rheumatology highlights 2012
TRANSCRIPT
Rheumatology Rheumatology Highlights 2012Highlights 2012
Farhan Tahir MD, FACRFarhan Tahir MD, FACRRheumatology DivisionRheumatology Division
Doylestown Hospital, Abington Doylestown Hospital, Abington Memorial Hospital, Rheumatic Disease Memorial Hospital, Rheumatic Disease
Associates, Ltd.Associates, Ltd.
DisclosureDisclosure
Speaker for Amgen, Abbott and Speaker for Amgen, Abbott and AuxiliumAuxilium
ObjectivesObjectives
Overview of current trends in osteoporosis Overview of current trends in osteoporosis managementmanagement
Belimumab (trade name Belimumab (trade name BenlystaBenlysta) for systemic ) for systemic lupus erythematosuslupus erythematosus
Rituximab (trade name Rituximab (trade name RituxanRituxan) for ANCA ) for ANCA associated vasculitisassociated vasculitis
Tocilizumab (trade name Tocilizumab (trade name ActemraActemra) for ) for rheumatoid arthritisrheumatoid arthritis
Collagenase clostridium histolyticum ( trade Collagenase clostridium histolyticum ( trade name name XiaflexXiaflex) for Dupuytren's contracture) for Dupuytren's contracture
Musculoskeletal ultrasound in rheumatologyMusculoskeletal ultrasound in rheumatology
Burden of OsteoporosisBurden of Osteoporosis
Hip Hip fractures are the leading cause of serious complicationsfractures are the leading cause of serious complications
MortalityMortality ; first year after hip fracture ; first year after hip fracture > 30% for men > 30% for men and about and about 17% for women17% for women
> than half of hip fracture survivors > than half of hip fracture survivors require skilled care and require skilled care and have permanent disability have permanent disability
Vertebral Vertebral and forearm fractures also cause major socioeconomic and forearm fractures also cause major socioeconomic impactimpact
2005 to 20252005 to 2025, estimated osteoporosis-related fractures will , estimated osteoporosis-related fractures will increase from increase from 2 million to 3 million2 million to 3 million, and cost will increase from , and cost will increase from $17 $17 billion to $25 billionbillion to $25 billion
Burden on healthcareBurden on healthcare
AACEAACE Executive summary recommendationsExecutive summary recommendations
Measures to prevent bone lossMeasures to prevent bone loss calcium, vitamin D (30-calcium, vitamin D (30-60ng/ml), limit alcohol, smoking & caffeine, weight bearing 60ng/ml), limit alcohol, smoking & caffeine, weight bearing exercises, adequate protein intakeexercises, adequate protein intake
Who needs to be screened Who needs to be screened Women 65 or older, younger Women 65 or older, younger with increased risks, secondary osteoporosis, prevalent vertebral with increased risks, secondary osteoporosis, prevalent vertebral fractures (VFA)fractures (VFA)
Who needs treatmentWho needs treatment fx hip, spine; T score =/>-2.5, Tscore fx hip, spine; T score =/>-2.5, Tscore <-2.5 w/+FRAX ( major fx risk>20%, hip>3%)<-2.5 w/+FRAX ( major fx risk>20%, hip>3%)
What drugs to useWhat drugs to use: : First lineFirst line: alendronate, risendronate, : alendronate, risendronate, zolendronic acid, denosumab; zolendronic acid, denosumab; 22ndnd line line: ibendronate ; : ibendronate ; 22ndnd-3-3rdrd raloxifene raloxifene ; last; last: calcitonin; : calcitonin; failure to bisphosphonatesfailure to bisphosphonates: teriparatide: teriparatide
AACE AACE Executive summary recommendationsExecutive summary recommendations
Monitor DEXAMonitor DEXA 1-2 yrs until stable then 2yrs(more discussions to 1-2 yrs until stable then 2yrs(more discussions to follow), spine & hip, ideal if same facility, machine, technologist; follow), spine & hip, ideal if same facility, machine, technologist; bone turnover markersbone turnover markers
How long should treatment lastHow long should treatment last mild osteoporosis 4-5 years mild osteoporosis 4-5 years then drug holiday, if high risk 10 years treatment then 1-2 yr drug then drug holiday, if high risk 10 years treatment then 1-2 yr drug holiday; (my opinion switching MOAs)holiday; (my opinion switching MOAs)
