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The Use of Tocilizumab (Actemra), an Interleukin-6 receptor antagonist, for the treatment of rheumatoid arthritis in Methotrexate Refractory patientsDanielle Cronin. Third -year Pharm. D CandidateAdvisor: Dr. GuffeyUniversity of Georgia College of PharmacyObjectivesBriefly discuss the pathophysiology of Rheumatoid Arthritis (RA)Review the primary and secondary treatment options for RADiscuss the role of Tocilizumab in treating RAEvaluate the primary literature for the use of Tocilizumab when treating patients with an inadequate response to Methotrexate (MTX)What is Rheumatoid Arthritis?Autoimmune diseaseInflammation of joints and surrounding tissuesSmall joints of hands, feet, wrists, and anklesProgressive 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~SATORI3EtiologyCan occur at any ageMore prevalent in the 7th decadeFemalesGenetic predisposition HLA-DR4 or HLA-DR1 antigensExposure 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.4Pathophysiology

TNF, IL-1, IL-6Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp.1505-1515). New York: McGraw-Hill Companies, Inc.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 bone5PathophysiologyChronic inflammation of synovial tissue lining the joint capsule leads to pannus formation

CartilageSynoviumNormal Knee JointCartilageBoneInflamed synovial membranePatellaSynovial fluidFemurRA Knee JointBonePannus 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

6Clinical PresentationSignsWarm, tender, swollen jointsSymmetrical joint involvementRheumatoid 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 bookhttp://www.health.com/health/condition-article/0,,20327387,00.html7

Clinical PresentationSymptomsJoint pain and stiffness lasting > 6 weeksFatigueWeaknessLow-grade feverLoss of appetiteMuscle painJoint deformity late disease

Duration of stiffness is usually correlated with disease activityMorning stiffness lasting longer than 1 hourFatigue may be seen more in the afternoon

Stiffness and muscle aches may precede the development of joint swelling

~Theapy bookhttp://www.medscape.com/viewarticle/546105_2

8Clinical PresentationLab TestsRheumatoid factorErythrocyte sedimentation rate (ESR)C-reactive protein (CRP)Normocytic normochromic anemiaThrombocytosis

Joint fluid aspirationTurbid due to increased WBCJoint radiographsPeriarticular osteoporosisJoint space narrowing or erosionsMost 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 joints9Diagnosis CriteriaMust have at least 4 of 7 criteriaAmerican College of Rheumatology (ACR) 1987 CriteriaMorning stiffness *Arthritis of 3 or more joint areas *Arthritis of hand joints *Symmetric arthritis *Rheumatoid nodulesSerum rheumatoid factorRadiographic changes* must be present for at least 6 weeksMorning 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 10 joints (at least 1 small joint)5B - Serology (at least 1 test result is needed for classification)

Negative RF and negative ACPA0Low-positive RF or low-positive ACPA2High-positive RF or high-positive ACPA3Updated 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

http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp

11Diagnosis CriteriaThe 2010 ACR-EULAR classification criteria for RAC - Acute-phase reactants (at least 1 test result is needed for classification)Normal CRP and normal ESR0Abnormal CRP or abnormal ESR1D - Duration of symptoms 1.5 fold ULNSignificant renal impairmentDMARDs (except MTX) 4 weeks before startAnti-TNF agents within 12 weeks Leflunomide within 6 monthsMethods Patients randomly assigned to 1 of 7 treatment groups1 controlMTX + placebo3 monotherapy 2, 4, or 8 mg/kg Tocilizumab + placebo3 combination therapy 2, 4, or 8 mg/kg Tocilizumab + MTXTocilizumab every 4 weeks for 16 weeksMTX weekly

MethodsMethodsPrimary end point ACR20 response at week 16Secondary end pointsACR50ACR70DAS28Results - Monotherapyp < 0.05The 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

28Results - Combinationp < 0.05p < 0.001ACR20 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 + MTX29

