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Tocilizumab

Class: Disease-modifying Antirheumatic Drugs
Chemical Name: Immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA k-chain, dimer
Molecular Formula: C6428H9976N1720O2018S42
CAS Number: 375823-41-9
Brands: Actemra

Warning(s)

  • Serious Infections
  • Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.1 (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating tocilizumab therapy in patients with chronic or recurring infections.1

  • Evaluate patients for latent tuberculosis infection prior to and periodically during tocilizumab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating tocilizumab therapy.1

  • Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment.1 If serious infection develops, discontinue tocilizumab until infection is controlled.1

REMS:

FDA approved a REMS for tocilizumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of tocilizumab and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant humanized IgG1 monoclonal antibody specific for interleukin-6 (IL-6) receptor.1 3 4 5 6 9 10 11 13

Uses for Tocilizumab

Rheumatoid Arthritis in Adults

Used to manage moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF; TNF-α) blocking agents.1

Can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, minocycline, sulfasalazine7 ).1 3 4 5 6

Slideshow: Drug Treatment for Rheumatoid Arthritis - What Are Your Options?

Do not use concomitantly with other biologic DMARDs, such as TNF blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), and selective costimulation modulators (e.g., abatacept); concomitant use has not been studied and there is a possibility of increased immunosuppression and increased risk of infection.1

Tocilizumab Dosage and Administration

General

  • Do not initiate tocilizumab therapy in patients with ANC <2000/mm3, platelet count <100,000/mm3, or ALT or AST concentration >1.5 times the ULN.1

Concomitant Therapy

  • Methotrexate, other nonbiologic DMARDs, NSAIAs, and corticosteroids may be continued in patients with rheumatoid arthritis.1

  • Do not use concomitantly with other biologic DMARDs.1 (See Rheumatoid Arthritis in Adults under Uses.)

REMS Program

  • FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for tocilizumab.14

  • The REMS program consists of a medication guide that must be provided to patients (see Advice to Patients) and a communication plan that includes initial and/or periodic communications targeting selected groups of clinicians.14

  • The goals are to inform patients and health care providers about the serious risks associated with the drug (see Cautions: Warnings/Precautions).14

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion once every 4 weeks.1

Tocilizumab injection concentrate must be diluted prior to IV administration.1

Allow tocilizumab infusion solutions to reach room temperature prior to administration.1 (See Storage under Stability.)

Do not infuse tocilizumab simultaneously through the same IV line with other drugs.1

Dilution

Dilute tocilizumab injection concentrate in 0.9% sodium chloride injection to provide a total volume of 100 mL (i.e., remove a volume of diluent equal to the total required volume of the injection concentrate from a 100-mL bag or bottle of 0.9% sodium chloride injection prior to adding the injection concentrate).1 Slowly add the total required volume of tocilizumab injection concentrate to the diluent; gently invert bag or bottle to mix the solution.1

Tocilizumab infusion solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.1

Discard any unused portion remaining in the vial since the injection concentrate contains no preservative.1

Rate of Administration

Infuse dose over 60 minutes; do not administer by rapid IV injection (e.g., IV push or bolus).1

Dosage

Adults

Rheumatoid Arthritis
IV

Initially, 4 mg/kg once every 4 weeks; may increase to 8 mg/kg once every 4 weeks based on clinical response.1 Doses >800 mg are not recommended (see Special Populations under Pharmacokinetics).1

Dosage Modification or Discontinuance for Toxicity
IV

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.1

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur in patients receiving tocilizumab 8 mg/kg every 4 weeks, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or temporarily interrupt or discontinue therapy (see tables).1

Table 1. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Value

ALT or AST Value

Recommendation

>1 to 3 times ULN

Modify dosage of concomitant DMARDs if appropriate1

 

For persistent increases within this range, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or interrupt tocilizumab therapy until ALT/AST values have returned to normal1

>3 to 5 times ULN (confirmed by repeat testing)

Interrupt tocilizumab therapy until ALT/AST values are <3 times ULN and follow recommendations for ALT/AST values of >1 to 3 times ULN1

 

For persistent increases of >3 times ULN, discontinue tocilizumab1

>5 times ULN

Discontinue tocilizumab1

Table 2. Recommended Dosage Adjustment Based on Absolute Neutrophil Count (ANC)

ANC (cells/mm3 )

Recommendation

>1000

Maintain current dosage1

500–1000

Interrupt tocilizumab therapy1

 

When ANC is >1000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1

<500

Discontinue tocilizumab1

Table 3. Recommended Dosage Adjustment Based on Platelet Count

Platelet Count (cells/mm3)