What are high risk for bone lossWhat are high risk for bone loss rheumatologic diseases, rheumatologic diseases, endocrinopathies, malabsoprtion, renal failure or hypercalciuria, endocrinopathies, malabsoprtion, renal failure or hypercalciuria, medications, malnutrition, vitamin D deficiency, neuromuscular medications, malnutrition, vitamin D deficiency, neuromuscular disordersdisorders
Who is at risk of fallWho is at risk of fall elderly, frail, impaired vision & hearing, elderly, frail, impaired vision & hearing, sedatives, slipper rugs etcsedatives, slipper rugs etc
NOF GuidelinesNOF Guidelines
FRAXFRAX
FRAX in USAFRAX in USA Consider therapies Consider therapies in postmenopausal women and men aged 50 years and in postmenopausal women and men aged 50 years and
older, ifolder, if
hip or vertebral fracturehip or vertebral fracture T-score ≤ -2.5 (T-score ≤ -2.5 (exclude secondary causes)exclude secondary causes)
Low bone mass (T-score -1.0to -2.5) and a 10-year Low bone mass (T-score -1.0to -2.5) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20%of a major osteoporosis-related fracture ≥ 20%
Effectiveness Vs AdherenceEffectiveness Vs Adherence
Postmenopausal osteoporosis screening, cost-Postmenopausal osteoporosis screening, cost-effective, initiation at age 55 years effective, initiation at age 55 years Cost-Effectiveness of Cost-Effectiveness of Different Screening Strategies for Osteoporosis in Postmenopausal Women Author(s): Nayak Smita Different Screening Strategies for Osteoporosis in Postmenopausal Women Author(s): Nayak Smita
, Annals of Int Medicine, Volume: 155 Issue: 11 , Annals of Int Medicine, Volume: 155 Issue: 11
Patients are prepared to Patients are prepared to accept higher absolute accept higher absolute fracture risk fracture risk thanthan doctors doctors Differing perceptions of intervention Differing perceptions of intervention thresholds for fracture risk: a survey of patients and doctors: Osteoporosis International Url: thresholds for fracture risk: a survey of patients and doctors: Osteoporosis International Url: http://dx.doi.org/10.1007/s00198-011-1823-7
Only a third of patients Only a third of patients agree to second agree to second administration of Zolendronic acid administration of Zolendronic acid Persistence with intravenous Persistence with intravenous zoledronate in elderly patients with osteoporosis, Osteoporosis International, zoledronate in elderly patients with osteoporosis, Osteoporosis International, http://dx.doi.org/10.1007/s00198-011-1881-x
Fracture risk reductionFracture risk reduction
HCP: Room for HCP: Room for improvementimprovement
Poor AdherencePoor Adherence
High Risk PopulationHigh Risk Population
Bone mineral density (BMD) and clinical risk factors Bone mineral density (BMD) and clinical risk factors (CRFs) for fracture predict fracture risk better than BMD (CRFs) for fracture predict fracture risk better than BMD or CRFs aloneor CRFs alone
Fracture Risk Assessment in Clinical Practice: T-scores, FRAX, and Beyond; Clinical Reviews in Fracture Risk Assessment in Clinical Practice: T-scores, FRAX, and Beyond; Clinical Reviews in Bone and Mineral Metabolism 2010-09-01Bone and Mineral Metabolism 2010-09-01
Many CRFs; including women with CVD Many CRFs; including women with CVD Women with Cardiovascular Women with Cardiovascular Disease Have Increased Risk of Osteoporotic Fracture, Calcified Tissue International Disease Have Increased Risk of Osteoporotic Fracture, Calcified Tissue International http://dx.doi.org/10.1007/s00223-010-9431-7
Hip fracture incidence was significantly higher in women Hip fracture incidence was significantly higher in women having wide NSA (8.52%)- Older pts, debatable having wide NSA (8.52%)- Older pts, debatable Prediction of Prediction of incident hip fracture by femoral neck bone mineral density and neck‐shaft angle: a 5‐year incident hip fracture by femoral neck bone mineral density and neck‐shaft angle: a 5‐year longitudinal study in post‐menopausal women longitudinal study in post‐menopausal women The British Journal of Radiology 57130600; The British Journal of Radiology 57130600; published ahead of print November 17, 2011,published ahead of print November 17, 2011,