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***** p < 0.05*** p < 0.001Decrease 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.30Authors ConclusionsInfusions of Tocilizumab every 4 weeks, with or without background MTX therapy, produce marked and dose-related improvement in RA disease activity4 and 8 mg/kg doses of Tocilizumab resulted in higher ACR50 and ACR70 responses after only 4 infusionsHigh ACR20 response from placebo + MTXPossibly not all MTX non-respondersLimitationsStudy length only 16 weeksMaximum efficacy may not have been achievedPossibly not all patients were MTX non-respondersFunded by Roche GroupMTX take 4-6 weeks to take effect, only 4 weeks was required so some patients may not have been true MTX non-responders32Study 2Study 2Effect of Interleukin-6 Receptor Inhibition with Tocilizumab in Patients with Rheumatoid Arthritis (OPTION Study): a double-blind, placebo-controlled, randomized trialSmolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten RThe Lancet. 2008 Mar; 371:987-997ObjectiveAssess the therapeutic effects of blocking IL-6 using Tocilizumab for patients with Rheumatoid ArthritisSubjects - InclusionsAdultModerate to severe, active RA > 6 monthsActive RA:Swollen joint count 6Tender joint count 8CRP > 10 mg/LORESR 28 mm/h

Age for adults was not specified

Average age ~50 years

Majority females36Subjects - InclusionsMethotrexate 12 weeks beforeStable dose (10-25 mg/week) 8 weeksInadequate response to MethotrexateActive diseaseNSAIDs and oral glucocorticoids permitted if on a stable dose for 6 weeks prior37Subjects - ExclusionsOther autoimmune diseases or significant systemic involvement secondary to RAVasculitis, pulmonary fibrosis, Feltys syndromeFunctional Class IV RAPrevious or current inflammatory joint disease other than RACurrently active or previous recurrent bacterial, viral, fungal or other infections

Class IV: limited in ability to perform usual self-care, work, and other activities38Subjects - ExclusionsClinically significant abnormalities on chest radiographHepatitis B or CRecurrent Herpes ZosterActive liver diseasePrevious unsuccessful treatment with an anti-TNF agentMethods73 centers in 17 countries 24 weeksRandomly assigned to 1 of 3 treatment groupsReceived treatment every 4 weeksMethodsTo have a Power of 90% it was calculated that at least 210 patients were required for each arm of the study.41MethodsContinued stable dose of MTXReceived folic acid to minimize any MTX toxicityDuring the study, patients could not receiveDMARDs other than MTXNew doses of NSAIDs or oral glucocorticoids

All patients received folic acid supplementation to help minimize any MTX toxicity42MethodsPatients were evaluated byLab ValuesPhysical assessmentEfficacy assessments Weeks 2, 4, 8, 12, 16, 20, and 24CBC and LFTs were monitored at each visit--treatment was stopped with ALT or AST increases

Fasting lipid concentrations43MethodsPrimary outcome measures20% 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 questionaire44ACR20Measure improvement in tender or swollen joint countsImprovement in 3 of the 5 following:Acute phase reactantPatient assessmentPhysician assessmentPain scaleDisability/Functional questionnaire 20% improvementMethodsSecondary endpoints:ACR50ACR70Disease activity score using 28 joint counts (DAS28)Remission < 2.6Hemoglobin concentrationsESRCRP mean concentrationsHealth 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 disability46Results566 patients completed the studyPrimary outcome analysis: ACR20 response

Tocilizumab 4 mg/kg (n = 213)Tocilizumab 8 mg/kg (n = 205)Placebo (n = 204)Number of patients102 (48%)120 (59%)54 (26%)p value vs placebop < 0.0001p < 0.0001n/aNumerical differences between placebo and Toc 8 mg/kg by week 247ResultsClinical responseat week 24Toc. 4 mg/kg (n = 213)Toc. 8 mg/kg (n = 205)Placebo (n = 204)ACR50Number of patients76 (31%)90 (44%)22 (11%)p value vs placebop < 0.001p < 0.001

n/aACR70Number of patients26 (12%)45 (22%)4 (2%)p value vs placebop < 0.001

p < 0.001n/aDAS 28