Slide 1
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
**
***
***** 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