DEXA in New York TimesDEXA in New York Times
Bone Density TestingBone Density Testing
Bone-Density Testing Interval and Transition Bone-Density Testing Interval and Transition to Osteoporosis to Osteoporosis in Older Womenin Older Women
New England Journal of Medicine; Jan 19,2012New England Journal of Medicine; Jan 19,2012 Aim:Aim: To guide decisions about the interval between BMD testsTo guide decisions about the interval between BMD tests Methods : Methods : 4957 women, 67 or older4957 women, 67 or older Normal BMD (T score femoral neck and total hip, −1.00 or Normal BMD (T score femoral neck and total hip, −1.00 or
higher)higher) Osteopenia (T score, −1.01 to −2.49)Osteopenia (T score, −1.01 to −2.49) No history of hip or clinical vertebral fractureNo history of hip or clinical vertebral fracture No treatment for osteoporosisNo treatment for osteoporosis Followed 15 yearsFollowed 15 years
Margaret L. Gourlay, M.D., M.P.H.etal Study of Osteoporotic Fractures Research Margaret L. Gourlay, M.D., M.P.H.etal Study of Osteoporotic Fractures Research GroupGroup
Primary end pointPrimary end point The BMD testing interval The BMD testing interval : Time for 10% to develop : Time for 10% to develop
osteoporosis before having a hip or clinical vertebral osteoporosis before having a hip or clinical vertebral fracturefracture
Three subgroups of osteopeniaThree subgroups of osteopenia Mild : Mild : -1.01 to -1.49-1.01 to -1.49
Moderate : Moderate : -1.50 to -1.99-1.50 to -1.99
Advanced : Advanced : -2.00 to -2.49-2.00 to -2.49
Results and Results and
RecommendationsRecommendations Time interval needed for Time interval needed for 10% in the group to develop 10% in the group to develop
osteoporosisosteoporosis 16.816.8 years for women with normal BMD years for women with normal BMD 17.317.3 for women with mild osteopenia for women with mild osteopenia 4.74.7 years for women with moderate osteopenia years for women with moderate osteopenia 1.11.1 years (95% CI, 1.0 to 1.3) for women with advanced years (95% CI, 1.0 to 1.3) for women with advanced
osteopeniaosteopenia
Retesting based on initial DEXARetesting based on initial DEXA 15 years 15 years for normal bone density or mild osteopeniafor normal bone density or mild osteopenia 5 years 5 years for women with moderate osteopeniafor women with moderate osteopenia 1 year 1 year for women with advanced osteopenia. for women with advanced osteopenia.
Myths and FactsMyths and FactsBisphosphonatesBisphosphonates
Oteonecrosis of jaw (ONJ) Oteonecrosis of jaw (ONJ) High incidence in cancer pts; High incidence in cancer pts; 2-11%, enhanced risk w/concomitant use of oral steroids, chemo, 2-11%, enhanced risk w/concomitant use of oral steroids, chemo, dental extraction, diabetes, tobacco usedental extraction, diabetes, tobacco use
Bone PainBone Pain very uncommon adverse effects, resolves with very uncommon adverse effects, resolves with discontinuationdiscontinuation
Atrial fibrillationAtrial fibrillation no definitive association, incidental or no definitive association, incidental or underlying c.v. diseaseunderlying c.v. disease
Current Opinion in Rheumatology: July 2009 - Volume 21 - Issue 4 - p 363-368Current Opinion in Rheumatology: July 2009 - Volume 21 - Issue 4 - p 363-368
Cancer Cancer no rise in risk of cancer, avoid in Barrett’s esophagus; ?no rise in risk of cancer, avoid in Barrett’s esophagus; ?protective breast, colorectal cancer protective breast, colorectal cancer Cardwell, (2012), Exposure to oral Cardwell, (2012), Exposure to oral bisphosphonates and risk of cancer. International Journal of Cancer. doi: 10.1002/ijc.27389bisphosphonates and risk of cancer. International Journal of Cancer. doi: 10.1002/ijc.27389
Myths and FactsMyths and Facts
Subtrochanteric and femoral shaft fracturesSubtrochanteric and femoral shaft fractures: : affect affect elderly, incidence increased (2002 to 2009), obesity and dementia elderly, incidence increased (2002 to 2009), obesity and dementia
