1. Tumor Necrosis Factor Inhibitors Box Warnings
Nina Elk, Pharm.D. Internal Medicine Resident (PGY2) Kingsbrook Jewish Medical Center
Department of Pharmacy Brooklyn, New York

2. TNF Inhibitors Available on the Market
Etanercept (Enbrel®) – soluble TNF receptor fusion protein
Infliximab (Remicade®) – chimeric anti-TNF-alpha antibody
Adalimumab (Humira®) – human monoclonal anti-TNF-alpha antibody
Certolizumab pegol (Cimzia®) – antigen-binding fragment of humanized monoclonal antibody coupled to polyethylene glycol

3. TNF Inhibitors Box Warnings

4. TNF Inhibitors Box Warnings
Infliximab (Remicade®) August 1998
Etanercept (Enbrel®) November 1998
Adalimumab (Humira®) January 2002
Certolizumab (Cimzia®)
April 2008
Fungal infections (9/2008) √
Bacterial infections (5/2008)
Hepatosplenic-T-cell lymphoma
(5/2008)

5. FDA MedWatch Warning Malignancy Association with TNF Inhibitors
“ [Posted 06/03/2008] FDA issued an Early Communication About an Ongoing Safety Review to inform healthcare professionals that the Agency is investigating a possible association between the use of Tumor Necrosis Factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. Until the evaluation is completed, healthcare providers, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults when deciding how to best treat these patients.”

6. TNF Inhibitors Place in Therapy
Rheumatoid arthritis
Crohn’s disease
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Plaque psoriasis

7. Role of TNF in Inflammation
The cytokine network in inflammation. TNF is responsible for regulation of immune cells, induce apoptosis, inhibit tumorigenesis and inhibit viral production. This is a TNF-dependent cytokine cascade illustrating a crucial role of TNF. Key interacting cells are CD4+T and macrophages. Macrophages activate CD4+T cells by releasing inflammatory proteins including TNF which is the is the group of proteins which induce apoptosis in cells, so the role of TNF is crucial in conditions like rheumatoid arthritis and crohn’s disease where the destruction of the cells occurs. The existent TNF-alpha inhibitors work by blocking the destructive action of TNF.

8. Complications Associated with TNF Inhibitors
Infections – bacterial, viral, fungal
Mycobacterial infection – tuberculosis
Malignancy
Injection/infusion reactions
Induction of autoimmunity
Demyelinating disease
Heart failure

9. Risk of Serious Infections Mechanism
TNF important component of immune system
Enhanced endothelial cell activation
Inflammatory cell recruitment
Procoagulant role (infection spread limited)
Activates macrophages for phagocytosis
Inhibition of TNF can cause serious infections

10. TNF Inhibitors Cause Severe Infections Evidence in Literature
Drug
Trial
Patient #
Duration
Risk of infection
Infliximab
3 mg/kg or 6 mg/kg
Every 8 weeks
ASPIRE
1049
54 weeks
2-fold
Adalimumab
40 mg
every other week
PREMIER
799
2 years
Etanercept
Retrospective case review
23,733
N/A
Certolizumab
200 mg or 400 mg every 2 weeks
RAPID 2
619
24 weeks
2 ½ -fold

11. Infliximab – Induced Pneumocystis Jiroveci Pneumonia Case Report
Patient
69 y/o female with PMH: RA X 5 years, diabetes mellitus, no history of infection
RA treatment
Infliximab + methotrexate
Reaction onset
3 weeks after infliximab initiation (infliximab 3 doses received)
Reaction
Exertional dyspnea and fever. Broncho-alveolar lavage detected Pneumocystosis jiroveci
Management
Trimethoprim/sulfamethoxazole started and condition improved within 1 week
NK et. al. 2007;45(4): Japanese

12. Link Between TNF Inhibitors and Tuberculosis
Patients with latent tuberculosis infection (LTBI) have Mycobacterium tuberculosis (Mtb) bacilli contained in granulomas
TNF is required for maintenance of granuloma structure
Macrophages, multinucleated giant cells
Tumor necrosis factors inhibit TNF which sets Mtb bacilli free
Latent tuberculosis transforms into active tuberculosis
MTb are viable organisms and exist in slow state of replication , in majority of people who are infected they will not cause active disease, however once Mtbs are activated disease occurs. Usually, prophylactic treatment for several months will reduce the risk of progression from LTBI to active TB.

