1. The Use of Tocilizumab (Actemra®), an Interleukin-6 receptor antagonist, for the treatment of rheumatoid arthritis in Methotrexate Refractory patients
Danielle Cronin. Third -year Pharm. D Candidate
Advisor: Dr. Guffey
University of Georgia College of Pharmacy

2. Objectives
Briefly discuss the pathophysiology of Rheumatoid Arthritis (RA)
Review the primary and secondary treatment options for RA
Discuss the role of Tocilizumab in treating RA
Evaluate the primary literature for the use of Tocilizumab when treating patients with an inadequate response to Methotrexate (MTX)

3. What is Rheumatoid Arthritis?
Autoimmune disease
Inflammation of joints and surrounding tissues
Small joints of hands, feet, wrists, and ankles
Progressive destruction of cartilage and bone in multiple joints
Dysregulation of humoral and cell-mediated components of the immune system
Chronic inflammation leads to deformities
~Picture from google health
~SATORI

4. Etiology Can occur at any age Females Genetic predisposition
More prevalent in the 7th decade
Females
Genetic predisposition
HLA-DR4 or HLA-DR1 antigens
Exposure to unknown environmental factors
“The major histocompatibility complex molecules, located on T lymphocytes, appear to have an important role in most patients with RA. These molecules can be characterized using human lymphocyte antigen (HLA) typing. Majority of patients with RA have HLA-DR4, HLA-DR1, or both antigens in their MHC region. HLA-DR4 antigen is 3.5 times more likely to develop RA than those with other HLA-DR antigens. MHC region is important, but not the sole determinant, because patients can have RA without these HLA types.

5. Pathophysiology
1 - Igs activate the complement system, thus amplifying the immune response by enhancing chemotaxis, phagocytosis, and release of lymphokines. Here the antigen-presenting cell phagocytizes the antigen (Igs??).
2 – Antigen is presented to T lymphocyte. The processed antigen is recognized by the MHC proteins on the surface
3 – This results in T and B cell activation
4 – Activated T cells produce cytotoxins and cytokines
*Cytotoxins are directly toxic to tissues
*Cytokines stimulate further activation of inflammatory processes and attract cells to areas of inflammation
--TNF, IL-1, IL-6
*Macrophages are also stimulated to release prostaglandins and cytotoxins
– Activated B cells produce plasma cells which form antibodies that work with complement to result in the accumulation of polymorphonuclear leukocytes (PMNs). PMNs release cytotoxins, oxygen free radicals and hydroxyl radicals which promote cellular damage to synovium and bone
TNF, IL-1, IL-6
Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp ). New York: McGraw-Hill Companies, Inc.

6. Inflamed synovial membrane
Pathophysiology
Chronic inflammation of synovial tissue lining the joint capsule leads to pannus formation
Normal Knee Joint
RA Knee Joint
Femur
Synovial fluid
Patella
Pannus – invades cartilage and eventually the bone surface, producing erosions of bone and cartilage and leads to joint destruction
*End result could be: loss of joint space and motion, bony fusion, and chronic deformity
~Images from google health
~Therapy book
Inflamed synovial membrane
Synovium
Cartilage
Bone
Cartilage
Bone

7. Clinical Presentation
Signs
Warm, tender, swollen joints
Symmetrical joint involvement
Rheumatoid nodules
Swelling feels soft and spongy – due to soft tissue proliferation and fluid accumulation in the joint capsule
Rheumatoid nodule – local swelling or tissue lump that is firm to touch
--asymptomatic and do not require special intervention
~Therapy book

8. Clinical Presentation
Symptoms
Joint pain and stiffness lasting > 6 weeks
Fatigue
Weakness
Low-grade fever
Loss of appetite
Muscle pain
Joint deformity – late disease
Duration of stiffness is usually correlated with disease activity
Morning stiffness lasting longer than 1 hour
Fatigue may be seen more in the afternoon
Stiffness and muscle aches may precede the development of joint swelling
~Theapy book