as risk factorsas risk factors Journal of Bone and Mineral Research, Vol. 27, No. 1, January 2012, pp 130–Journal of Bone and Mineral Research, Vol. 27, No. 1, January 2012, pp 130–137137
Teriparatide and osteosarcomaTeriparatide and osteosarcoma: : single case, association single case, association not established, 300,000 pt( baseline risk 1:250,000/yr)not established, 300,000 pt( baseline risk 1:250,000/yr)
Vigilance, rather than alarmVigilance, rather than alarm, is needed to manage , is needed to manage adverse events associated with bisphosphonate adverse events associated with bisphosphonate use for osteoporosis use for osteoporosis Drugs & Therapy Perspectives: 1 February 2012 - Volume 28 - Issue 2 - pp 20-23
Atypical (low energy) fracturesAtypical (low energy) fractures
The Journal of Bone & Joint Surgery.The Journal of Bone & Joint Surgery. 2009; 2009; 91:2556-2561 doi:10.2106/JBJS.H.01774 91:2556-2561 doi:10.2106/JBJS.H.01774
How to decide How to decide
Osteopenia associated with either low energy Osteopenia associated with either low energy fracture(s) or very high risk for future fracture fracture(s) or very high risk for future fracture (assessed by FRAX) warrants therapy (assessed by FRAX) warrants therapy Treatment of Treatment of osteopenia, Reviews in Endocrine & Metabolic Disordersosteopenia, Reviews in Endocrine & Metabolic Disorders
Bone turnover markers (+BMD, CRF, FRAX) Bone turnover markers (+BMD, CRF, FRAX) could best address the efficacy of treatment of could best address the efficacy of treatment of
osteoporosisosteoporosis Is There a Place for Bone Turnover Markers in the Assessment of Is There a Place for Bone Turnover Markers in the Assessment of
Osteoporosis and its Treatment? Jean-Pierre Devogelaer, Rheumatic Disease Clinics of North Osteoporosis and its Treatment? Jean-Pierre Devogelaer, Rheumatic Disease Clinics of North America - August 2011 (Vol. 37, Issue 3, Pages 365-386, DOI: 10.1016/j.rdc.2011.07.002)America - August 2011 (Vol. 37, Issue 3, Pages 365-386, DOI: 10.1016/j.rdc.2011.07.002)
GIO and osteoporosis GIO and osteoporosis treatmenttreatment
Effects on MortalityEffects on Mortality
Newest FDA approved Newest FDA approved treatmenttreatment
Denosumab Denosumab
DenosumabDenosumab((Trade name Prolia)
First biologic antiresorptive therapy for osteoporosis First biologic antiresorptive therapy for osteoporosis with efficacy and safety in patients with renal with efficacy and safety in patients with renal impairment impairment The RANKL Pathway and Denosumab Robin K. Dore , Rheumatic Disease Clinics The RANKL Pathway and Denosumab Robin K. Dore , Rheumatic Disease Clinics of North America - August 2011 (Vol. 37, Issue 3, Pages 433-452, DOI: 10.1016/j.rdc.2011.07.004)of North America - August 2011 (Vol. 37, Issue 3, Pages 433-452, DOI: 10.1016/j.rdc.2011.07.004)
Fully human monoclonal antibody against RANK ligandFully human monoclonal antibody against RANK ligand Released 6/2010Released 6/2010 Antiresorptive agent but rapid offset compared to Antiresorptive agent but rapid offset compared to
BpsBps(which bind avidly to bone and remain in bone for extended time intervals)(which bind avidly to bone and remain in bone for extended time intervals)
RANKL- RANK interaction, leads to osteoclastogenesisRANKL- RANK interaction, leads to osteoclastogenesis Denosumab reduces osteoclastogenesis to reduce resorption Denosumab reduces osteoclastogenesis to reduce resorption
and improve bone densityand improve bone density 60mg administered by subcutaneous injection every six months 60mg administered by subcutaneous injection every six months
Mechanism of ActionMechanism of Action
www.arcmesa.org/7153/monograph.php
Denosumab and Bone turnoverDenosumab and Bone turnover
FREEDOMFREEDOM
Fracture Reduction of Denosumab in Fracture Reduction of Denosumab in Osteoporosis Every 6 MonthsOsteoporosis Every 6 Months
Methods: Methods: 7868 women, lumbar/femoral T -2.5-4.0, D/P 7868 women, lumbar/femoral T -2.5-4.0, D/P injection every 6 months for 36 monthsinjection every 6 months for 36 months