Recommendation

50,0000–100,000

Interrupt tocilizumab therapy1

 

When platelet count is >100,000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1

<50,000

Discontinue tocilizumab1

Prescribing Limits

Adults

Rheumatoid Arthritis
IV

Maximum 800 mg per dose.1

Special Populations

Hepatic Impairment

Use is not recommended.1

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment; not evaluated in moderate or severe renal impairment.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Tocilizumab

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic infections) reported, particularly in patients receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids).1 Opportunistic infections include tuberculosis, cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis.1 Infections may be disseminated.1

Do not initiate tocilizumab in patients with active infections, including localized infections.1 Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.1

Closely monitor patients during and after treatment with tocilizumab for the development of signs or symptoms of infection.1 If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.1 If serious infection, opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.1

Evaluate all patients for latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.1 When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection prior to tocilizumab therapy.1 Consider initiation of antimycobacterial therapy prior to initiation of tocilizumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.1 Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.1

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.1

Viral reactivation can occur in patients receiving immunosuppressive therapies.1 Herpes zoster exacerbation reported in patients receiving tocilizumab.1

GI Perforation

GI perforation reported, usually as a complication of diverticulitis and most commonly in patients receiving concomitant therapy with NSAIAs, corticosteroids, or methotrexate.1 The relative contribution of these agents versus tocilizumab to the occurrence of GI perforation remains to be determined.1

Caution is advised if tocilizumab is used in patients at risk for GI perforation.1

Promptly evaluate patients with new-onset abdominal symptoms for evidence of GI perforation.1

Hematologic Effects

Possible neutropenia or thrombocytopenia.1

Reduction in neutrophil count to <1000/mm3 reported in 1.8 or 3.4% of patients receiving tocilizumab 4 or 8 mg/kg every 4 weeks, respectively, in conjunction with nonbiologic DMARD therapy for 24 weeks; approximately one-half of cases occurred during first 8 weeks of therapy.1 Decreases in neutrophil count to <1000/mm3 did not appear to be associated with serious infection.1

Monitor neutrophil and platelet counts every 4–8 weeks in patients receiving tocilizumab.1 Dosage adjustment or discontinuance may be necessary.1 (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Hepatic Effects

Elevated transaminase concentrations may occur.1 In clinical trials, changes were reversible following reduction of the tocilizumab or concomitant DMARD dosage or interruption of tocilizumab therapy and were not associated with clinical evidence of hepatic injury.1

Incidence and magnitude of transaminase elevations were increased with concomitant use of hepatotoxic drugs (e.g., methotrexate).1

Monitor serum ALT and AST every 4–8 weeks in patients receiving tocilizumab.1 Monitor other liver function tests when clinically indicated.1 Dosage adjustment or discontinuance of tocilizumab or concomitantly administered DMARDs may be necessary.1 (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Effects on Serum Lipids

Increased serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, and/or HDL-cholesterol reported.1

Monitor lipoprotein concentrations 4–8 weeks after initiation of tocilizumab therapy and approximately every 24 weeks thereafter.1 Manage lipid disorders as clinically appropriate.1

Malignancies

Immunosuppressive therapy may increase the risk of malignancies.1 Whether treatment with tocilizumab affects development of malignancies remains to be determined.1 Malignancies were reported in clinical trials.1

Sensitivity Reactions

Serious hypersensitivity reactions, including fatal anaphylaxis, reported;1 15 anaphylactic and anaphylactoid reactions generally have occurred during the second to fourth infusions of the drug.1

Have appropriate agents and equipment available for immediate use in case a serious hypersensitivity reaction occurs.1 If a serious hypersensitivity reaction occurs, immediately stop the drug infusion, provide appropriate supportive care, and permanently discontinue the drug.15

Nervous System Effects

Effect of tocilizumab on demyelinating disorders remains to be determined.1 Multiple sclerosis and chronic inflammatory demyelinating polyneuropathy reported rarely in patients receiving tocilizumab.1

Monitor patients receiving tocilizumab for signs and symptoms suggestive of a demyelinating disorder.1 Exercise caution when considering tocilizumab therapy in patients with preexisting or recent-onset demyelinating disorders.1

Immunization

Do not administer live vaccines to patients receiving tocilizumab.1 Administer all age-appropriate vaccines, except for live vaccines, prior to initiation of tocilizumab therapy.1

Information not available regarding immune response to vaccines in patients receiving tocilizumab or regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving tocilizumab.1