9. Clinical Presentation
Lab Tests
Joint fluid aspiration
Rheumatoid factor
Turbid – due to increased WBC
Erythrocyte sedimentation rate (ESR)
Joint radiographs
C-reactive protein (CRP)
Normocytic normochromic anemia
Periarticular osteoporosis
Joint space narrowing or erosions
Thrombocytosis
Most patients with RA form antibodies call Rheumatoid Factors – these have not been identified as pathogenic, nor does the quantity of these circulating antibodies always correlate with disease activity. Seropositive patients tend to have more aggressive course of illness over those who are seronegative.
ESR and CRP – when elevated are markers for inflammation
Anemia is inversely related to inflammatory disease activity
Thrombocytosis – elevated platelet count
--platelet counts are directly related to disease activity
Periarticular osteoporosis – osteoporosis around the joints

10. American College of Rheumatology (ACR) 1987 Criteria
Diagnosis Criteria
American College of Rheumatology (ACR) 1987 Criteria
Morning stiffness *
Arthritis of 3 or more joint areas *
Arthritis of hand joints *
Symmetric arthritis *
Rheumatoid nodules
Serum rheumatoid factor
Radiographic changes
Must have at least 4 of 7 criteria
Morning stiffness - Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement
Arthritis of 3 or more joint areas - soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints
Arthritis of hand joints - At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint
Symmetric arthritis - Simultaneous involvement of the same joint areas on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)
Rheumatoid nodules - Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician
Serum rheumatoid factor - Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
Radiographic changes - Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)
* must be present for at least 6 weeks

11. The 2010 ACR-EULAR classification criteria for RA
Diagnosis Criteria
The 2010 ACR-EULAR classification criteria for RA
A – Joint Involvement
1 large joint
2-10 large joints 1
1-3 small joints (with or without involvement of large joints) 2
4-10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5
B - Serology (at least 1 test result is needed for classification) 
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
Updated diagnosis criteria for 2010, but the studies I looked at were prior to 2010 and use the ACR 1987 criteria.
New criteria has more weight on serology and autoimmune diagnostics with no mention of radiographic changes as being diagnostic
--intent of the new criteria is to catch the disease early and avoid damages with treatment

12. The 2010 ACR-EULAR classification criteria for RA
Diagnosis Criteria
The 2010 ACR-EULAR classification criteria for RA
C - Acute-phase reactants (at least 1 test result is needed for classification) 
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR 1
D - Duration of symptoms 
<6 weeks
≥6 weeks
Score ≥6/10 is needed for classification of definite RA

13. Goals of Treatment Improve or maintain functional status
Controlling disease activity and joint pain
Improving quality of life
Slowing destructing joint changes
Complete disease remission

14. Non-pharmacologic Treatment
Rest
Occupational and physical therapy
Assistive devices
Weight loss
Surgery
Rest is important to relieve stress on inflamed joints, thus preventing further destruction. It helps relieve pain.
However, too much rest can be bad…it can lead to decreased range of motion and muscle atrophy.
Surgery – joint replacement

15. Treatment of RA – 1st Line
Early treatment!
Disease Modifying Anti-Rheumatic Drugs (DMARD)
MTX, hydroxychloroquine, sulfasalazine, leflunomide
Others less frequently used due to toxicity and lower efficacy
Low-dose oral glucocorticoids and NSAIDS
Symptomatic relief
Rapid improvement while waiting for DMARD to be effective
DMARD should be started within 3 months of symptom onset
DMARDs – MTX, hydroxychloroquine, sulfasalazine, leflunomide
--MTX is often chosen because of superior outcomes with long-term data and has a lower cost
--Leflunomide has similar long term efficacy
MTX inhibits cytokine production and purine biosynthesis which may be responsible for its anti-inflammatory properites
--rapid onset
--Aes: GI, pulmonary, hepatic
**Folic acid supplementation may reduce some AEs without loss of efficacy
NSAIDs and/or corticosteroids can be used to symptomatic relief, as needed
--Rapid improvement while DMARDs may take weeks to have a benefit.
--NSAIDs have no impact on disease progression
--Coritcosteroids have long-term complication risks (ie – osteoporosis)
MTX – Methotrexate

16. Treatment of RA – 2nd Line
Biologic agents
Non-biologic DMARD failure
Anti-TNF agents
Etanercept, Infliximab, Adalimumab
IL-1 receptor antagonists
Anakinra, Rituximab
IL-6 receptor antagonist
Tocicluzimab
Combination therapy
Combination therapy with 2 or more DMARDs may be effective when a single-DMARD treatment is unsuccessful