Primary end pointPrimary end point: : New vertebral fracture, non vertebral New vertebral fracture, non vertebral and hip secondary end pointsand hip secondary end points
Results:Results: DecreaseDecrease Vertebral fractures 68% Vertebral fractures 68% (2.3% vs. 7.2%, P<0.001)(2.3% vs. 7.2%, P<0.001)
Hip fractures 40% Hip fractures 40% (0.7% vs. 1..2%, P<0.04)(0.7% vs. 1..2%, P<0.04)
Safety:Safety: No increase in risk of cancer, infection, delayed wound No increase in risk of cancer, infection, delayed wound healing, ONJ, hypocalcaemia. Increase in eczema in 3%(P<0.001)healing, ONJ, hypocalcaemia. Increase in eczema in 3%(P<0.001)
N Engl J Med 2009; 361;756-65N Engl J Med 2009; 361;756-65
Lumbar BMDLumbar BMD
Hip BMDHip BMD
Cortical Bone PorosityCortical Bone Porosity
Freedom Extension DataFreedom Extension Data
Denosumab Denosumab DiscontinuationDiscontinuation
Denosumab vs. Denosumab vs. BisphosphonatesBisphosphonates
Increased bone mineral density Increased bone mineral density lumbar 6%, hip 9%, lumbar 6%, hip 9%, reduced risk of all type of fracturesreduced risk of all type of fractures
Blocks the formationBlocks the formation, , function and survival of osteoclasts vs. function and survival of osteoclasts vs. BNP block the function and survival but not formationBNP block the function and survival but not formation
Magnitude of vertebral risk Magnitude of vertebral risk reduction similar to IV reduction similar to IV Zolendronic acid and greater than oral bisphosphonates ( same for non Zolendronic acid and greater than oral bisphosphonates ( same for non vertebral fractures in both options)vertebral fractures in both options)
Median reduction in bone resorption Median reduction in bone resorption 86% in 1 month, 86% in 1 month, more than other anti resorptive agentsmore than other anti resorptive agents
Better than IV Zolendronic acid Better than IV Zolendronic acid (bone metastasis(bone metastasis)) Better adherence Better adherence to oral agents, 50% pts stop oral agent in 1yrto oral agents, 50% pts stop oral agent in 1yr
Safety DataSafety Data
Safety DataSafety Data
TeriparatideTeriparatide FORTEO (teriparatide [rDNA origin] injection) for FORTEO (teriparatide [rDNA origin] injection) for
subcutaneous use, U.S. Approval: 2002subcutaneous use, U.S. Approval: 2002 Recommended dose is 20 mcg subcutaneously once a dayRecommended dose is 20 mcg subcutaneously once a day Administered into the thigh or abdominal wallAdministered into the thigh or abdominal wall Maximum use of the drug no more than 2 years (life time)Maximum use of the drug no more than 2 years (life time)
Teriparatide-Anabolic Teriparatide-Anabolic agentagent
Finite Element AnalysisFinite Element Analysis
TeriparatideTeriparatideAnabolic agentAnabolic agent
Teriparatide and Vertebral Teriparatide and Vertebral strengthstrength
Belimumab for SLEBelimumab for SLE
BelimumabBelimumab
B-lymphocyte stimulator (BLyS)-B-lymphocyte stimulator (BLyS)-specific inhibitor specific inhibitor BLyS-specific inhibitor blocks the binding of BLyS-specific inhibitor blocks the binding of
soluble BLyS, a B-cell survival factorsoluble BLyS, a B-cell survival factor
Does not bind B cells directly, but by binding Does not bind B cells directly, but by binding BLyS and inhibits the survival of B cellsBLyS and inhibits the survival of B cells
Reduces auto reactive B cells, and reduces the Reduces auto reactive B cells, and reduces the differentiation of B cells into immunoglobulin-differentiation of B cells into immunoglobulin-producing plasma cells producing plasma cells
Mechanism of actionMechanism of action
PathophyiologyPathophyiology Blys bindingBlys binding
Clinical TrialsClinical Trials
>50% of pts 3 or more active organ systems , >50% of pts 3 or more active organ systems , mucocutaneous, immunology, musculoskeletal mucocutaneous, immunology, musculoskeletal
Randomly assigned to receive Belimumab 1 mg/kg, 10 Randomly assigned to receive Belimumab 1 mg/kg, 10 mg/kg, or placebo in addition to standard of care.mg/kg, or placebo in addition to standard of care.