Laboratory Monitoring

Monitor neutrophil counts, platelet counts, and serum ALT and AST concentrations every 4–8 weeks during tocilizumab therapy.1 Monitor other liver function tests when clinically indicated.1 Monitor lipoprotein concentrations 4–8 weeks after initiation of therapy and approximately every 24 weeks thereafter.1

Immunogenicity

Antibodies to tocilizumab detected in sera of about 2% of tocilizumab-treated patients; about 11% of these patients experienced hypersensitivity reactions resulting in drug discontinuance.1 Neutralizing antibodies detected in about 1% of patients receiving the drug.1

Specific Populations

Pregnancy

Category C.1

Pregnancy registry at 877-311-8972.1

Lactation

Not known whether tocilizumab is distributed into milk or is absorbed systemically following ingestion.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Geriatric patients in general may have a higher incidence of infections than younger adults.1 In clinical trials of tocilizumab, serious infections reported more frequently in patients ≥65 years of age than in younger adults.1 Use tocilizumab with caution in this age group.1

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment, including those with serologic evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.1 Use in patients with active hepatic disease or hepatic impairment is not recommended.1

Renal Impairment

Not evaluated in patients with moderate to severe renal impairment.1

Common Adverse Effects

Upper respiratory tract infection,1 3 4 5 nasopharyngitis,1 3 4 headache,1 3 4 5 hypertension,1 3 4 5 increased ALT concentrations.1 3 4 5

Interactions for Tocilizumab

May alter expression of CYP isoenzymes including 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4; effects on CYP2C8 or transporters (e.g., P-glycoprotein) not elucidated.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes.1 Because IL-6 may down-regulate CYP isoenzymes, inhibition of IL-6 by tocilizumab in rheumatoid arthritis patients may restore CYP enzyme activity to higher levels.1 Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.1

Drugs metabolized by CYP isoenzymes that have a low therapeutic index and require individualized dosing: Carefully monitor therapeutic effect and serum concentrations following initiation or discontinuance of tocilizumab; adjust dosage as needed.1

Other CYP3A4 substrates: Caution advised when a reduction in efficacy would be undesirable.1

Specific Drugs

Drug

Interaction

Comments

Contraceptives, oral

Possible increased metabolism of oral contraceptive1

Caution advised1

Corticosteroids

Concomitant use does not appear to affect clearance of tocilizumab1

Cyclosporine

Possible increased metabolism of cyclosporine1

Carefully monitor therapeutic effect and serum concentrations of cyclosporine following initiation or discontinuance of tocilizumab; adjust dosage as needed1

Dextromethorphan

Reduction in exposure to dextromethorphan and dextrorphan following initiation of tocilizumab reported in rheumatoid arthritis patients receiving dextromethorphan1

(In rheumatoid arthritis patients not receiving tocilizumab, systemic exposure to dextromethorphan is similar to, but exposure to dextrorphan is decreased, compared with values in healthy individuals1 )

DMARDs, biologic (e.g., TNF blocking agents)

Possible increased immunosuppression and increased risk of infection; concomitant use not studied1

Concomitant use not recommended1

HMG CoA reductase inhibitors (statins)

Statins metabolized by CYP isoenzymes (e.g., atorvastatin, lovastatin): Possible increased metabolism of the statin1

Simvastatin: Reduction in exposure to simvastatin and simvastatin acid following initiation of tocilizumab reported in rheumatoid arthritis patients receiving simvastatin (values were similar to or slightly higher than values observed after simvastatin administration in healthy individuals); exposure to simvastatin and simvastatin acid increased following discontinuance of tocilizumab1

(Systemic exposure to simvastatin and simvastatin acid is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals)1

Caution advised1

When selecting simvastatin dosages for patients with rheumatoid arthritis, consider the potential for altered systemic exposure to the drug following initiation or discontinuance of tocilizumab1

Methotrexate

Concomitant use does not appear to affect clearance of tocilizumab or exposure to methotrexate1

NSAIAs

Concomitant use does not appear to affect clearance of tocilizumab1

Omeprazole

Reduction in exposure to omeprazole following initiation of tocilizumab reported in rheumatoid arthritis patients receiving omeprazole (values were slightly higher than values observed after omeprazole administration in healthy individuals)1

(Systemic exposure to omeprazole is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals1 )

Theophylline

Possible increased metabolism of theophylline1

Carefully monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of tocilizumab; adjust dosage as needed1