17. ACTEMRA (Tocilizumab)
Humanized monoclonal antibody
First IL-6 receptor inhibitor
Prevents signaling to inflammatory mediators
Indicated for adults with moderately to severely active RA after failure of at least 1 tumor necrosis factor (TNF) antagonist

18. ACTEMRA (Tocilizumab)
1 hour IV infusion every 4 weeks
Starting dose 4 mg/kg
Increase to 8 mg/kg based on clinical response
Black box warning – Serious infection
Tuberculosis test prior to administration

19. Literature Search PubMed Search Limits
Randomized, controlled trials
Human Trials
English
Publication dates
Search Terms – “Tocilizumab and Methotrexate”
Returned 8 results

20. Study 1

21. Study 1
“Double-Blind Randomized Controlled Clinical Trial of Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients With Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate.”
Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T
Arthritis & Rheumatism Sep; 54(9):

22. Objectives
Establish the safety and efficacy of repeat infusions of Tocilizumab, a humanized IL-6 receptor antibody, alone and in combination with MTX for the treatment of RA

23. Subjects - Inclusions N = 359 patients
RA diagnosis per ACR 1987 criteria
Disease duration of at least 6 months
Active disease: ≥ 6 tender joints and ≥ 6 swollen joints
ESR ≥ 28 mm/hr and/or
CRP level ≥ 10 mg/L
Inadequate response to MTX or disease flare while receiving MTX
Dose must be stabilized for at least 4 weeks prior to study
Active disease numbers based on 28- joint count
Stabilized on MTX dose at least 4 weeks prior to study

24. Subjects – Exclusions Leukopenia Thrombocytopenia Hepatic dysfunction
AST and ALT levels > 1.5 fold ULN
Significant renal impairment
DMARDs (except MTX) 4 weeks before start
Anti-TNF agents within 12 weeks
Leflunomide within 6 months

25. Methods Patients randomly assigned to 1 of 7 treatment groups
1 control
MTX + placebo
3 monotherapy
2, 4, or 8 mg/kg Tocilizumab + placebo
3 combination therapy –
2, 4, or 8 mg/kg Tocilizumab + MTX
Tocilizumab – every 4 weeks for 16 weeks
MTX – weekly

26. Methods 359 patients randomized Toc 2 mg/kg n = 53 41 completed
Toc 2 mg/kg + MTX n = 52
46 completed
Toc 4 mg/kg + MTX n = 49
42 completed
Toc 8 mg/kg + MTX n = 50
MTX n = 49
40 completed

27. Methods Primary end point Secondary end points
ACR20 response at week 16
Secondary end points
ACR50
ACR70
DAS28

28. Results - Monotherapy p < 0.05
The primary end point was the ACR20 response at week 16
--Significant response seen for 4 and 8 mg/kg Toc groups, but not for the 2 mg/kg group compared with the MTX + placebo group

29. Results - Combination p < 0.05 p < 0.001
ACR20 repsonses for patients receiving combo therapy of Tocilizumab + MTX was significant at all doses of Toc compared with the placebo.
ACR50 and ACR 70 responses only had significant responses with the combination of Toc 8 mg/kg + MTX
p < 0.001

30. ** *** ** p < 0.05 *** p < 0.001
Decrease in all DAS28 scores was greater than the Controlled (MTX) group, except for Toc 2 mg/kg
Statistically significant for 8 mg/kg groups (both mono and combo txs) as well as the 4 mg/kg + MTX group.
Pvalues noted.

31. Author’s Conclusions
Infusions of Tocilizumab every 4 weeks, with or without background MTX therapy, produce marked and dose- related improvement in RA disease activity
4 and 8 mg/kg doses of Tocilizumab resulted in higher ACR50 and ACR70 responses after only 4 infusions
High ACR20 response from placebo + MTX
Possibly not all MTX non-responders

32. Limitations Study length only 16 weeks
Maximum efficacy may not have been achieved
Possibly not all patients were MTX non-responders
Funded by Roche Group
MTX take 4-6 weeks to take effect, only 4 weeks was required so some patients may not have been true “MTX non-responders”