Intravenously over a 1-hour period on Days 0, 14, 28, and Intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48-72then every 28 days for 48-72
The primary efficacy endpoint : SLE Responder Index or The primary efficacy endpoint : SLE Responder Index or SRI to suggest worsening SRI to suggest worsening
Trial 2 and 3 rd met the endpoints, Placebo versus Trial 2 and 3 rd met the endpoints, Placebo versus 10mg/kg dose; 34% vs 43%; 34% vs 58% 10mg/kg dose; 34% vs 43%; 34% vs 58%
Clinical TrialsClinical Trials
SummarySummary Active, autoantibody-positive, systemic lupus Active, autoantibody-positive, systemic lupus
erythematosus who are receiving standard therapy erythematosus who are receiving standard therapy
Not indicated in severe active lupus nephritis or Not indicated in severe active lupus nephritis or severe active lupus cerebritis severe active lupus cerebritis
Intravenous10 mg/kg at 2-week intervals for the first Intravenous10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals 3 doses and at 4-week intervals
Adv events and Caution; prophylactic medications Adv events and Caution; prophylactic medications reduce infusion reaction and risk of immunogenicityreduce infusion reaction and risk of immunogenicity
Rituximab in ANCA Rituximab in ANCA vasculitisvasculitis
Rituximab in autoimmune Rituximab in autoimmune disordersdisorders
B cell depleting monoclonal antibody, attacks B B cell depleting monoclonal antibody, attacks B cells CD 20+lymphocytescells CD 20+lymphocytes
FDA approved for RA FDA approved for RA ( SLE, Sjogren’s syndrome, HCV ( SLE, Sjogren’s syndrome, HCV cryoglobulinemic vasculitis, Antiphospholipid syndrome and ANCA cryoglobulinemic vasculitis, Antiphospholipid syndrome and ANCA vasculitis )vasculitis )
Replaced “standard of care” Replaced “standard of care” Cyclophosphamide in ANCA Cyclophosphamide in ANCA associated vasculitis, effective but has high rates of death and associated vasculitis, effective but has high rates of death and adverse eventsadverse events
Small series showed remission -80 to 90% in refractory Small series showed remission -80 to 90% in refractory ANCA vasculitis with better safety profileANCA vasculitis with better safety profile
Two pivotal NEJM published RCTs Two pivotal NEJM published RCTs
Mechanism of ActionMechanism of Action
www.rituxan.com/lymphoma/hcp/MOA/index.m
RAVERAVE
Rituximab versus Cyclophosphamide for Rituximab versus Cyclophosphamide for ANCA-associated vasculitisANCA-associated vasculitis
Design:Design: US based ,197 ptsUS based ,197 pts Methods:Methods: 375mg/m2 once a week for 4 weeks, control 375mg/m2 once a week for 4 weeks, control
group (oral cyclophosphamide 2mg/kg ), 1-3 pulse group (oral cyclophosphamide 2mg/kg ), 1-3 pulse solumedrol followed by prednisone 1mg/kgsolumedrol followed by prednisone 1mg/kg
Primary end pointPrimary end point was remission of disease was remission of disease without prednisone at 6 monthswithout prednisone at 6 months
Results:Results: 64% patients in Rituximab arm and 53% 64% patients in Rituximab arm and 53% in control arm reached primary end point and in control arm reached primary end point and met criteria of non inferiority P<0.001met criteria of non inferiority P<0.001
Stone JH - Stone JH - N Engl J MedN Engl J Med - 15-JUL-2010; 363(3): 221-32 - 15-JUL-2010; 363(3): 221-32
RAVERAVE Safety:Safety: No significant differences in adverse No significant differences in adverse
effectseffects Conclusion:Conclusion: Rituximab was non inferior Rituximab was non inferior More effective is inducing remission for More effective is inducing remission for
refractory relapsing disease, 67% (34/51) vs. refractory relapsing disease, 67% (34/51) vs. 42% (21/50) in control group42% (21/50) in control group
Same efficacy as cyclophosphamide in major Same efficacy as cyclophosphamide in major renal disease or alveolar hemorrhagerenal disease or alveolar hemorrhage
Stone JH - Stone JH - N Engl J MedN Engl J Med - 15-JUL-2010; - 15-JUL-2010; 363(3): 221-32363(3): 221-32
RITUXVAS RITUXVAS
Take home messageTake home message
Rituximab was efficacious in inducing remission Rituximab was efficacious in inducing remission particularly for refractory relapsing casesparticularly for refractory relapsing cases
Adverse effect profile Adverse effect profile First line and even better for induction of First line and even better for induction of