Vaccines, live

Avoid live vaccines (see Immunization under Cautions)1

Warfarin

Possible increased metabolism of warfarin1

Carefully monitor therapeutic effect of warfarin following initiation or discontinuance of tocilizumab; adjust dosage as needed1

Tocilizumab Pharmacokinetics

Absorption

Plasma Concentrations

Increase in dosage from 4 mg/kg to 8 mg/kg every 4 weeks associated with greater-than-proportional increases in AUC and trough plasma concentrations.1

Distribution

Extent

Not known whether tocilizumab is distributed into milk.1

Elimination

Half-life

Steady-state half-life: Up to 11 days at dosage of 4 mg/kg every 4 weeks; up to 13 days at dosage of 8 mg/kg every 4 weeks.1

Clearance decreases as dose increases.1 At low tocilizumab concentrations, concentration-dependent nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.1

Special Populations

As body size increases, linear clearance increases.1 Following a weight-based dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg.1

Pharmacokinetics not formally studied in renal or hepatic impairment.1 Population pharmacokinetic data indicate that mild renal impairment (Clcr ≥50 mL/minute but <80 mL/minute) does not alter pharmacokinetics.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C; do not freeze.1 Protect vials from light.1

Following dilution, 2–8°C or room temperature for up to 24 hours.1 Protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Actions

  • Binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.1 3 4 5 9 10

  • IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types (e.g., T-cells, B-lymphocytes, monocytes, fibroblasts, synoviocytes, endothelial cells) and has a broad spectrum of biologic activities,1 3 4 5 9 10 12 including involvement in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.1 4 5 9 10 12

  • IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease.4 9 10 12 Elevated levels of IL-6 in serum and synovial fluid correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.3 5 9 10 12

Advice to Patients

  • A copy of the manufacturer’s patient information (medication guide) for tocilizumab must be provided to all patients.1 (See REMS Program under Dosage and Administration.) Importance of advising patients about potential benefits and risks of tocilizumab.1 Importance of patients reading the medication guide prior to initiation of therapy and each time they receive an infusion of the drug.1

  • Risk of increased susceptibility to infection.1 Importance of informing clinicians immediately if any signs or symptoms suggestive of infection (e.g., fever; sweating; cough; dyspnea; diarrhea; burning or pain upon urination; warm, red, or painful skin) develop.1

  • Risk of GI perforation.1 Importance of informing clinician immediately if severe, persistent abdominal pain occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., biologic antirheumatic drugs, immunizations) and OTC drugs, as well as any other illnesses (e.g., history of tuberculosis; concomitant, chronic, or recurring infections).1

  • Importance of periodic laboratory monitoring.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tocilizumab (recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection concentrate, for IV infusion

20 mg/mL

Actemra

Genentech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Genentech. Actemra (tocilizumab) injection prescribing information. South San Francisco, CA; 2011 Jan.

2. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

3. Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69:88-96. [PubMed 19297346]

4. Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008; 371:987-97. [PubMed 18358926]

5. Genovese MC, McKay JD, Nasonov EL et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008; 58:2968-80. [PubMed 18821691]

6. Emery P, Keystone E, Tony HP et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008; 67:1516-23. [PubMed 18625622]

7. Saag KG, Teng GG, Patkar NM et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59:762-84. [PubMed 18512708]

8. Hoffmann-LaRoche Inc. FDA arthritis advisory committee briefing document for tocilizumab biologic license application 125276. Nutley, NJ; 2008 Jul 29.

9. Plushner SL. Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2008; 42:1660-8. [PubMed 18957621]

10. Sebba A. Tocilizumab: the first interleukin-6-receptor inhibitor. Am J Health Syst Pharm. 2008; 65:1413-8. [PubMed 18653811]

11. . Drugs for rheumatoid arthritis. Treat Guidel Med Lett. 2009; 7:37-46; quiz 47-8. [PubMed 19390497]

12. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007; 65 Suppl 1:S4-10. [PubMed 17708744]

13. Marti L, Golmia R, Golmia AP et al. Alterations in cytokine profile and dendritic cells subsets in peripheral blood of rheumatoid arthritis patients before and after biologic therapy. Ann N Y Acad Sci. 2009; 1173:334-42. [PubMed 19758170]

14. Actemra (tocilizumab) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2010 Mar 18.

15. Barron H. Dear healthcare professional letter regarding important safety information regarding tocilizumab (Actemra/Roactemra). South San Francisco, CA; 2010 Sep.

16. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

17. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. [PubMed 8507213]

18. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent. Arthritis Rheum. 1998; 41:1564-70. [IDIS 411264] [PubMed 9751088]

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