33. Study 2

34. Study 2
“Effect of Interleukin-6 Receptor Inhibition with Tocilizumab in Patients with Rheumatoid Arthritis (OPTION Study): a double-blind, placebo-controlled, randomized trial”
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R
The Lancet Mar; 371:

35. Objective
Assess the therapeutic effects of blocking IL-6 using Tocilizumab for patients with Rheumatoid Arthritis

36. Subjects - Inclusions Adult
Moderate to severe, active RA > 6 months
Active RA:
Swollen joint count ≥ 6
Tender joint count ≥ 8
CRP > 10 mg/L OR
ESR ≥ 28 mm/h
Age for adults was not specified
Average age ~50 years
Majority females

37. Subjects - Inclusions Methotrexate ≥ 12 weeks before
Stable dose (10-25 mg/week) ≥ 8 weeks
Inadequate response to Methotrexate
Active disease
NSAIDs and oral glucocorticoids permitted if on a stable dose for 6 weeks prior

38. Subjects - Exclusions
Other autoimmune diseases or significant systemic involvement secondary to RA
Vasculitis, pulmonary fibrosis, Felty’s syndrome
Functional Class IV RA
Previous or current inflammatory joint disease other than RA
Currently active or previous recurrent bacterial, viral, fungal or other infections
Class IV: limited in ability to perform usual self-care, work, and other activities

39. Subjects - Exclusions
Clinically significant abnormalities on chest radiograph
Hepatitis B or C
Recurrent Herpes Zoster
Active liver disease
Previous unsuccessful treatment with an anti-TNF agent

40. Methods 73 centers in 17 countries 24 weeks
Randomly assigned to 1 of 3 treatment groups
Received treatment every 4 weeks

41. Methods 812 patients screened 623 patients enrolled
Placebo n= 204 patients
189 patients completed
Toc 4 mg/kg n=214 patients
186 patients completed
Toc 8 mg/kg n=205 patients
191 patients completed
To have a Power of 90% it was calculated that at least 210 patients were required for each arm of the study.

42. Methods Continued stable dose of MTX
Received folic acid to minimize any MTX toxicity
During the study, patients could not receive
DMARDs other than MTX
New doses of NSAIDs or oral glucocorticoids
All patients received folic acid supplementation to help minimize any MTX toxicity

43. Methods Patients were evaluated by Efficacy assessments Lab Values
Physical assessment
Efficacy assessments
Weeks 2, 4, 8, 12, 16, 20, and 24
CBC and LFTs were monitored at each visit
--treatment was stopped with ALT or AST increases
Fasting lipid concentrations

44. Methods Primary outcome measures
20% improvement in RA signs and symptoms according to ACR criteria (ACR20 response) at 24 weeks
ACR20 – measures improvement in tender or swollen joint counts and improvement of 3 of the 5 following parameters:
--acute phase reactant (ie – sedimentation rate)
--patient assessment
--physician assessment
--pain scale
--disability/functional questionaire

45. ACR20 Measure improvement in tender or swollen joint counts
Improvement in 3 of the 5 following:
Acute phase reactant
Patient assessment
Physician assessment
Pain scale
Disability/Functional questionnaire
20% improvement

46. Methods Secondary endpoints: ACR50 ACR70
Disease activity score using 28 joint counts (DAS28)
Remission < 2.6
Hemoglobin concentrations
ESR
CRP mean concentrations
Health Assessment Questionnaire-Disability Index (HAQ-DI)
Low Hgb concentrations are indicative of chronic inflammation
HAQ-DI – assess physical function
-tests the ability to do daily activities using 20 questions in 8 domains
-Final HAQ score is the mean of the highest scores from the 8 domains and ranges from 0 to 3
-higher levels = greater disability

47. Results 566 patients completed the study
Primary outcome analysis: ACR20 response
Tocilizumab 4 mg/kg (n = 213)
Tocilizumab 8 mg/kg (n = 205)
Placebo
(n = 204)
Number of patients
102 (48%)
120 (59%)
54 (26%)
p value vs placebo
p <
n/a
Numerical differences between placebo and Toc 8 mg/kg by week 2

48. Results Clinical response at week 24 Toc. 4 mg/kg (n = 213)
Placebo
(n = 204)
ACR50
Number of patients
76 (31%)
90 (44%)
22 (11%)
p value vs placebo
p < 0.001
n/a
ACR70
26 (12%)
45 (22%)
4 (2%)
DAS 28 <2.6
21/156 (13%)
47/171 (27%)
1/121 (0.8%)
p =
Significantly greater response over placebo for both Tocilizumab groups with ACR50, ACR70, and DAS28.