refractory casesrefractory cases Azathioprine appears to be reasonable choice for Azathioprine appears to be reasonable choice for
maintenancemaintenance
TocilizumabTocilizumab
Tocilizumab for rheumatoid Tocilizumab for rheumatoid arthritisarthritis
Chronic inflammation leads to production of IL-6; cytokine Chronic inflammation leads to production of IL-6; cytokine with its receptor expressed on effectors cellswith its receptor expressed on effectors cells
Effector cells cause and prolong inflammationEffector cells cause and prolong inflammation Humanized anti IL-6 receptor IgG1Humanized anti IL-6 receptor IgG1 inhibits IL-6 binding to inhibits IL-6 binding to
receptor and interferes cytokine effects.receptor and interferes cytokine effects. Its an IV infusion administered over one hourIts an IV infusion administered over one hour Potent inhibitor of CRP production and improves Potent inhibitor of CRP production and improves
inflammation induced anemiainflammation induced anemia Approved for RA patients who are TNF non responders, Approved for RA patients who are TNF non responders,
marketed as “Actemra”marketed as “Actemra”
Mechanism of ActionMechanism of Action
Arthritis Research & Therapy 2006 8(Suppl 2):S2 doi:10.1186/ar1916
RADIATERADIATE
Design:Design: Double blind, RCT, Europe and USADouble blind, RCT, Europe and USA Methods:Methods: 500 pts500 pts Primary outcome:Primary outcome: ACR 20 @ 24 wks, secondary ACR 20 @ 24 wks, secondary
outcomes ACR50/70, DAS and HAQoutcomes ACR50/70, DAS and HAQ Results:Results: Primary and secondary end pointsPrimary and secondary end points 50% in MTX+ 8mg/kg vs. 10% in control50% in MTX+ 8mg/kg vs. 10% in control Conclusion:Conclusion: Tocilizumab plus MTX is effective in Tocilizumab plus MTX is effective in
achieving rapid and sustained improvement in TNF non achieving rapid and sustained improvement in TNF non respondersresponders
Ann Rheum Dis 2008. doi:10.1136/ard.2008:092932Ann Rheum Dis 2008. doi:10.1136/ard.2008:092932
Good Safety ProfileGood Safety Profile
Reversible elevation of transaminases 3ULN- 6% in MTX + Reversible elevation of transaminases 3ULN- 6% in MTX + TocilizumabTocilizumab
Serious infections/100 pts : 3, 6 vs. 2.3 compared to MTXSerious infections/100 pts : 3, 6 vs. 2.3 compared to MTX Elevated serum cholesterol (large molecule, not @MI)Elevated serum cholesterol (large molecule, not @MI) Transient neutropeniaTransient neutropenia Gastrointestinal adverse events including diverticular Gastrointestinal adverse events including diverticular
perforation, may suppress and delay detection of perforation, may suppress and delay detection of diverticulitisdiverticulitis
Musculoskeletal Musculoskeletal UltrasoundUltrasound
Musculoskeletal Musculoskeletal UltrasoundUltrasound
Tool for real time examination of musculoskeletal Tool for real time examination of musculoskeletal structures of intereststructures of interest
In trained hands, serves a great diagnostic tool with In trained hands, serves a great diagnostic tool with fraction of the cost and radiationfraction of the cost and radiation
RCTs have shown improved injections technique and RCTs have shown improved injections technique and provided objective assessment of response to provided objective assessment of response to treatmenttreatment
Useful in assessment of tendinopathy, tenosynovitis, Useful in assessment of tendinopathy, tenosynovitis, bursitis and joint effusions which are difficult to assess bursitis and joint effusions which are difficult to assess on physical examon physical exam
Neovasculization of synovial tissues with doppler Neovasculization of synovial tissues with doppler images help detect active disease related to images help detect active disease related to inflammationinflammation
Image source Image source http://www.ultrasoundcases.info/, , http://www.essr.org/cmshttp://www.essr.org/cms
Shoulder pathologiesShoulder pathologiesBicepital tendinosisBicepital tendinosis
TransverseTransverse Longitudinal Longitudinal
Normal TransverseNormal Transverse
Supraspinatus Supraspinatus calcificationcalcification
NormalNormal
LongitudinalLongitudinal TransverseTransverse
Supraspinatus tearSupraspinatus tear
NormalNormal
LongitudinalLongitudinal
Subacromail bursitisSubacromail bursitis
Calcification of bursaCalcification of bursa