13. TNF-inhibitors Cause Tuberculosis Infection Evidence
Adalimumab
Clinical trial data
Infliximab
Postmarketing data
Etanercept
Patients
(Patient-years)
2,500
(4900)
198,235
(227,559)
>150,000
(>230,000)
TB reports: US
Outside US 13
3 (33%)
10 (67%)
172
110 (64%)
62 (36%) 38
34 (90%)
4 (10%)
Time to onset
3-8 months
3–6 months
11 months
Certolizumab Pegol
Study
Duration
Patient #
TB cases
TB onset
RAPID 2
168 days
4,650 5
58 – 169 days

14. Adalimumab-Induced Disseminated Tuberculosis Case Report
Patient
71 y/o woman
PMH: COPD, sleep apnea, osteoporosis
RA treatment
Adalimumab 40 mg sq every other week
Reaction onset
18 months after treatment initiation
Reaction
Ascites, asthenia, anorexia, miliary nodules of peritoneal surfaces
Management
Rifampin, isoniazid, pyrazinamide
RA The Lancet 2007;370:564

15. TNF Inhibitors and Malignancy
Patients with RA at risk for malignancy
Autoimmune dysfunction
Chronic inflammation
TNF induces apoptosis of tumor cells
Medications used concomitantly increase risk of cancer
Methotrexate
Azathioprine
Cyclophosphamide

16. Trials Reporting TNF Inhibitors and Malignancy Risk
Infliximab and Adalimumab
Placebo
N = 3493
N = 1512
Odd Ratio 3.3
(95%CI, 0%-25%)
TB et al. JAMA 2006;295:

17. FDA Investigates TNF Inhibitors Risk of Malignancy
30 cancer cases reported to FDA from 1998 – 2008
Infliximab
Adalimumab
Etanercept
Ten year study planned for Certolizumab to evaluate long term risks

18. Non-Small-Cell Lung Cancer Associated with Infliximab Case Report
Patient
69 y/o female, former smoker X 35 years
Crohn’s disease management
MTX + Infliximab (2000 – 2004), adalimumab (2004 – 2006)
Reaction
Non-small cell lung cancer with TNF receptors
Management
Discontinuation of adalimumab and complete resolution of symptoms
NEJM 2008;359:

19. Recommendations to Prevent Serious Infections
Routine screening
Histoplasmosis, coccidiosis, listeria monocytogenes
Avoid unpasteurized products and undercooked meat
Educate patients to self report fever, respiratory problems
Routine CBC test to check for left shift

20. Recommendations to Prevent Tuberculosis
Thorough evaluation prior to TNF inhibitor treatment
History of TB
Risk factors
Tuberculin skin test (TST) for LTBI > 5mm positive
Immunocompromised patients false (+)ve TST results
Chest X-ray prior to treatment
BCG vaccination yield (+)ve TST
T-SPOT TB test more sensitive to LTBI
Positive for LTBI begin treatment
Isoniazid 300 mg daily X 9 months
Rifampicin 600 mg +/- isoniazid 300 mg X 4 months
Monitor LFTs baseline and monthly

21. Recommendations to Reduce Risk of Malignancy
Evaluate patient risk for malignancy prior to TNF inhibitors initiation
Review medications which can further increase risk of malignancy
Evaluate malignancy risk and benefit from immunosuppressants

22. Take Home Message TNF inhibitors possess risk on
Infections
Tuberculosis
Malignancy
Vigilant monitoring for signs and symptoms of adverse reactions
Patient education related to risk of malignancy and serious infections
Keep abreast with FDA warnings due to ongoing investigations with TNF inhibitors