49. Results Toc. 4 mg/kg (n = 213) Toc. 8 mg/kg (n = 205) Placebo
Clinical response at week 24
Toc. 4 mg/kg
(n = 213)
Toc. 8 mg/kg (n = 205)
Placebo
(n = 204)
CRP (mg/L)
-16.6
-25.1
-3.5
p =
p <
ESR (mm/h)
-25.5
-39.5
-7.1
HAQ
-0.52
-0.55
-.34
Hemoglobin concentration (g/L)
9.2
12.4
-0.3
RF concentration (U/mL)
-8.5
-65.1
17.1
p = 0.58
p = 0.08
By week 24 there was a significant response is most all laboratory data
Rheumatoid factor concentration had decreased from baseline by week 24 in both Tocilizumab groups; however, it was not significant as noted by the p values

50. Tolerability Upper respiratory tract infections
Total cholesterol, HDL, and LDL were all increased in the Tocilizumab groups
Reasons for withdrawal
Serious infections
Elevated liver enzymes
Upper respiratory tract infections are expected with involvement of IL-6 in the immune response, previous experience with Tocilizumab treatment and knowledge of agents that interfere with immune repsonse
Active RA patients typically have lower lipid concentrations that the general population due to the inflammatory processs
--increases in lipid levels coincide with a decrease in CRP levels

51. Limitations 6 month trial time 90% power was not reached
Did not assess inhibition of structural damage
Actual number of patients enrolled was less than planned
Funded by Roche Group
6 month trial time – needs long term follow up and assess safety
Inhibition of structural damage is an important part of RA treatment
--Analysis of radiographic changes
Power is over 90%; however, conservative assumptions led to a smaller initial sample size and lower than expected drop out rate

52. Author’s Conclusions
Inhibiting IL-6 mediated pro-inflammatory effects significantly and rapidly improves the signs and symptoms of RA
Significant improvement from baseline for all ACR criteria
Rapid improvement in efficacy endpoints seen over the first 2 weeks of Tocilizumab treatment

53. Seminarian’s Conclusions
Tocilizumab is a safe and effective drug
Expected side effects with a monoclonal antibody
More studies are needed
Long term safety
Elevated liver enzymes and lipid levels
Comparison to other biologic agents
Newer diagnosis criteria
More studies needed to compare Tocilizumab to other biologic agents - this will help determine where to put in treatment outline.

54. References
Smolen J, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial. Lancet Mar; 371:
Maini R, et al. Double-Blind Randomized Controlled Clinical Trial of the Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients With Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate. Arthritis & Rheumatism Sep; 54(9):
Sebba, A. Tocilizumab: The first interleukin-6 receptor inhibitor. American Journal of Health-System Pharmacy Aug; 65:
Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp ). New York: McGraw-Hill Companies, Inc.
Genovese M, et al. Interleukin-6 Receptor Inhibition With Tocilizumab Reduces Disease Activity in Rheumatoid Arthritis With Inadequate Response to Disease-Modifying Antirheumatic Drugs. Arthritis & Rheumatism Oct; 58(10):
The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis. (2010). Practice Management. Retrieved January 5, 2011, from American College of Rheumatology. Website:
1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis. (1987). Practice Management. Retrieved January 5, 2011, from American College of Rheumatology. Website:
Kavanaug A, et al. Tocilizumab for the Treatment of Rheumatoid Arthritis. (2010) Hotline. Retrieved January 15, 2011, from American College of Rheumatology. Website:

55. Questions?

56. Cost Drug Cost per month1 DMARD MTX (20 mg/wk) $74 IL-6 Antagonist
Tocilizumab $
TNF Antagonist
Enbrel
$1790
Adalimumab
$1820
Infliximab
$1410 (every 8 weeks)
IL-1 Antagonist
Abatacept
$1660
Rituximab
$13,400 **
** 2 infusions – duration of benefit variable, retreatment based on disease reactivation
1 –
2 – Kavanaug