Anterior recess effusion Anterior recess effusion of Kneeof Knee
LongitudinalLongitudinal
NormalNormal
Prepatellar bursitisPrepatellar bursitis
LongitudinalLongitudinal
NormalNormal
Baker’s CystBaker’s Cyst
LongitudinalLongitudinalTransverseTransverse
NormNormal al
Rheumatoid ArthritisRheumatoid ArthritisWrist : Thickened Wrist : Thickened
synovitissynovitis
LongitudinalLongitudinal
NormalNormal
Detecting Erosions and Detecting Erosions and HypervascularityHypervascularity
LongitudinalLongitudinal
Median Nerve Median Nerve Carpal tunnel syndromeCarpal tunnel syndrome
LongitudinalLongitudinalTransverseTransverse
TransverseTransverseNormal Normal
Ultrasound guided Ultrasound guided injectionsinjections
Knee JointKnee Joint Baker's cystBaker's cyst
A P R I L 1 , 2 0 1 0 • FAMILY PRACTICE A P R I L 1 , 2 0 1 0 • FAMILY PRACTICE NEWSNEWS
Ultrasound Guided Musculoskeletal Ultrasound Guided Musculoskeletal Procedures, Ultrasound Clinics, Volume Procedures, Ultrasound Clinics, Volume 2, Issue 4, October 20072, Issue 4, October 2007
Subacromial bursitisSubacromial bursitis Hip jointHip joint
AJUM May 2010; 13 (2):11-15AJUM May 2010; 13 (2):11-15 http://www.orthohealing.com/http://www.orthohealing.com/2007/10/2007/10/
Clostridium Collagenase Clostridium Collagenase HistolyticumHistolyticum
Dupuytren’s contractureDupuytren’s contracture Injectable Collagenase Injectable Collagenase
Clostridium Clostridium DC is a progressive genetic disorder of pathologic DC is a progressive genetic disorder of pathologic
collagen production and depositioncollagen production and deposition Nodules coalesce to form cord, extending longitudinally Nodules coalesce to form cord, extending longitudinally
causing shortening and flexion contracturecausing shortening and flexion contracture Surgical fasciectomy has been the only treatment Surgical fasciectomy has been the only treatment
which had significant complication risk and suboptimal which had significant complication risk and suboptimal successsuccess
First series of 35 First series of 35 patients with 44 affected joints patients with 44 affected joints published in J Hand Surg;24(4):629-36 showed published in J Hand Surg;24(4):629-36 showed potential of clostridial collagenase injections as first potential of clostridial collagenase injections as first non surgical treatment non surgical treatment
In 2007 a RCT of 33 cases In 2007 a RCT of 33 cases proved efficacy of proved efficacy of Collagenase injection, 16/23 received 0-5 degree Collagenase injection, 16/23 received 0-5 degree extension with 1 injection and 21/23 with 3 injectionsextension with 1 injection and 21/23 with 3 injections
CORD ICORD IN Engl J Med 2009;361:968-79N Engl J Med 2009;361:968-79
CORD 1CORD 1 Method Method
308 patients308 patients 2: 1 Ratio2: 1 Ratio 3 injection allowed3 injection allowed
Primary end pointPrimary end point Reduction in primary contracture 0-5 of full extension Reduction in primary contracture 0-5 of full extension
ResultsResults 64% contractures achieved primary point compared 64% contractures achieved primary point compared to to
6.8% in placebo, P<.002. 6.8% in placebo, P<.002.
Mean time : 56 daysMean time : 56 days MCP had better success rates than PIP ( 76% vs. 40%)MCP had better success rates than PIP ( 76% vs. 40%) mean change in contracture was 48 degreesmean change in contracture was 48 degrees success was 89% when contracture was less than 50 success was 89% when contracture was less than 50
degreesdegrees Adverse effects Adverse effects
LocalLocal No meaning full systemic adverse reactionNo meaning full systemic adverse reaction
Mean degree of Mean degree of improvement improvement
Case seriesCase series
Courtesy Dr C. Michael Franklin M.D.Courtesy Dr C. Michael Franklin M.D.
Before (~25 degrees)Before (~25 degrees) After- full extension After- full extension
Series of Three Series of Three CasesCases
Courtesy Dr C. Michael Courtesy Dr C. Michael Franklin M.D.Franklin M.D.
Pre-XiaflexPre-Xiaflex Post Xiaflex full extensionPost Xiaflex full extension
Note post injection Note post injection ecchymosisecchymosis
Patient # 2Patient # 2
Patient # 3Patient # 390 degree flexion 90 degree flexion contracturecontracture Post Xiaflex –full extensionPost Xiaflex –full extension
Courtesy Dr C. Michael Franklin M.DCourtesy Dr C. Michael Franklin M.D..
