Side Effects
•
Infusion Reactions
•
Infection
•
? Increased cancer (lymphoma) risk
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
TOCILIZUMAB (ACTEMRA)
• 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
TOFACITINIB (XELJANZ)
• 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)?
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).
https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/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?
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
APREMILAST (OTEZLA)
•
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
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).
http://www.cdc.gov/arthritis/basics/lupus.htm
BELIMUMAB (BENLYSTA)
•
Inhibits B cell activating Factor (BAFF)
•
IV infusion
•
Side Effects
• Infection
• Urinary tract infection
• Pulmonary infections
• Depression
• Increased risk for cancer
(Lymphoma)?
AUTOINFLAMMATORY DISORDERS
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???
ANAKINRA (KINERET)
•
Inhibits IL-1, decreasing inflammation
•
Daily (perhaps multiple times daily)
subcutaneous injection
•
Side Effects
• Injection site reactions
• Not so much…
CANAKINUMAB (ILARIS)
•
Inhibits IL-1, decreasing inflammation
•
“Long-acting anakinra”
OSTEOPOROSIS
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.
DENOSUMAB (PROLIA)
•
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
MOVING FORWARD…
•
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.
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)